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Central Control of the Cardiovascular and Respiratory Systemsand Their Interactions in Vertebrates

EDWIN W. TAYLOR, DAVID JORDAN, AND JOHN H. COOTE

School of Biological Sciences and Department of Physiology, The University of Birmingham, Edgbaston,

Birmingham; and Department of Physiology, Royal Free and University College Medical School,

Hampstead, London, United Kingdom

I. Introduction 856II. Patterns of Ventilation and Central Respiratory Pattern Generation 858

A. Mammals 859B. Cyclostomes 859C. Fish 859D. Air-breathing fish 862E. Amphibians 862F. Reptiles 864G. Birds 866

III. Afferent Innervation of the Circulatory and Respiratory Systems 867A. Mammals 867B. Fish 869C. Air-breathing fish 870D. Amphibians 871E. Reptiles 873F. Birds 874

IV. Cranial Autonomic Innervation of the Cardiorespiratory System 874A. Mammals 874B. Cyclostomes 875C. Elasmobranch fish 876D. Teleost fish 878E. Air-breathing fish 878F. Amphibians 879G. Reptiles 881H. Birds 882

V. Sympathetic Innervation of the Cardiorespiratory System 883A. Mammals 883B. Cyclostomes 885C. Elasmobranch fish 885D. Teleost fish 886E. Amphibians 886F. Reptiles 887G. Birds 887

VI. Central Control of Cardiorespiratory Interactions 888A. Mammals 888B. Fish 893C. Air-breathing fish 897D. Amphibians 897E. Reptiles 898F. Birds 899

VII. Concluding Comments 900

Taylor, Edwin W., David Jordan, and John H. Coote. Central Control of the Cardiovascular and RespiratorySystems and Their Interactions in Vertebrates. Physiol. Rev 79: 855–916, 1999.—This review explores the funda-mental neuranatomical and functional bases for integration of the respiratory and cardiovascular systems in

PHYSIOLOGICAL REVIEWS

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vertebrates and traces their evolution through the vertebrate groups, from primarily water-breathing fish and larvalamphibians to facultative air-breathers such as lungfish and some adult amphibians and finally obligate air-breathersamong the reptiles, birds, and mammals. A comparative account of respiratory rhythm generation leads to consid-eration of the changing roles in cardiorespiratory integration for central and peripheral chemoreceptors andmechanoreceptors and their central projections. We review evidence of a developing role in the control ofcardiorespiratory interactions for the partial relocation from the dorsal motor nucleus of the vagus into the nucleusambiguus of vagal preganglionic neurons, and in particular those innervating the heart, and for the existence of afunctional topography of specific groups of sympathetic preganglionic neurons in the spinal cord. Finally, weconsider the mechanisms generating temporal modulation of heart rate, vasomotor tone, and control of the airwaysin mammals; cardiorespiratory synchrony in fish; and integration of the cardiorespiratory system during intermittentbreathing in amphibians, reptiles, and diving birds. Concluding comments suggest areas for further productiveresearch.

I. INTRODUCTION

This review explores the mechanisms of central con-trol and coordination of the respiratory and cardiovascu-lar systems in vertebrates. Animals have evolved sophis-ticated control mechanisms enabling them to match theirrates of oxygen uptake to their rates of aerobic metabo-lism. As the relative effectiveness of respiratory gas ex-change over lungs or gills is determined not only by theirphysical dimensions but also by the rates and patterns oftheir ventilation and perfusion, it is essential that theselatter components are controlled, both individually and inrelation to one another. It has long been recognized thatthe overall rates of flow of air or water and of blood overthe respiratory surfaces are matched according to theirrespective capacities for oxygen so that the ventilation-to-perfusion ratio varies from ;1 in air-breathers to 10 ormore in water-breathers, with the bimodal, air/water-breathers among the lungfishes and amphibians showingvariable ratios (286, 498). However, these overall ratiosignore the pulsatile and sometimes intermittent nature ofboth ventilation and perfusion. Careful study of respira-tory and cardiac rhythms often shows them to be tempo-rally related in ways that may optimize respiratory gasexchange. Control of these cardiorespiratory interactionsresides in the central nervous system that integrates af-ferent inputs from a range of central and peripheral re-ceptors and coordinates central interactions betweenpools of neurons generating the respiratory rhythm anddetermining heart rate variability. Thus, although the ab-sence of a heart beat signifies death, a high and unvaryingheart rate can indicate incipient brain death.

Many aspects of the brain circuitry of this remarkablysensitive system seem to have been highly conservedthroughout evolution. Thus the regulatory mechanismsthat operate in the central nervous systems of lowerchordates such as the elasmobranch fishes show a re-markable degree of homology with those that operate inmammals, including humans (606). Homology literallymeans “of the same essential nature” having affinity ofstructure and origin. In this review, we examine apparenthomologies in the cardiorespiratory control system of

vertebrates, in terms of the location and phenotype of theneuronal substrate, the pattern of central nervous system(CNS) connections, the development and conservation offundamental rhythms of nerve discharge, and neuroeffec-tor mechanisms. Of course, we are aware that a strictlyphylogenetic approach to comparative physiology is inap-propriate, since parallel evolution can result in clear ho-mologies of structure and function in distantly relatedspecies. Accordingly, we have emphasized the topograph-ical similarities and their apparent evolution and treatedthe functional role of central nervous connections sepa-rately, while drawing parallels with their structural bases.We have not attempted to draw a phylogenetic tree forcontrol of cardiorespiratory function; rather, we haveexplored its evolutionary roots. We show that there areconsiderable similarities in the topography and functionalcharacteristics between groups of neurons in the hind-brain and spinal cord of the different vertebrate groups.However, there are also significant differences, the prob-lem then being to know when it is reasonable to general-ize and when not.

There are important differences in the constructionof the respiratory and cardiovascular systems in verte-brates, related to their modes of respiration. Fish typicallypropel water unidirectionally over the gills, using ventila-tory muscles that operate around the jaws and skeletalelements in the gill arches lining the pharynx. Adult am-phibians, which lack a diaphragm, retain the buccal forcepump for tidal lung ventilation; their larvae are aquaticgill-breathers. Thus, in fish and amphibians, the majorrespiratory muscles are cranial muscles, innervated bymotoneurons with their cell bodies in the brain stem.Reptiles retain an elaborate buccal, hyoidean force pump,but ventilate the lungs primarily with a thoracic aspiratorypump, although they typically lack a diaphragm. Mam-mals have aspiratory lungs, and ventilation is accom-plished by coordinated contractions of diaphragmatic,intercostal and/or abdominal muscles innervated from thespinal cord, with only some accessory respiratory mus-cles (e.g., for control of the glottis) innervated by cranialnerves. Consequently, medullary respiratory neuronssend axons down the spinal cord to innervate spinal

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motoneurons. The respiratory system in birds resemblesthat of mammals, except that they lack a diaphragm andthe lungs are ventilated by volume changes in the air sacs.

The cardiovascular system is undivided in a typicalfish, with the heart delivering blood into the branchialvasculature and an arterioarterial respiratory route con-ducting blood directly from the gills to the systemic cir-cuit. A parallel arteriovenous route through the branchialcirculation is probably nutritive, rather than constituting afunctional shunt past the respiratory route. In contrast,mammals and birds have a completely divided circulatorysystem, with separate pulmonary and systemic circuits.Air-breathing fish, amphibians, and most reptiles havemore or less incompletely divided circulatory systems,allowing differential perfusion of the pulmonary circuit.This ability may be an essential component of their inter-mittent patterns of ventilation, often associated with pe-riods of submersion. Amphibians may, in addition, utilizebimodal respiration. Larval amphibians possess gills, of-ten in combination with developing lungs, while adultamphibians can switch between cutaneous and lungbreathing (e.g., during graded hypoxia or submersion) sothat the distributing effect of vascular mechanisms are ofparamount importance.

Despite these major differences in the constructionand mode of operation of their respiratory and cardiovas-cular systems, evidence is accumulating that the verte-brates share some important similarities in the mecha-nisms of central generation of the respiratory rhythm,control of the cardiovascular system and, more specifi-cally in the present context, in the central nervous andreflex generation of cardiorespiratory interactions. Thecentral theme of this review is the evolution of the mech-anisms of integration and coordination that match bloodflow to ventilatory movements, a relationship probablyfundamental to the success of vertebrates. Accordingly,we address such questions as the origin and nature oftonic nervous activity to the heart, to blood vessels, and tothe airways. It may be that our review of the evolutionaryrelationships between cardiorespiratory control systemsin vertebrates will illuminate our current inadequate un-derstanding of the fundamental mechanisms underlyingthe observed interrelationships between respiratory con-trol and cardiac control.

Knowledge of this complex area is of course domi-nated by the results of medically oriented research onmammals. To thoroughly review the mammalian litera-ture is beyond the scope and length constraints of thecurrent account. Instead, reference will be made in therelevant sections to recent extensive reviews. Readersrequiring a more detailed account of the mammalian lit-erature thus have points of access to that debate, withoutunduly lengthening the current review, or unbalancing itin relation to the available information from “lower” ver-tebrates. Each aspect of the review, therefore, begins with

a summary of our current understanding of the extensivemammalian literature. This then underpins the subse-quent comparative survey of the other vertebrate groups,considered in turn from fish, through amphibians andreptiles to birds, in relation to our more thorough under-standing of the mammalian pattern. The treatment of eachgroup is necessarily uneven because of the limitations onour knowledge so that the sections on “fish” are some-times divided between elasmobranchs and teleosts andsometimes not. It must be emphasized here that, unlikethe mammals and birds, the so-called “lower vertebrate”groups have a complex phylogeny; that is to say that fish,amphibian, or reptile is an umbrella term describing verydiverse groups of animals, some relatively little studied.Because the respiratory and cardiovascular systems andtheir innervation in the lower vertebrates are less wellknown than those of mammals, some brief descriptions ofselected examples are included to illuminate the accountof the mechanisms of their control.

Some consideration of the mechanisms of ventilationand of the generation of the respiratory rhythm in the CNSis a necessary prelude to a review of the control ofcardiorespiratory interactions. Consequently, a very briefoverview of this area in mammals leads to a comparativeaccount of our more limited understanding of the mech-anisms in lower vertebrates, which includes descriptionsof their patterns of ventilation and their origins in thebrain stem, plus a consideration of the factors determin-ing the onset and frequency of bouts of intermittentbreathing in air-breathing fish, amphibians, and reptiles.

We then describe the innervation of the reflexogenicareas supplying the cardiovascular and respiratory sys-tems and implicated in the generation of cardiorespira-tory interactions, including central and peripheral chemo-receptors, arterial baroreceptors, and mechanoreceptorssupplying the respiratory system. There follows a reviewof the evidence for functional chemoreceptors and mech-anoreceptors in fish, including air-breathing fish, and inamphibians, which considers the developing roles forcentral chemoreceptors, lung stretch receptors, and arte-rial baroreceptors as the vertebrates evolved from primar-ily water-breathing to facultative and then to obligateair-breathing forms.

A review of the efferent innervation of the cardiovas-cular and respiratory systems is initiated by considerationof the cranial autonomic outflow. Beginning with a de-tailed description of the central locations of vagal pregan-glionic neurons (VPN) in mammals, which emphasizes theimportance of the nucleus ambiguus (nA), a comparativeaccount of the central origins of vagal efferents innervat-ing the cardiovascular and respiratory systems in lowervertebrates follows. This considers evidence of a devel-oping role in the control of cardiorespiratory interactionsfor neurons relocated from the dorsal motor nucleus ofthe vagus (DVN) into the nA. Description of the sympa-

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thetic innervation of the cardiorespiratory system ex-plores evidence for the existence of functionally orga-nized specific groups of cells, including the possiblefunctional importance of the arrangement of their den-dritic fields, in the control of heart rate, vasomotor con-trol, and the control of airway resistance.

The review culminates in a consideration of the cen-tral control of cardiorespiratory interactions in mammals,with a necessarily less detailed comparison of the mech-anisms in lower vertebrates. This account begins with aconsideration of control of the heart then progresses to areview of the role of central interactions and reflex inputsin the generation of cardiorespiratory modulation of heartrate, vasomotor tone, and control of the airways in mam-mals. Discussion of the role of neurons and their connec-tions within the nucleus of the solitary tract (NTS) and theventrolateral medulla in the generation of cardiorespira-tory interactions is followed by a consideration of thegeneration of respiratory oscillations in sympathetic car-diovascular neurons. A comparative account of the cen-tral and peripheral interactions resulting in cardiorespira-tory synchrony in fish is followed by consideration of theinteractions responsible for control of the cardiorespira-tory responses of intermittent breathers among the am-phibians, reptiles, and diving birds.

We conclude the review with a summary of the ap-parent evolutionary changes in the control systems de-scribed in lower vertebrates, toward the more fully inves-tigated systems in mammals, which attempts to identifyareas that merit the urgent attention of comparative phys-iologists. The identification of these areas is made in theknowledge that comparative studies are becoming everharder to fund from the agencies that support academicresearch. It is our task to emphasize that such studies arenot only of great intrinsic interest but can further illumi-nate our understanding of mammalian, and therefore hu-man, systems.

II. PATTERNS OF VENTILATION AND CENTRAL

RESPIRATORY PATTERN GENERATION

Mammals characteristically display continuous,rhythmic, aspiratory breathing to maintain their relativelyhigh rates of oxygen uptake and carbon dioxide excre-tion. Exceptions are the fetus and neonate which oftenshow intermittent cycles of breathing related to sleepstates (260) and diving or hibernating mammals whichsuspend or markedly reduce breathing and heart rates forvarying periods but otherwise show typical cardiorespi-ratory control mechanisms. Patterns of ventilatory me-chanics are defined solely in terms of the time spent ininspiration and expiration and the rate of air flow. Com-binations of these variables produce the more familiarcomponents of breathing, namely, frequency, tidal vol-

ume, and minute ventilation. From neurophysiologicaldata, the mammalian ventilatory cycle has been dividedinto three distinct neural phases in which each phasereflects a “state” of the oscillating network rather than aparticular configuration of the motor output. In otherwords, a cycle phase in this context means a recurringepisode when one or more groups of neurons in thenetwork discharge a characteristic pattern of action po-tentials (528, 529). These phases have been defined asinspiration, postinspiration (passive expiration), and ex-piration (active expiration). The postinspiratory phase isa period of inspiratory braking, which is also referred toas the first stage of expiration (EI) (364, 528).

Pattern is more complex in arrhythmic or episodicbreathers, such as the amphibians and reptiles, where thecomponents of breathing frequency also include numberof breaths per episode and an apneic or nonventilatoryperiod of variable duration. Kogo and Remmers (364)have recently discussed the similarity of the respiratoryphases between amphibians and mammals. Their intra-and extracellular recordings of respiratory neurons inbullfrogs provide solid evidence to argue that lower ver-tebrates also have a three-phase respiratory cycle. Ac-cording to their analysis, the first phase is expiration, andit occurs when the glottis is first opened. This is thenfollowed by inspiration, which is produced by the briskactivation of the buccal levators to push air back into thelungs. The last phase is a period of breath holding, duringwhich neurons other than those involved in the produc-tion of the two other phases were shown to be active. Thisphase corresponds to the postinspiratory phase describedpreviously for mammals. They conclude their discussionby stating that this analysis is consistent with that of Packet al. (487), who suggest that lungfish, which also have abuccal force pump, have a postinspiratory phase.

The mechanisms underlying respiratory rhythmogen-esis in mammals are only now being resolved (67, 529,585), and even less is known about respiratory rhythmo-genesis in nonmammalian species. Recordings from iso-lated brain stem-spinal cord preparations in lamprey(539), bullfrog (427), and turtle (178) have shown rhyth-mic respiratory-related discharges in spinal and cranialmotoneurons. Because these preparations can produce arespiratory rhythm in the absence of afferent feedback(with the possible exception of input from central oxygenchemoreceptors, when present) it would appear that acentral respiratory pattern generator is present in all ver-tebrates. At the same time, because it is possible to elim-inate breathing by artificially meeting the convective re-quirements of an animal (e.g., external membrane lung,unidirectional gill or lung ventilation; for review, see Ref.440), it would appear that the CPG requires some externalstimulus to trigger respiratory events.


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A. Mammals

The neural substrate responsible for respiratoryrhythm generation and mediation of respiratory reflexeslies within the brain stem of mammals. Groups of respi-ratory premotoneurons and neurons innervating upperairway muscles are found in the caudal medulla near thenA and the Botzinger complexes. In addition, at least onesite of respiratory rhythmogenesis has been identified, inneonatal mammals, in the “pre-Botzinger” complex whichis situated in the reticular formation of the rostral me-dulla, at the level of the hypoglossal nuclei (585). Theseoutflows probably derive, in an evolutionary sense, fromthe branchial motoneurons of more primitive, gill-breath-ing vertebrates that retain their primary roles in respira-tory rhythm generation in present-day fish and larval am-phibians. Accordingly, the reticular formation is thoughtto be the site both of the primary respiratory rhythmgenerator in fish and amphibians and of the respiratoryand suckling rhythms in neonatal mammals.

Because the detailed organization of central respira-tory control in mammals has been exceedingly well re-viewed recently (67, 200, 529), a brief synopsis, for com-parison with nonmammalian vertebrates, will besufficient here. Two models have been proposed to try toexplain respiratory rhythmogenesis in mammals. One pro-poses that the central respiratory rhythm generator con-sists of burster or pacemaker neurons, which show spon-taneous rhythmic oscillations in membrane potential inthe absence of synaptic inputs or alternatively require atonic excitatory input before they exhibit rhythmic oscil-latory activity. The second postulates that respiratoryrhythm is produced by neural networks that exhibit os-cillatory behavior due to synaptic interactions alone. In-deed, although pacemaker-like neurons have been identi-fied in the pre-Botzinger region in neonatal mammals invitro, when sensory input was removed (585), most re-cently Richter (529) has argued for a hybrid of these twoin vivo, whereby under normal conditions of sensoryinput, the synaptic interactions between respiratory neu-rons override the effects of pacemaker inputs. In theirrecent review of the literature on the central control ofbreathing in mammals, Bianchi et al. (67) have proposedthat respiratory rhythm is not generated by a single con-ditional pacemaker process. Their argument was basedon the assumption that brain stem respiratory activityresults from the sequential activation of many popula-tions of neurons to produce a three-phase motor act(breathing) in which each process is conditioned by theprevious one and initiates the next. An alternate viewwould be that the coordination of the groups of respira-tory neurons would be performed by a different entity.This entity would be responsible for processing the rele-vant sensory signals and would ensure precise spatial andtemporal pattern of muscle activation during each breath

so that the respiratory system meets the demand of theorganism. It is to help understand the relationship be-tween respiratory rhythm and pattern that the concept ofa central respiratory pattern generator has emerged (203,439). Because the mechanisms underlying the generationof central respiratory rhythms are not the prime subject ofthis review, central pattern generation will be referred tononspecifically and the generator designated as the CPG.

B. Cyclostomes

This group of vertebrates is composed of the myxi-noids (e.g., Myxine, the hagfish) and the petromyzontes(e.g., Lampetra, the lamprey). They are jawless fishes,possibly related to the primitive, extinct agnathans, butwith highly specialized life-styles. In the hagfishes, wateris drawn in through the nostrils by the action of a mus-cular membrane known as the velum and exits from aseries of gill pouches via a single external opening. Theammocoete larva of the lamprey has a series of finelydivided gill slits which it ventilates unidirectionally bymeans of the velum. Water flow is utilized both for gasexchange and filter-feeding. Adult lampreys are ectopara-sites and have powerful suckers around the mouth withwhich they attach themselves to their fish hosts. The gillsare enclosed in a series of pouches that are ventilatedwith tidal flow of water in and out of the small externalopenings of each pouch. Expiration is the active phasewith muscles in the walls of the pouches contractingagainst the elastic recoil of the branchial basket.

Spontaneous bursts of respiration-related activityhave been recorded from the isolated brain stem of thelamprey. Recording sites included respiratory motor nu-clei in the caudal half of the medulla, innervating theVIIth, IXth and Xth cranial nerves and sites near thetrigeminal (Vth) motor nuclei, in the rostral half of themedulla (538, 541, 622). Periodic bursts of small spikesrecorded from the rostral medulla, at the levels of the Vmotor nuclei, continued after isolation of the isthmic-trigeminal region by transections and occurred beforebursts recorded from the IX and X cranial nerve roots.Electrical stimulation of this area excited respiratory mo-toneurons monosynaptically and could entrain or resetthe respiratory rhythm. These observations suggest thatthe motor pattern for respiration is at least partly gener-ated and coordinated in the rostral half of the medulla inthe lamprey and is transmitted to respiratory motoneu-rons through descending pathways (539).

C. Fish

Water contains less oxygen per unit volume than airand yet is considerably more dense and viscous. Conse-quently, fish have to work relatively hard to extract suf-


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ficient oxygen from water and normally exhibit continu-ous rhythmical breathing movements of the buccal andseptal or opercular pumps. Fish use cranial muscles forgill ventilation. These are innervated by a dorsal group ofcranial nerves exiting from the brain stem and termed thebranchial nerves (536). This series of nerves containssensory fibers and in most cases visceral motor compo-nents (Fig. 1). The nerves innervating respiratory musclesinclude the trigeminal Vth which provides the major in-nervation to the mouth region of all vertebrates, includingthe maxillary branch to the upper jaw and mandibularbranch to the lower jaw, responsible for motor control ofthe jaw-closing muscles. Jaw opening is passive in routineaquatic ventilation (31, 285). The facial VIIth nerve pro-vides the hyomandibular branch to the branchial musclesin the hyoid arch, including the levator hyoidei and, inteleosts, the opercular muscles. The glossopharyngealIXth and the vagal Xth cranial nerves innervate the gillarches and in particular provide afferent innervation ofthe mechanoreceptors and chemoreceptors important inventilatory control and efferent innervation to intrinsicrespiratory muscles in the gill arches. These branchialnerves have their efferent cell bodies and afferent sensoryprojections located dorsomedially in the brain stem, closeto the fourth ventricle, in a rostrocaudally sequential se-ries (607; Fig. 2).

Rhythmic ventilatory movements continue in fish af-ter brain transection to isolate the medulla oblongata,although changes in pattern indicate that there are influ-ences from higher centers (563). Central recording andmarking techniques have identified a longitudinal strip ofneurons with spontaneous respiration-related bursting ac-tivity, extending dorsolaterally throughout the whole ex-tent of the medulla (36, 564, 565, 636). These neuronsmake up elements of the trigeminal Vth, facial VIIth,glossopharyngeal IXth, and vagal Xth motor nuclei, whichdrive the respiratory muscles, together with the descend-ing trigeminal nucleus and the reticular formation (Fig. 1).All the motor nuclei are interconnected, and each re-ceives an afferent projection from the descending trigem-

inal nucleus and has efferent and afferent projections toand from the reticular formation (29). The intermediatefacial nucleus, which receives vagal afferents from the gillarches that innervate a range of tonically and physicallyactive mechanoreceptors (164) as well as chemorecep-tors (607), projects to the motor nuclei (34). Finally, areasin the midbrain such as the mesencephalic tegmentumhave efferent and afferent connections with the reticularformation (33, 335). The respiratory rhythm apparentlyoriginates in a diffuse respiratory pattern generator in thereticular formation, and this remains functional underanesthesia (29).

Some fish will exhibit episodic breathing patternswhen exposed to particular environmental conditionssuch as hyperoxia. Carp were shown to possess a groupof neurons with phase-switching properties, situated inthe dorsal tegmentum at the level of the caudal midbrain.This group of respiratory rhythmic neurons (termed typeA neurons) do not sustain continuous respiration butappear to play a key role in the control of episodic breath-ing. Indeed, type A neurons fire just before the onset of abreathing bout during intermittent respiration. Further-more, stimulation of this area of the brain stem, during aventilatory pause, brings forward the onset of the nextbreathing bout (334).

Central recordings from the medulla oblongata of thecarp suggested that adjacent neurons have different firingpatterns (30). These authors identified the target musclefor individual motoneurons by simultaneous recordingsof neuronal activity and electromyograms (EMG) fromthe respiratory muscles. In contrast, retrograde intra-ax-onal transport of horseradish peroxidase (HRP) alongnerves that innervate the respiratory muscles revealedthat in the brain stem of elasmobranchs the neurons in thevarious motor nuclei are distributed in a sequential series(607). Recordings of efferent activity from the central cutends of the nerves innervating the respiratory muscles ofthe dogfish Scyliorhinus canicula (52) and the ray Raia

clavata (E. W. Taylor and J. J. Levings, unpublished data)have revealed that the branches of the Vth, VIIth, IXth,

FIG. 1. Diagram of distribution of componentsof cranial nerves involved in control of ventilationin a shark (Squalus). Roman numerals refer to cra-nial nerves: V1, ophthalmic ramus of trigeminalnerve; V2, maxillary division; V3, mandibular divi-sion of trigeminal; VII Pal, palatine ramus of facialnerve; X, vagus nerve supplying branchial branchesto gill arches 2–5, cardiac and visceral branches;XII, trunk of conjoined occipital and anterior spinalnerves to form hypobranchial nerve innervatingventral muscles inserted on pectoral column andused in feeding and forced ventilation; hm, hyoman-dibular; lat, lateral line trunk; occ n, occipitalnerves; s op, superficial ophthalmic; S, position ofspiracle; sp n, anterior spinal nerves; 1–5, positionof gill slits. [From Taylor et al. (613).]


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and Xth cranial nerves fire sequentially in the order of thesequential rostrocaudal distribution of their motonuclei inthe brain stem and rostral spinal cord. The resultantcoordinated contractions of the appropriate respiratorymuscles may relate to their original segmental arrange-ment before cephalization, an arrangement which is re-tained in the hindbrain of the fish in the sequential topo-graphical arrangement of the motor nuclei, including thesubdivisions of the vagal motonucleus (Fig. 2). This tra-ditional view of the origin of the jaws and visceral archesand their innervation (161) has recently been questionedon the basis of developmental studies of the role of neuralcrest cells (215). These suggest a separate origin for thejaws as feeding structures, independent of the visceral

arches, which combined ventilation with filter-feeding, aview supported by study of marker genes (586). A possi-ble evolutionary antecedent of the jaws may be the velumof filter feeding protochordates or larval cyclostomes(M. A. Smith, personal communication).

Both elasmobranchs and teleosts can recruit an ad-ditional group of muscles into the respiratory cycle toprovide active jaw occlusion. These are derived phyloge-netically from the forward migration of four anterior myo-tomes (the hypaxial muscles) to form a complex ventralsheet of muscle, inserted between the pectoral girdle, thelower jaw, and the ventral processes of the hyoid andbranchial skeleton. They are associated primarily withsuction feeding and ingestion in water-breathing fishes

FIG. 2. Right: schematic diagram of a dorsal view of hindbrain of dogfish, Scyliorhinus canicula, to showdistribution of motonuclei (indicated by hatched areas) supplying efferent axons to cranial nerves innervating respira-tory muscles and heart. These are adductor mandibulae nucleus of cranial nerve V, supplying closing muscles in jaw;facial motor nucleus of VII, supplying muscles of jaw and spiracle; glossopharyngeal nucleus of IX, supplying first gillarch; dorsal motor nucleus of vagus Xm, which is divided rostrocaudally into separate subnuclei innervating branchialarches 2–4 (Xm 1–3), branchial arch 5 plus branchial cardiac nerve (Xm4), and heart plus anterior regions of gut (X vis).Lateral nucleus of vagus (Xl) supplies axons solely to branchial cardiac nerve. Hypobranchial nucleus (hy) suppliesaxons to feeding muscles via occipital nerve XI and anterior spinal nerves (not shown). Other labels indicate cerebellumthat overhangs medulla and is outlined by heavy line, a cerebellar auricle (aur) octavus nerve (VIII) and spinal canal(spc). Obex marks position where roof of 4th ventricle is devoid of nervous tissue rostrally and covered by choroidplexus. Left: a diagrammatic transverse section (T.S.) taken at obex; through medulla of dogfish (indicated by dividedline on right panel) to show vertical and horizontal disposition of vagal and hypobranchial nuclei. Labels indicate a vagalrootlet (X), dorsal motor nucleus of vagus (Xm), lateral vagal nucleus (Xl), vagal sensory nucleus (Xs), hypobranchialnucleus (hy) and sulci in 4th ventricle (4th V), namely, sulcus medianus inferior (smi), sulcus intermedius ventralis (siv),and sulcus limitans of His (slH). [From Taylor (608).]


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(285) but can be recruited into the respiratory cycle dur-ing periods of vigorous, forced ventilation such as mayoccur following exercise or deep hypoxia (32, 285). Thesemuscles are innervated by the hypobranchial nerve,which contains elements of the occipital nerves and theanterior spinal nerves (Figs. 1 and 2). The hypobranchialnerve in fish is the morphological equivalent of the hypo-glossal nerve that innervates the muscles of the tongue inreptiles, birds, and mammals. These muscles are utilizedin suckling by infant mammals, an activity likely to re-quire its own central oscillator, which is thought to residein the reticular formation.

In the dogfish and ray, rhythmic opening and closingof the mouth occurs during ingestion of food, implying thecentral generation of a feeding rhythm (391). The neuralmechanisms operative in the control of masticatoryrhythms in fish remain unexplored, although it has beenargued that the respiratory and feeding rhythms in fish aregenerated by separate groups of interneurons (32). It isnow well established that in mammals the masticatoryrhythm is generated in the hindbrain, in the reticularformation (481), and the same has been suggested forbirds (181). It is interesting, in this regard, that the CPG infish is thought to reside in the reticular formation (29).

Preliminary studies on dogfish, in which simultaneousrecordings were made of efferent activity in the central cutend of a branchial branch of the vagus and of a branch of thehypobranchial nerve in decerebrate, paralyzed fish, con-firmed that the hypobranchial nerve is inactive during nor-mal fictive ventilation (Taylor and Levings, unpublisheddata). Short sequences of bursting activity were elicited inthe silent hypobranchial nerve by activation of tongue mech-anoreceptors and skin stretch receptors on the jaw (stimuliassociated with feeding). Periods of spontaneous, respira-tion-related bursting activity could be elicited by stimulationof gill proprioreceptors and chemoreceptors (this latter re-sponse to experimental oxygen deprivation) and by intrave-nous injection of norepinephrine, which increases ventila-tion in dogfish, possibly due to central stimulation ofrespiratory neurons (517, 615). The mechanisms involved inrecruitment of hypobranchial motoneurons into the respira-tory rhythm have not been studied.

D. Air-Breathing Fish

Air-breathing fish retain gills, ventilated by cranialmuscles, for the uptake of a variable proportion of theiroxygen requirements, dependent on species and condi-tions, and excretion of most of their carbon dioxide.Gulping of air is achieved through the action of the samemuscles in all air-breathing fish. These are elements of thejaw musculature, innervated by cranial nerve V, togetherwith hypobranchial musculature, identified by Liem (396,397) such as the geniohyoideus and sternohyoideus mus-

cles. The combined action of jaw and hypobranchial mus-cles in the generation of feeding or air-gulping, indepen-dently of the visceral arches, may derive from theirseparate embryological and evolutionary origins (586).Liem (397) described the sequence of events associatedwith air-breathing in the primitive actinopterygian, thebowfin (Amia calva), a fish that utilizes a well-vascular-ized swimbladder as an air-breathing organ (ABO), andsuggested that the action of air-breathing would requirelittle change in the pattern of neural control required forsuction feeding and/or coughing, with the exception ofcontrol over glottal opening. Brainerd (82) has suggestedseparate origins for air-pumping mechanisms in acti-nopterygian fishes (derived from the suction feeding/coughing pumps) and sarcoptergian lung fish and amphib-ians (the branchial irrigation pump). However, bothpumps utilize the same sets of muscles and possibly thesame central oscillators. In the bowfin, there appear to betwo types of air breath, one that involves exhalationfollowed by inhalation (designated “type I” air breaths bythe authors) and one that simply involves inhalation(“type II” air breaths), and it is suggested that type Ibreaths are respiratory in nature, whereas type II breathshave a buoyancy-regulating function (266).

Reorganization of the CNS associated with the evolu-tion of air-breathing has been poorly studied in fish. It hasbeen suggested that the African lungfish (Protopterus ae-

thiopicus) possesses two separate central rhythm genera-tors, one for gill ventilation and the other for air-breathing(205). With regard to actinopterygian, air-breathing fishes,there is probably a CPG for gill ventilation located in thereticular formation of the hindbrain, similar to that of water-breathing fish (29). In the bowfin, catecholamine infusionstimulates gill ventilation, apparently via a central mecha-nism, but has no effect on air-breathing in normoxia orhypoxia (422, 423), indicating that central sites controllinggill ventilation and air-breathing are pharmacologically andpossibly spatially different. The central sites responsible forcontrol of air-breathing reflexes in fish are still unknown.Some authors have suggested that air-breathing is criticallydependent on afferent feedback (568, 575, 577) and, asstated above, is simply a reorganization of coughing andsuction-feeding movements requiring relatively little neuralreorganization (397, 575, 577). In the bowfin, spectral anal-ysis indicates that there is an inherent rhythmicity to type I(i.e., respiratory-related) air-breathing, both in normoxia andhypoxia (267). These authors suggest, however, that thisperiodicity may be driven by changes in blood oxygen statusthat occur during the interbreath interval, rather than by aCPG for air-breathing.

E. Amphibians

Amphibian tadpole larvae have gills ventilated byactivity in cranial muscles, with branchial performance


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comparable to teleost fish, but carry out a large propor-tion (60%) of respiratory gas exchange over their perme-able skin. As development proceeds, the lungs assumeincreasing importance in oxygen uptake, although theskin remains the major exchange surface until metamor-phosis is nearly complete (91). In adult amphibians, mostoxygen is taken up from the lungs, ventilated by thebuccal cavity, but the skin retains a predominant role inthe excretion of carbon dioxide (80%, r 5 7.5).

The sequence of air flow in the breathing cycle oflungfish and amphibians such as bullfrogs is similar. Un-like air-breathing fish, which must open their mouth toaspirate ambient air into their buccal cavity at the onset ofthe breathing cycle, frogs aspirate air via nostrils. Eventhough this modification imposes a slight resistance to gasflow, it eliminates the energy expenditure associated withgulping air at the water surface (213, 214). Lung ventila-tion usually occurs episodically in bullfrogs. A breathingcycle begins by activation of the buccal depressor mus-cles that brings buccal pressure below ambient, and air isaspired into the buccal cavity via the nostrils. The laryn-geal dilator muscles then contract to open the glottis, andthis allows outflow of pulmonary gas that exits by thenostrils. Subsequent closure of the nostrils coincides witha brisk contraction of the buccal levators, which pushesthe bolus of gas through the glottis and into the lungs. Theglottis then closes, and the inflated lung is held at apositive pressure. Lung inflation cycles, in which a seriesof inhalations occur without an intervening expiratoryphase, are associated with experimental hypoxia or hy-percapnia (640).

Typically, after a bout of lung breathing, there fol-lows a series of elevations and depressions of the floor ofthe buccal cavity, called buccal oscillations. These small-amplitude, low-pressure buccal movements may helpflush the buccal cavity from the previous expiration, be-fore the next air breath (166, 168, 213, 214, 648), althoughtheir primary role may be olfaction (650). It has beensuggested that they may be remnants of the mechanismsof gill ventilation used by the premetamorphic tadpolestages, and homologous to gill ventilations in fish, andthat their rhythm may reflect vestiges of the centralrhythm generator for gill ventilation (209, 395, 487, 576).Buccal oscillations and lung ventilations are produced bythe same muscles. The primary difference between thesetwo events is the force of the contraction and the posi-tions of the glottis and nares. Lung ventilations are asso-ciated with more forceful contractions with the glottisopen and nares closed; buccal oscillations are associatedwith less forceful contractions with the nares open andthe glottis closed. In resting animals, buccal oscillationsoccur more or less continuously and are interrupted byperiodic lung ventilations, which normally occur at a timewhen another buccal oscillation would have been initi-ated. Regardless of the level of respiratory drive, there

appears to be an intrinsic rhythm to lung inflation events,increasing respiratory drive simply appears to result inthis rhythm being expressed a greater percentage of thetime.

These observations suggest at least two possible sce-narios. The first is that there is a single central rhythmgenerator whose output is integrated with inputs fromhigher centers and peripheral feedback (mechano- andchemoreceptors) at two distinct pattern generators. Atlow levels of respiratory drive, only output from the pat-tern generator driving buccal oscillations is produced, butas respiratory drive increases, output is generated fromthe pattern generator driving lung inflation, which leads tothe increase in the force of buccal contraction and theswitch in the state of the nares and glottis. The otherpossibility is that there are two distinct rhythm genera-tors, with expression of the lung rhythm being conditionalupon a higher level of central and/or peripheral receptorinput. However, the fact that lung ventilation always oc-curs at a time when a buccal oscillation would otherwisehave occurred suggests that if there are separate rhythmgenerators, they are entrained to a large degree. Kinkead(354) has described some circumstantial evidence for theexistence of two central respiratory rhythm generators inthe bullfrog. Hypercapnia had no effect on the frequencyof lung inflations but reduced both the occurrence ofbuccal oscillations and their instantaneous frequencywhen they did occur. This might suggest that there areseparate rhythms for lung inflation and buccal oscillation,which can be uncoupled.

Recently, a number of investigators have used invitro preparations of the larval or adult anuran brain stemto examine the mechanisms of respiratory rhythmogen-esis (209, 427–429, 491). Recordings of fictive breathing inisolated brain stem preparations revealed spontaneousneural output from the roots of cranial nerves V, VII, X,and XII. However, these bursts were synchronous, imply-ing that the spatiotemporal relationships between burstsof activity in these nerves in the intact animal rely onfeedback from peripheral receptors. Microinjections ofglutamate into rostral areas of the bullfrog brain stem,near the VII motor nucleus, caused a brief excitation offictive breathing (427). Interestingly, this area corre-sponds to the pre-Botzinger area of the reticular forma-tion in the mammalian brain stem, considered to be theprimary site for respiratory rhythmogenesis in the neo-nate (e.g., Ref. 523). The CPG in fish is thought to residein the reticular formation (29). Other pharmacologicalinvestigations support the suggestion that the neural net-works associated with respiratory rhythmogenesis maybe well conserved during vertebrate evolution (640).

Extracellular recording from in vitro brain stem aswell as spinal cord preparations of Rana catesbeiana

tadpoles and adults revealed that it is possible to manip-ulate the two types of neural activity associated with


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buccal or lung breathing independently, using pharmaco-logical agents (209, 428, 487, 585, 637). Superfusion of anin vitro brain stem-spinal cord preparation from the bull-frog tadpole with chloride-free saline eliminated therhythmic bursts associated with gill ventilation while aug-menting lung bursts, indicating that the former arise froma GABAergic, network-type rhythm generator, whereaslung ventilatory rhythms arise from pacemaker cells(209). This apparent discrimination is of interest in com-parison to the situation described in fish, where gill ven-tilation may depend on pacemaker cells located in thereticular formation, and in adult mammals, where lungventilation may be dependent on activity in neural net-works. The evolution/development of air-breathingrhythms may have required a new motor pattern in theCNS rather than one that evolved from progressive mod-ification of the branchial rhythm generator (354, 577).This may have evolved from the generator for the feedingrhythm that can be recruited by the respiratory CPGduring forced ventilation in fish or when air-breathing fishgulp air at the water surface, as described above.

A recent report by Brainerd and Monroy (83) de-scribed activity in hypaxial muscles during exhalation insalamanders, possibly representing a primitive condition,intermediate between the buccal force pump of fish andthe thoracic/abdominal aspiration pump of reptiles, birds,and mammals. Although similar data are not available foranuran amphibians, which may have lost this function,these data raise important considerations regarding theevolution of the control of ventilation in amphibians,which imply that descending fibers from the brain stem,innervating spinal motoneurons can have important rolesin some species, anticipating their roles in the supposedlymore advanced tetrapods.

Amphibians often breathe intermittently, with boutsof ventilation interrupted by quiescent periods or, inaquatic species or stages, submersion. Intermittentbreathing patterns are common in lower vertebrates, suchas reptiles and amphibians, and contrast with the contin-uous breathing patterns of nondiving birds and mammalsin their apparent lack of constancy and intrinsic rhythm.Many researchers have ascribed the genesis of breathingepisodes in amphibians and reptiles to the inherent oscil-lations of blood oxygen and/or CO2/pH levels associatedwith intermittent breathing, rather than to the action of a“mammalian-type” central control mechanism. In thismodel, lung ventilations are induced when a certain arte-rial PO2 (PaO2

) or arterial PCO2 (PaCO2) threshold is

reached and breathing ceases when the blood gas valueshave been brought back within a certain range (79, 568,649). The observation that breathing is completely sup-pressed when convective requirements are met by unidi-rectional ventilation (354, 357, 580, 649) indicates thatlung ventilation is conditional upon a minimal stimulatoryinput (439, 576, 580, 649). However, these experiments

were conducted with some degree of lung inflation, whichmay have overridden peripheral chemoreceptor drive.Preliminary evidence from experiments on decerebrate,paralyzed, and unilaterally ventilated toads suggests thatpulmonary stretch receptor inputs may be important inthe initiation of breathing. When fictive ventilation hadbeen suppressed by unilateral ventilation, it was inducedby lung deflation (640). Clearly, chemoreceptor and lungmechanoreceptor inputs influence the respiratory CPG,but their central interactions are unknown.

Several studies suggest that episodic breathing doesnot necessarily reflect the phasic nature of afferent che-moreceptor or mechanoreceptor inputs. Unidirectionallyventilated toads (580, 640, 649) can still display episodicbreathing or fictive ventilation, although this experimen-tal procedure has been assumed to maintain blood gasesconstant, and in paralyzed animals, lung distension con-stant, and thus produces only tonic chemoreceptor andmechanoreceptor input. These data imply that the mech-anisms underlying episodic breathing may be an intrinsicproperty of the central respiratory control system, a viewwhich seems confirmed by the observation that the motoroutput from a brain stem-spinal cord preparation of thebullfrog was episodic, in the absence of any possiblefeedback from the periphery (354). The central generationof these episodic breathing patterns has been localized tothe nucleus isthmi in the brain stem of the bullfrog (354,356). This mesencephalic structure is the neuranatomicalequivalent of the pons in mammals, which contributes tothe control of breathing pattern (202).

Whether episodic air-breathing is generated by cen-tral or peripheral mechanisms, it is vulnerable to inputsfrom centers higher in the CNS. In their recent review,Burggren and Infantino (90) described how adult malenewts reduced air-breathing frequency to maximize timefor courtship behavior toward females during the breed-ing season. Foraging or searching for prey can impact onsurfacing behavior in amphibians. Larval salamanderssupplied with benthic food showed reductions in buoy-ancy (which reflects degree of lung inflation) and fre-quency of air breaths compared with plankton feeders.These larvae also reduced air-breathing frequency duringdaylight hours, presumably to reduce the risk of aerialpredation. A similar interpretation was placed on the verydifferent periods of surface breathing between day andnight in Xenopus laevis (288).

F. Reptiles

Reptiles are typically committed air-breathers, hav-ing dry scaly skin and well-developed lungs. They are anancient and highly polyphyletic class of vertebrates. Ex-tant members show diverse respiratory and cardiovascu-lar mechanisms, including some they share with the am-


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phibians, such as an incompletely divided circulatorysystem and periodic ventilation, often combined with pe-riods of submersion. Accordingly, generalizations regard-ing the topography and control of their cardiorespiratorysystems must be avoided. The anapsids or turtles andtortoises are the most primitive extant group of reptiles.However, their ventilatory mechanisms are highly special-ized to account for their shell. This incorporates theirvertebrae and ribs so that the lungs cannot be ventilatedby movements of the thoracic cage as in other tetrapodvertebrates, and lung ventilation is greatly restrictedwhen the animal retreats into its shell. In the tortoise,Testudo, the forelimbs move in and out as the animalbreathes; the turtles have sheets of muscle wrappedaround the viscera or under the skin at the anterior andposterior openings of the shell, which contract alternatelyto ventilate the lungs. Thus the respiratory muscles areelements of the limb or body wall musculature, inner-vated by spinal nerves. Many of the freshwater turtles areextremely tolerant of anoxia, experienced when deniedaccess to air by submersion under ice in frozen ponds. Inthe crocodilians, which have a divided circulatory systemand may be more closely related to the birds rather thanother reptiles, breathing movements are driven by mus-cles of the body wall moving the liver, which is attachedto a transverse connective tissue sheet resembling a mam-malian diaphragm.

Lizards, in common with all other reptiles (exceptsome crocodilians), lack a diaphragm. However, unlikemodern amphibians, they do have ribs, and lung ventila-tion has long been considered to be generated by inter-costal muscles acting on the rib cage, with a primitivebuccopharyngeal or gular pump, like that described inamphibians, utilized primarily for olfaction. As lizards runin a serpentine manner, employing segmental musclesfrom the body wall, it was asserted by some investigatorsthat they are unable to breathe while running. Recentlythese views have been questioned. Whole animal plethys-mography, together with recordings of EMG from respi-ratory muscles, in the agamid lizard, Uromastyx microl-

epis, revealed that the prevailing mode of ventilation inthe lightly anesthetized animal involved the intercostalmuscles in triphasic lung inflation and deflation, with bothpassive and active expiratory stages, interrupted by peri-ods of breath-hold (7). However, an alternative mode ofventilation involved a gular pump that alternated with thecostal pump. After a short passive expiration, a bout ofbuccal pumping caused a progressive increase in lungvolume, followed by breath-hold (Fig. 3). Gular pumpingcommenced as lightly anesthetized lizards were warmedfrom 30 to 35°C, as part of their normal daily cycle oftemperature variation, and could be induced by tactilestimulation of conscious lizards. A parallel study, usingX-ray imaging of varanid lizards, Varanus exanthemati-

FIG. 3. Patterns of ventilation in lightly anesthetised agamid lizard, Uromastyx microlepis. Animal was inserted intoa whole body plethysmograph to record lung volume changes. Activity in thoracic and gular pumps were recorded aselectromyograms (EMG) from appropriate muscles. Recordings from intercostal muscles in thorax included electrocar-diogram (ECG). Blood pressure was recorded from a cannulated femoral artery. Traces were from below: 1) lungventilation recorded as pressure changes in plethysmograph (increased pressure signifies lung inflation); 2) EMG fromintercostal muscles, together with ECG; 3) EMG from geniohyoid muscle; 4) EMG from sphincter colli muscle; 5) bloodpressure. A series of thoracic aspiratory pumping movements, which inflated lungs, terminated in a bout of gularpumping, which also resulted in lung inflation. A second bout of gular pumping was seemingly initiated by a singlethoracic breathing movement. Heart rate appeared unaffected, and variations in blood pressure did not appear to referto breathing movements. (From M. Al-Ghamdi J. F. X. Jones, and E. W. Taylor, unpublished data.)


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cus, has revealed that when at rest they rarely used anaccessory gular pump. However, during recovery fromexercise, all animals used gular pumping in addition to acostal pump, with between one and five gular pumpingmovements following costal inspiration. These clearlycaused lung inflation, with caudal translation of the vis-ceral mass (84). More recently, these lizards have beenshown to employ gular pumping when walking, thus over-coming the supposed mechanical constraint on activelung ventilation during exercise (486).

The existence of anatomically and functionally sepa-rate thoracic and gular respiratory pumps in lizards wouldseem to require separate sites of central respiratoryrhythm generation. However, this interesting possibilityremains unexplored. Putative sites of respiratory patterngeneration, having similarities in neural organization andactivation to those extensively documented for mammals,have been described for turtles (603). However, the directcontribution of these populations of neurons and theirpotential integration of sensory information in determin-ing the generation of respiratory movements remain un-clear (439). In turtles, the basic output of the CPG isepisodic, even under experimental conditions when allsensory feedback appears tonic (178). Experiments per-formed on reptiles demonstrated that mild anesthesia andbrain stem section at the level of the rostral rhomben-cephalon (metencephalon) abolish these breathing epi-sodes, i.e., the animals now breathe in an uninterruptedfashion (461–463). Vagotomy also affects the breathingpattern by reducing the number of breaths per episode incrocodilians (461–463). It is interesting to note, however,that vagotomy had no effect on the breathing patternwhen it was performed after episodic breathing had beenabolished by a caudal midbrain transection (463).

As in amphibians, it has been suggested that theinitiation of bouts of discontinuous breathing may owemore to thresholds for stimulation of central and periph-eral chemoreceptors than to patterns dictated by a centralrhythm generator (439). This may enable the flexibility ofresponse essential for an ectothermic vertebrate, sincethe thresholds for stimulation will vary with temperature,in accordance with the animal’s oxygen demand. How-ever, unidirectionally ventilated alligators display epi-sodic breathing (179) so that centrally generated rhyth-micity may have a role in its initiation.

G. Birds

Birds, like their endothermic relatives the mammals,typically breath continuously and rhythmically, to supplytheir high demand for oxygen, thus sustaining their highmetabolic rate. In both groups, ventilation is cyclic, withair sucked into the lungs during inspiration and expelledat expiration. However, birds do not have a diaphragm,

and lung volume appears to vary little over the respiratorycycle. Instead, tidal volume is taken up by thin-walled,highly extensible air sacs. Respiratory gas exchange takesplace over the walls of the well-vascularized parabronchiin the lung, which, because of the unique structure of therespiratory apparatus, are ventilated unidirectionally. Thewalls of the parabronchi bear air capillaries, the func-tional equivalent of mammalian alveoli, which are in inti-mate contact with blood capillaries, providing highly ef-fective exchange conditions between blood and air,described as cross-current flow (553).

The respiratory rhythm in birds is assumed to arisefrom a CPG, evidenced by the virtually constant periodsof inspiration and expiration recorded from birds at var-ious levels of ventilatory output (440). Other respiratoryvariables, such as tidal volume and interbreath interval,do vary, presumably under the influence of inputs fromcentral and peripheral receptors. Breathing hyperoxic gasmixtures reduces ventilation in birds, implying a chemo-receptive drive to ventilation in normoxia (553). Divingbirds can show prolonged apneas, associated particularlywith forced submersion or extended “escape” dives, dur-ing which stimulation of water receptors in the airwaysoverrides respiratory drive. Control of the complex suiteof reflex cardiorespiratory responses shown by divingbirds to forcible submersion in the laboratory (apnea,profound bradycardia, and marked increase in peripheralresistance) and their very different responses during tele-metered natural dives have been comprehensively re-viewed (98, 589).

The pools of neurons in the medulla that generate thepatterned activity driving the respiratory muscles in birdsappear to resemble those described in mammals (153). Apneumotaxic center, similar in location and functionalcharacteristics to that previously described in mammals,has been postulated to exist in dorsal mesencephalicregions of the brain (553). Sections caudal to this regionabolish rhythmic respiratory activity that can, however,be reinstated by rhythmic electrical stimulation of thevagus nerves. The normal respiratory period in birds maybe set by cyclical changes in lung CO2 levels. In a unidi-rectionally ventilated bird preparation, when insufflatedCO2 levels were raised to stimulate spontaneous breath-ing cycles, then periodically varied around this level, therespiratory movements of the bird were found to lockonto the imposed fluctuations in CO2 (553).

It has long been recognized that lung ventilation maybe coordinated with wing beat in birds. Compressiveeffects of wing upstroke and expansive effects of down-stroke may assist airflow through the lung, in coordina-tion with activity in respiratory muscles. The correspon-dence between the two rhythms varies from a ratio of 1:1in crows and pigeons up to 5:1 (wing beats per breath) inducks and pheasants (95). Bats, as flying mammals, showsimilar patterns of coordination and also share a relatively


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large heart and increased blood oxygen capacity withtheir flying cousins, the birds. Respiratory frequency in-creases immediately upon take off in pigeons, indicatingthat a combination of central and peripheral nervousmechanisms, as well as mechanical considerations, islikely to be influencing the relationship. Stimulation ofventilation with CO2 during flight did not alter the phasiccoordination patterns between respiratory and wingbeatcycles in either pigeons or magpies (77), suggesting thatneural interactions between control centers in the CNSare important. A potent influence of locomotor centers inthe brain stem upon respiratory center motor output (orvice versa) in geese and ducks has been demonstrated byFunk et al. (207, 208). Their studies on decerebrate geeseindicated that, in the absence of feedback from flappingwings, there was a predominantly 1:1 ratio between thetwo motor outputs, implying direct recruitment of one bythe other. The various patterns of coordination seen infree-flying birds clearly require feedback from peripheralreceptors.

III. AFFERENT INNERVATION OF THE

CIRCULATORY AND RESPIRATORY

SYSTEMS

A. Mammals

The activity of the different types of sensory recep-tors in the cardiovascular system and the airways ofmammals has been described in several reviews (123, 489,490, 544). In addition, the cardiovascular and respiratoryresponses evoked in mammals by stimulation of arterialchemoreceptors have been reviewed very recently (138,415). Accordingly, the well-known characteristics of thesemammalian sensors and the responses they engender arenot described here but are referred to, for comparison, inthe descriptions of their equivalents in nonmammalianvertebrates, in which their roles are still not yet fullyunderstood.

The central projections from the various reflexogenicsites in the mammalian cardiorespiratory system are,however, of direct relevance to the current account. Awide variety of afferent fibers transmitting sensory infor-mation arises from the heart, vascular, and ventilatorysystems of mammals. Arterial baroreceptors are locatedin the walls of the carotid sinus and aortic arch whilearterial chemoreceptor afferents are located in the carotidand aortic bodies, and probably elsewhere in the circula-tion. Both the atria and ventricles of the heart containmechano- and chemoreceptive afferents in their walls.Within the respiratory system there is a wide variety ofsensory afferents (both mechano- and chemosensitive)throughout the respiratory tract, from the nasal cavity tothe alveolar walls. These circulatory and respiratory af-

ferents include both myelinated and unmyelinated nervefibers and are located mainly in the trigeminal, glossopha-ryngeal, and vagus nerves. In addition, activity in severaltypes of somatic afferent can have actions on either orboth the respiratory and cardiovascular systems. In gen-eral, in both systems, the different afferents can be splitinto those involved in homeostasis, which monitor ongo-ing activity, whereas others, involved in defensive typereflexes, are only activated by more aversive types ofstimuli (120, 121).

Afferents from receptors in the cardiorespiratory sys-tem, travelling in the cranial nerves, terminate in the brainstem, in the NTS, and, to some extent, in the trigeminalnucleus. These make multiple synapses in distinct regionsof the NTS and show a large amount of overlap in theirterminal fields. This allows convergence of input ontopostsynaptic neurons in the NTS and may form part of theneural substrate by which various afferent inputs areintegrated into physiological response patterns, since it iswell known from reflex studies that simultaneous activa-tion of several afferent inputs may interact in either apositive or negative manner (see Ref. 121). At least someof these interactions occur as the afferent informationarrives at the CNS. There is some evidence for polysyn-aptic convergence and interactions of afferent inputs onpostsynaptic NTS neurons, but the extent of these inter-actions is still a matter of debate and has been discussedin detail previously (121, 328).

The topography of these central terminations hasbeen studied by a variety of techniques. The earliest stud-ies have been summarized and discussed previously(328). More detailed information has now become avail-able and will form the basis of this description. Histolog-ical studies employing degeneration (129), or more re-cently anterograde axonal transport of neuronal markers(337), have demonstrated that vagal afferents terminatepredominantly in the caudal two-thirds of the NTS,whereas glossopharyngeal afferents terminate in the ros-tral two-thirds, overlapping in the region around obex. Inaddition, there was a certain degree of topography oftermination within the different subnuclei of the NTS,based on organ of innervation (118, 204, 337). Althoughthere are different degrees of input to the different sub-nuclei of the NTS, there is no clear anatomical separationbetween the terminations of afferent fibers from the re-spiratory or circulatory systems.

These histological studies give little informationabout the function of the visualized afferents, a majorrestraint since both the vagus and glossopharyngeal nervecontain a large number of functionally different afferentfibers. Electrophysiological techniques have been used tomap terminations of afferents, whose function had beenidentified (Fig. 4). This antidromic mapping technique hasbeen used to delineate the terminal fields of slowly adapt-ing (176) and rapidly adapting (156) pulmonary stretch


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receptor afferents, arterial baroreceptor and chemorecep-tor afferents (174), and bronchial and pulmonary C-fiberafferents (370). Slowly adapting pulmonary stretch recep-tor afferents terminate rostral to obex, mainly in theipsilateral medial subnucleus with some innervation ofthe lateral and ventrolateral subnuclei. This latter regionis the location of the dorsal respiratory group (67, 188,189). In contrast, rapidly adapting pulmonary stretch re-ceptor afferents terminate more caudally, rostral and cau-dal to obex, mainly in the ipsilateral commissural nucleus,with less dense innervation of the medial and ventrolat-eral subnuclei and the contralateral commissural nucleus.Bronchial and pulmonary C-fiber afferents only project tomedial regions of the NTS spanning the obex region.Unlike myelinated pulmonary afferents, there are no ter-minations in the lateral, ventrolateral, or ventral subnu-clei of the NTS. Caudal to obex, the terminal fields arelocalized to the dorsal part of the commissural nucleus.This projection of C-fiber afferents is not dissimilar to thatof arterial chemoreceptor afferent fibers that terminate inthe medial and dorsomedial NTS and in the commissuralnucleus (320).

Although antidromic activation can delineate the ter-minal regions of functionally identified afferent fibers,there are limitations when the question of the fine

branches is addressed. The organization of preterminalprocesses and distribution of synaptic boutons for singlepulmonary stretch receptor afferents (both slowly andrapidly adapting) has been described (338, 339) by micro-injecting an HRP conjugate into axons impaled in thesolitary tract, allowing direct visualization of the terminalfields of the labeled afferents. The intermediate, ventral,ventrolateral, and interstitial nuclei were the only regionsof the NTS receiving terminals of slowly adapting recep-tor afferents, whereas rapidly adapting receptor afferentsterminated in the intermediate, dorsal, and dorsolateralsubnuclei more caudally. Similar studies (55, 557) haveshown that laryngeal afferents terminate mainly in theventral and ventrolateral NTS, with some projections tothe interstitial, dorsolateral, medial, and dorsomedial nu-clei.

Little is known about the postsynaptic neurons acti-vated by stimulation of bronchial or pulmonary C-fiberafferents, although neurons in the commissural and cau-dal part of the medial NTS can be activated by stimulationof C fibers in pulmonary branches of the vagus (58).Although some of these neurons also received input fromnonmyelinated afferents arising in the heart, they neverreceived input from myelinated afferents, from either theheart or lungs (58). In recent studies we have confirmedthat some neurons with these same properties are indeedactivated when phenylbiguanide is injected into the rightatrium (315, 317), whereas inspiratory neurons in theventrolateral NTS are inhibited by this stimulus (314).Finally, arterial baroreceptor terminals are restricted tothe ipsilateral NTS, rostral to the obex. The dorsolateraland dorsomedial subnuclei are the most often innervated,and the commissural nucleus also received some inner-vation (318). The central terminations of afferents arisingin the heart have not been studied in such detail, but typeA atrial receptor afferents have been shown to terminatein the dorsolateral and ventrolateral subnuclei (S. Dono-ghue and D. Jordan, unpublished observations).

In many species, activation of receptors in differentparts of the upper respiratory tract evokes similar cardio-respiratory responses (see Ref. 135). In dogs, cats, andmonkeys, stimulation of afferents in the superior laryn-geal nerve (SLN) or nasal mucosa results in apnea, bra-dycardia, and vasoconstriction. The trigeminal nucleus isone site where convergence of such afferent informationmay take place, since it receives afferent input from somevagal and glossopharyngeal fibers (351, 626) and SLN(258, 599). Indeed, some SLN fibers bifurcate, one branchterminating in the NTS and the other in the rostral trigem-inal nucleus (114). Neurons in both the rostral and caudalsensory trigeminal nuclei have been reported to receive aconvergent visceral and somatic inputs from stimulationof the SLN, glossopharyngeal nerves, tooth pulp, andcutaneous facial mechanoreceptors (282, 561). In addi-tion, Jordan and Wood (332) reported a group of neurons

FIG. 4. Summary of major regions of termination within nucleustractus solitarius (NTS) of cat cardiovascular and pulmonary afferentsas determined by antidromic mapping studies. Relative density of ipsi-lateral (●) and contralateral (E) regions of termination is denoted bynumber of dots, and most extensive regions of termination are shaded.[Modified from Jordan (321).]


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in the rostral trigeminal nucleus that were activated bySLN stimulation and mechanical stimulation of the nasalmucosa but were unaffected by tactile stimulation ofother parts of the face. Finally, stimulation of trigeminalafferents has been shown to evoke a short latency re-sponse in vagal nerves (238).

Clearly, the neurons of the NTS and trigeminal nu-cleus are not simple relay stations. Integration betweendifferent afferent inputs can occur here, and there is somedegree of functional organization within these nuclei. Un-fortunately, such detailed information is not availablefrom the other vertebrate groups, where similar studieshave yet to be performed.

B. Fish

1. Chemoreceptors

Oxygen-sensitive chemoreceptors exert dominantcontrol over cardiorespiratory reflexes in fish. The typicalresponse to ambient hypoxia is a reflex bradycardia andincreased ventilatory effort (607). Many studies supportthe existence of peripheral oxygen receptors on or nearthe gills of fish, and these were recently reviewed (93).However, the precise anatomical sites and functionalproperties of these peripheral chemoreceptors in fish re-main uncertain. Saunders and Sutterlin (551) observed anincrease in “breathing amplitude” in the sea raven whenthe dorsal aorta was perfused with hypoxic blood, andalso when perfusing the dorsal aorta with normoxic bloodduring ambient hypoxia, which they regarded as evidencefor both central and peripheral sites of oxygen receptoractivity. In the sturgeon, cyanide stimulated ventilation,both when added to inspired water and when injectedintra-arterially, indicating the presence of oxygen recep-tors sensitive to both internal and external milieu (425). Incontrast, Eclancher and Dejours (182) observed a venti-latory and cardiac response only to an intravascular in-jection of cyanide; no response was evident to cyanide inthe ventilatory water stream of teleosts, indicating thatthe PO2 receptors are located internally. Daxboeck andHoleton (159) found that irrigation of the anterior regionof the respiratory tract of the trout with hypoxic watercaused a reflex bradycardia but no change in ventilation,whereas McKenzie et al. (425) found that cyanide addedto the water stimulated a transient bradycardia in thesturgeon, whereas intra-arterial infusion was without ef-fect on heart rate, implying that different receptors areinvolved in the induction of the two overt responses tohypoxic exposure. Ventilation rate in trout varied in-versely with blood oxygen content, independently of par-tial pressure, indicating that arterial receptors respond torate of delivery of oxygen to the receptor site (511). Thereis some evidence for receptor sites outside the branchialapparatus, including the proposed existence of venous

oxygen receptors in fish (50, 617). Alternatively, Bamford(36) concluded that the most important site of oxygendetection in the trout is the brain.

The gill arches in fishes are innervated by cranialnerves IX and X, and it is these nerves that innervate thecarotid and aortic bodies of mammals. Bilateral section ofIX and X abolished the hypoxic bradycardia in the trout(584) but did not in elasmobranchs (547). Butler et al.(103) found it necessary to bilaterally section cranialnerves V, VII, IX, and X to abolish the hypoxic bradycardiain the dogfish and concluded that the oxygen receptorsare distributed diffusely in the orobranchial and para-branchial cavities. Laurent et al. (384) recorded oxygenchemoreceptor activity from branches of cranial nerve IXinnervating the pseudobranch in the tench. This organ isderived from the spiracle, which is open in elasmo-branchs, and because it receives arterialized blood flow-ing from the gills, it is ideally suited to monitor bloodoxygen levels. Although Smith and Davie (583) concludedthat oxygen receptors were innervated by the IXth cranialnerve in the salmon, bilateral denervation of the pseudo-branch in the trout had no effect on the changes inventilation volume after exposure to hypoxia and hyper-oxia (514). Afferent activity has been recorded from thebranchial branch of the vagus innervating the first gillarch of tuna and trout (93, 443). Receptors that increasedtheir rate of discharge in response to a decrease in therate of perfusion or oxygen level of the perfusate alsoresponded to ambient hypoxia. Fibers responding to hy-poxic water showed an exponential increase in rate ofdischarge to decreasing external oxygen partial pressure,with a sensitivity similar to that exhibited by mammaliancarotid body chemoreceptors (93).

Although fish have been shown to respond to hyper-capnia, there is no clear evidence of a role for centralchemoreceptors in the control of ventilation in fish (93,232, 512). Although hypercapnic acidosis stimulated ven-tilation in channel catfish, Ictalurus punctatus (92), theresponse was abolished by branchial denervation, indicat-ing that it resulted from stimulation of peripheral chemo-receptors, innervated by cranial nerves IX and X. Thesemay be the same receptors that respond to oxygen. Mam-malian carotid and aortic receptors respond both to oxy-gen and CO2/pH (571).

Similarly, there is no evidence that chemoreceptorstimulation produces behavioral arousal in fish similar tothe visceral alerting response that accompanies the stim-ulation of carotid chemoreceptors in mammals (415, 416).In fact, the unrestrained dogfish responds to environmen-tal hypoxia with a reduction in activity, which remainssuppressed throughout the hypoxic period, despite anincrease in circulating catecholamines (431). This is anal-ogous to the “playing dead” response shown by manyanimals, including some mammals (see Ref. 319), andwould seem to be the opposite of a defense or alerting


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response. The absence of clear visceral alerting or barore-ceptor responses in dogfish (see sect. IIIB2) precludestheir interference in chemoreceptor-induced changes inventilation or heart rate.

2. Mechanoreceptors

The respiratory muscles in fish contain length andtension receptors, in common with other vertebrate mus-cles, and the gill arches bear a number of mechanorecep-tors with various functional characteristics. Satchell andWay (550) characterized mechanoreceptors on thebranchial processes of the dogfish, and Sutterlin andSaunders (598) described receptors on the gill filamentsand gill rakers of the sea raven. De Graaf and Ballintinjn(163, 164) described slowly adapting position receptorson the gill arches and phasic receptors on the gill fila-ments and rakers of the carp. They interpreted their func-tion as maintenance of the gill sieve and detection of andprotection from clogging or damaging material. Mechan-ical stimulation of the gill arches is known to elicit the“cough” reflex in fish (e.g., Ref. 547) and a reflex brady-cardia (430, 604). These mechanoreceptors will be stim-ulated by the ventilatory movements of the gill arches andfilaments, but there is no direct evidence that they con-tribute to respiratory control on a breath-by-breath basis(93). Stimulation of branchial mechanoreceptors by in-creasing rates of water flow may be the trigger for thecessation of active ventilatory movements during “ramventilation” in fish (306, 511).

Despite the early recordings of apparent pressore-ceptor responses in elasmobranch fish (e.g., Ref. 293),evidence for the involvement of baroreceptors in vasomo-tor control in fish remains contentious. The evolution of arole for baroreceptor afferents and for vasomotor control,exercised via the sympathetic nervous system, in controlof the cardiovascular system, may be associated with theevolution of air-breathing. The gills of fish are supportedby their neutral buoyancy in water. Ventilation of the gillsgenerates hydrostatic pressures that fluctuate around, butpredominantly above, ambient. Arterial blood pressuresin the branchial circulation of fish and the pressure dif-ference across the gill epithelia are relatively low, despitethe fact that the highest systolic pressures are generatedin the ventral aorta, which leaves the heart to supply theafferent branchial arteries. Consequently, the need forfunctional baroreceptors in fish is not clear.

Increased arterial pressure has been shown to induce abradycardia in both elasmobranchs (409, 410) and teleosts(457). However, in both cases, the increase in pressurerequired to cause a significant reduction in heart rate wasrelatively high (10–30 mmHg), and dogfish seem not tocontrol arterial pressure after withdrawal of blood (50, 595).In teleosts, injection of epinephrine, which raised arterialpressure, caused a bradycardia, abolished by atropine (516),

whereas low-frequency oscillations in blood pressure, simi-lar to the Mayer waves in mammals, were abolished byinjection of the a-adrenoreceptor antagonist yohimbine(659). These data imply active regulation of vasomotor tone,and the balance of evidence indicates that functional arterialbaroreceptors may exist in the branchial circulation ofteleost fishes (24, 93).

The branchial branches of cranial nerves IX and Xprovide the afferent arm for the reflex changes in venti-lation and heart rate after stimulation of the gill arches orincreases in arterial pressure. Central stimulation ofbranchial nerves in both elasmobranchs (409, 668) andteleosts (456) caused a bradycardia. However, this couldhave stimulated mechanoreceptor and/or chemoreceptorafferents (see above). Afferent information reaching thebrain in the IXth and Xth cranial nerves is also known toinfluence the respiratory rhythm, with fictive breathingrate slowing in teleosts and increasing in elasmobranchsafter transection of the branchial nerves or paralysis ofthe ventilatory muscles (29, 52, 306). Central stimulationof branchial branches of the vagus in the dogfish withbursts of electrical pulses entrained the efferent activityin neighboring branchial and cardiac branches (607). Theentrained activity in the cardiac vagus drove the heart atrates either slower or faster than its intrinsic rate (seesect. VIB).

The branchial branches of cranial nerves IXth andXth supplying the gill arches of fish project to the sensorynuclei lying dorsally and laterally above the sulcus limi-tans of His immediately above the equivalent motor nucleiin the medulla. These have an overlapping, sequentialrostrocaudal distribution in the brain stem. Other thanthis generalization, the central projections of the sensoryafferents contributing to cardioventilatory control in fishhave not been identified (93).

C. Air-Breathing Fish

It has generally been considered that hypoxia, con-sequent upon stagnation of tropical freshwater habitats,was the environmental spur for the evolution, in the De-vonian era, of the ABO of air-breathing fishes. A contraryview proposes that lungs evolved in vertebrates primarilyto supply oxygen to the heart, before the evolution of thecoronary vessels (193). Stimuli for air-breathing in fishinclude hypoxia and hypercapnia, both modulated by in-creased temperature and exercise, which increase oxygendemand and CO2 production (306, 513, 575, 577). It is notyet established whether the increases in air-breathingobserved under these circumstances are stimulated bychanges in oxygen availability, delivery, or demand orwhether there are also responses to changes in blood pHor PCO2. However, in the bowfin Amia calva, there isevidence that air-breathing is only stimulated by changes


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in water or blood oxygen status, not by changes in plasmaacid-base status (422), and further evidence suggests thatbowfin do not possess any central chemosensitivity con-trolling gill ventilation or air-breathing (265).

Application of the oxygen chemoreceptor stimulantsodium cyanide (NaCN) into the ventilatory water streamof longnose gar (Lepisosteus osseus) inhibits gill ventila-tion and elicits air breathing, whereas NaCN given intothe bloodstream (dorsal aorta) stimulates both gill venti-lation and air-breathing (579). In the bowfin, only exter-nally applied NaCN elicits air-breathing, whereas bothexternal and internal NaCN stimulate gill ventilation(423). Both gar and bowfin utilize a well-vascularizedswimbladder as an ABO, and there are, to date, very fewstudies on the distribution of receptors stimulating air-breathing in fish that use other types of ABO. In theobligate air-breather the African lungfish, there are air-breathing responses to both internally and externally ap-plied NaCN (376), whereas in the facultative air-breatherAncistrus, which possesses suprabranchial chambers,hypoxia stimulates air-breathing but increased tempera-ture and exercise do not (231).

The sites and afferent innervation of oxygen-sensi-tive chemoreceptors that stimulate gill ventilation andair-breathing have been studied in various species of garand in the bowfin. They are found diffusely distributed inthe gills and pseudobranch, innervated by cranial nervesVII, IX, and X (423, 574, 579). In gar and bowfin, gilldenervation (with pseudobranch ablation in the lattercase) almost completely abolished air-breathing in nor-moxia and abolished responses to hypoxia and NaCN(423, 574), indicating that such responses are indeed de-pendent on afferent (oxygen chemoreceptor) feedback(568, 575, 577). Smatresk et al. (579) suggested that in garthere is central integration of input from internally andexternally oriented receptors whereby internal receptorsset the level of hypoxic drive and external receptors setthe balance between air-breathing and gill ventilation.

Air-breathing can also be stimulated by other factors,such as water-borne irritants (576) and stretch receptorsin the ABO (221, 266, 578). Stretch receptors in the swim-bladder of another primitive actinopterygian, the spottedgar (Lepisosteus oculatus), exhibit sensitivity to CO2

(578).There is no experimental evidence for baroreceptor

responses in air-breathing fish. Most air-breathing fishsupply their various ABO from the systemic circulation.Lungfish and all of the tetrapods have distinct pulmonaryarteries and veins in association with true lungs, havinghighly permeable surfaces; the lungfish Protopterus has adiffusion distance of 0.5 mm over the ABO, which issimilar to the mammalian lung (458). However, possiblybecause they retain gills, lungfish have similar, relativelylow blood pressures in the respiratory and systemic cir-cuits and may as a consequence not have a functional

requirement for baroreceptor responses to protect theirlungs against edema, resulting from hypertension. It couldof course be argued that control of blood pressure in arelatively low pressure system requires sensitive presso-reception. This remains to be demonstrated.

D. Amphibians

1. Chemoreceptors

In their detailed review (650), West and Van Vlietconsidered the roles of peripheral chemoreceptors andbaroreceptors in cardiorespiratory control in amphibians,while the factors influencing the progressive transitionfrom water to air-breathing during amphibian metamor-phosis were reviewed by Burggren and Infantino (90).Although chemoreceptive responses have been describedpreviously, the specific role of peripheral oxygen recep-tors in the regulation of breathing in amphibians has onlyrecently been identified (79). Jia and Burggren (304) mea-sured the time course of reflex changes in ventilation inunanesthetized larval bullfrogs at various developmentalstages. Inspiration of hypoxic water or NaCN causedrapid increases in the rate of gill ventilation, whereashyperoxic water reduced ventilation. These rapid re-sponses to hypoxia were eliminated by ablation of thefirst gill arches, suggesting that they are the site of theoxygen-sensitive chemoreceptors (305). A residual slowresponse was interpreted as stimulation of a second pop-ulation of receptors, possibly monitoring the cerebrospi-nal fluid (CSF). The rapid responses to hypoxia areblunted in later stage bullfrog larvae, in which the lungsare developing and the gills degenerating (304). In anearlier study of the bimodally breathing bullfrog tadpole,mild aquatic hypoxia was found to increase gill ventila-tion, but more severe hypoxia promoted high frequenciesof lung ventilation and a suppression of gill ventilation(645), which was in response both to lung inflation per seand the resulting increase in PO2 (646).

In the neotenous, gill-bearing axolotl, Ambystoma

mexicanum, both gill ventilation and air-breathing werestimulated by cyanide, infused either into the ventilatorywater stream or into the bloodstream (424). Cardiac re-sponses were complex with an initial bradycardia, pre-sumably in response to stimulation of peripheral chemo-receptors, followed by a tachycardia at the first air breath,possibly in response to stimulation of lung stretch recep-tors, a situation comparable to the mammalian responseto hypoxia (144, 145). Heart rate in the bullfrog tadpoledid not change during aquatic hypoxia, with access to air(645).

Although their larvae may retain functional oxygenreceptors on the gill arches, the carotid labyrinths areputative sites for oxygen receptors in adult amphibians.They are situated at the bifurcation of the internal and


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external carotid arteries and innervated by branches ofthe glossopharyngeal nerve, which projects its afferentfibers to the NTS in the brain stem (594). These receptorsare functionally similar to the mammalian carotid bodies,as they also respond to hypercapnia, and their dischargecan be modulated by sympathetic stimulation (294, 295).More recent studies have also shown that the receptorsare sensitive to oxygen partial pressure, rather than con-tent (650), a finding consistent with the results of wholeanimal study of the stimulus modality of the hypoxicventilatory response in toads (639). Elevated arterial lev-els of CO2/H1 increase discharge rate from the carotidlabyrinth of toads (650).

Although carotid labyrinth denervation caused a signif-icant reduction of resting ventilatory activity, in comparisonwith sham-denervated animals, it had no significant effect onthe ventilatory response to hypoxia in Xenopus laevis orBufo marinus (190, 649). These findings indicate that thecarotid labyrinth influences respiratory drive but is not es-sential for the control of ventilation during hypoxia in an-urans. Given that hypoxia is a poor ventilatory stimulant infrogs, it is not surprising that the current consensus, fromstudies performed on whole conscious animals, tends tominimize the importance initially accorded to the carotidlabyrinth in the regulation of ventilation. However, blood gaslevels in adult amphibians are not determined solely by ratesof lung ventilation; instead, the degree of shunting of bloodthrough the pulmonary circuit and/or the cutaneous vesselsmay have a major role in determining oxygen and CO2 levels.The degree of shunting is likely to be referred to input fromperipheral chemoreceptors. In the adult bullfrog, moreblood is directed toward the lungs during aquatic hypoxia,while aerial hypoxia elicits an increase in cutaneous perfu-sion (80). The return of blood to the right side of the heartfrom the cutaneous circulation may specifically serve toimprove oxygen supply to the myocardium, which in am-phibians is devoid of a coronary circulation (193).

Other putative oxygen-chemosensitive areas associ-ated with the aortic trunk have been identified in toads(294, 631). Furthermore, it appears that the pulmocutane-ous arteries of anurans may also be the site of an intra-arterial chemoreceptive zone. Injection of NaCN into thepulmocutaneous arches of anesthetized bullfrogs andconscious toads stimulated ventilation (398, 631). In theabsence of recordings from pulmocutaneous chemore-ceptors, however, the role of the pulmocutaneous arteryas a chemoreceptive site in amphibians is conjecture(650). The relative contribution of the latter two chemo-receptive sites to the hypoxic ventilatory or cardiovascu-lar responses in amphibians is yet to be investigated.

2. CO2/H1 receptors

Perfusion of the brain in anesthetized toads withartificial CSF having low pH/high CO2 significantly in-

creased ventilation in normoxia (580). A similar responsewas recorded from the in vitro preparation of the bullfrogbrain stem (355, 451). It appears that, as in most verte-brates (other than some fish) investigated thus far, toadshave central chemoreceptors, probably located on theventral surface of the medulla, which respond to acidic/hypercapnic challenge. Repeating these experiments inunanesthetized animals (85) indicated that the contribu-tion of peripheral receptors to respiratory drive was sec-ondary to the role of central chemoreceptors that contrib-uted ;80% of the total hypercapnic respiratory drive inthe toad, a similar proportion to that observed in mam-mals.

This dominant role for central chemoreceptors in thegeneration of respiratory drive in amphibians appears atmetamorphosis. An in vitro preparation of the isolatedbrain stem from the bullfrog tadpole displayed coordi-nated, rhythmic bursting activity in cranial nerves V, VII,and X, which could be characterized as representing fic-tive gill or lung ventilation. In early stage larvae, varia-tions in pH of the superfusate were without effect on gillor lung burst frequency. Later stage larvae showed anincreasing predominance of neural lung burst activity,which markedly increased in acid pH (625). The onset ofepisodic breathing patterns during metamorphosis wascoincident with developmental changes in the nucleusisthmi in the bullfrog, and it seems possible that thisregion of the brain stem is involved in integration ofcentral chemoreceptor information (354).

3. Pulmonary stretch receptors

Pulmonary stretch receptors (PSR) constitute an-other important source of feedback, contributing to thecontrol of breathing in amphibians. There are three dif-ferent types of PSR in amphibians responding to 1) thedegree of lung inflation, 2) the rate at which lung volumechanges, or 3) both stimuli (312, 444). These receptors areinnervated by afferent fibers in the pulmonary vagii (312,444) that project to the solitary tract in the brain stem(594). The receptors are mostly slowly adapting, and theirfiring rates decrease when the intrapulmonary CO2 con-centration is increased (371, 444). Although pure chemo-receptors sensitive to CO2 have not been identified in thelungs of frogs, the discharge of stretch receptors is suffi-ciently modulated by CO2 to have noticeable effects onthe breathing pattern. Vagotomy abolished the increase inbreathing frequency that anuran amphibians usually ex-hibit during hypercarbia (85, 580, 649), suggesting thatpulmonary vagal input is necessary for the production ofnormal respiratory chemoreflexes.

Pulmonary afferent fibers play a key role in the ter-mination of lung inflation in the adult and inhibition ofbuccal oscillation in the premetamorphic tadpoles. Theevidence is that pulmonary deafferentation by vagotomy


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in Xenopus results in an increase in the number of inspi-rations in a ventilatory period and overinflation of thelungs (190). Sectioning the pulmonary branch of the vagusnerve leads to an increase in the amplitude and frequencyof resting ventilation in the bullfrog (358, 359), indicatingthat PSR feedback modulates breathing pattern; however,these data also suggest that PSR feedback is not respon-sible for the onset/termination of the breathing episodes.This matter remains unresolved as recent studies of de-cerebrate, paralyzed anurans showed that lung inflationinhibited fictive breathing (364, 640), as would be pre-dicted from work on mammals, while another study, of asimilar preparation, indicated that lung inflation stimu-lated fictive breathing (359).

Amphibians that breath discontinuously, often in as-sociation with periods of submersion, typically displaylarge increases in heart rate and pulmonary blood flow atthe onset of bouts of lung ventilation. However, the con-tribution of lung stretch receptors to this response is notresolved (650). Whereas artificial lung inflation increasedheart rate in anesthetized toads, in conscious Xenopus

laevis, denervation of PSR did not abolish the increase inheart rate associated with lung inflation (190), and inlightly anesthetized animals, artificial lung inflation didnot affect heart rate, though pulmocutaneous blood flowincreased, presumably due to shunting (186). A similarresponse was demonstrated in Bufo marinus (647).

E. Reptiles

1. Peripheral oxygen receptors

Scattered groups of glomus cells have been identifiedin the connective tissue surrounding the main and collat-eral branches of the carotid arteries in lizards. This area isprofusely innervated by the superior laryngeal branch ofthe vagus nerve (535) and possibly the glossopharyngealnerve (4). Although activity in these putative receptorshas not been recorded, denervation of this area abolishedthe increase in ventilation shown by lizards when hypoxicor hypercapnic blood was injected into the carotid arch(130). In turtles, chemoreceptive tissue has been locatedon the aortic arch innervated by the superior and inferiorbranches of the vagus nerve (295). The former nerve isthought to correspond to the aortic nerve of mammals,whereas the latter arises from the ganglion trunci of thevagus. The inferior branch also innervates chemorecep-tors located on the pulmocutaneous artery of the turtle (3,298). These receptor groups have been shown to respondto changes in oxygen level, but their roles in establishingresting ventilatory drive or in reflex responses to hypoxiaare unknown (440). All primary afferent fibers of theglossopharyngeal and the majority of vagal afferent fibersenter the NTS in the monitor lizard (38).

Oxygen uptake in reptiles is dependent on PO2 down

to a critical level, below which aerobic metabolism isdepressed (439). This critical PO2 varies with temperatureand can be correlated with changes in the relative affinityfor oxygen (measured as P50) of the animal’s hemoglobin(568). Species having hemoglobin with a relatively highaffinity for oxygen, such as the turtle Chrysemys picta

(229), have greater hypoxic tolerance, and therefore alower threshold, but often show a more marked ventila-tory response at threshold than species having loweraffinity hemoglobin, such as the lizard Lacerta viridis

(466). Current theory suggests a role for heme protein inthe functioning of peripheral chemoreceptors (442).These data suggest that the peripheral oxygen receptorsrespond to a reduction in oxygen content (i.e., hypox-emia) or to rate of delivery of oxygen to the receptor,which includes blood flow, rather than to systemic hyp-oxia (i.e., a reduction in PO2). Similar characteristics havebeen attributed to arterial chemoreceptors in fish (511,512) and in birds and mammals (440).

Reptiles, in common with some air-breathing fish andamphibians, have pulmonary and systemic circulationsthat are incompletely separated so that some systemicvenous blood can bypass the lungs to reenter the systemiccirculation, while some arterialized blood can reenter thepulmonary circulation. Consequently, arterial blood gascomposition is affected by the degree of admixture ofoxygenated arterialized blood and oxygen-depleted ve-nous blood, rather than lung gas composition alone, as itis in mammals. This presents the intriguing possibilitythat regulation of these central vascular shunts, with ref-erence to peripheral chemoreceptors, may play an impor-tant role in control of arterial blood gas composition inreptiles, independent of ventilatory control (88, 640).

2. CO2/H1 receptors

The hypercapnic ventilatory response is well devel-oped in reptiles, and changes in PaCO2

rather than PaO2

provide the dominant drive to breathe (439, 441). Centralchemical control of ventilation in an ectothermic, air-breathing vertebrate was first demonstrated in the un-anesthetized turtle, Pseudemys scripta elegans (271). Per-fusion of the lateral and fourth cerebral ventricles withartificial CSF caused an increase in ventilation to fourtimes control, following a calculated pH change of only0.02 units. Inhalation of gas mixtures enriched with CO2

stimulates ventilation and affects pulmonary vagal activ-ity in crocodilians (441, 503). It causes ventilation volumeto rise, decreases periods of breath hold, and increasesthe number of breaths in each breathing episode. Snakesand lizards may respond to environmental hypercarbia,which stimulates lung receptors, with decreased ventila-tion but show a marked increase in response to venousCO2 loading (441).


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F. Birds

1. Peripheral oxygen receptors

In birds, chemoreceptive tissue is concentratedaround the common carotid arteries, close to the thyroidglands, and is innervated by vagal branches from thenodose ganglion (1). These receptors are thought to behomologous to the carotid bodies of mammals (459).Glomus tissue, which may be homologous to the aorticbodies of mammals, has been described within the aorticwalls of birds (618), and a recording from a putative aorticchemoreceptor in a duck has been reported (483). Allreceptors respond to changes in PO2, but in some birds,the threshold for a hypoxic ventilatory response is morestrongly correlated with blood oxygen content (78). Thecarotid chemoreceptors contribute to resting ventilatorydrive and may be solely responsible for reflex responsesto hypoxia or hyperoxia (81). Hypoxia stimulates breath-ing in conscious, anesthetized, or decerebrate birds (553).There are species differences in oxygen chemosensitivity.For example, Pekin ducks showed a much higher cardiacchronotropic sensitivity to hypoxia during forcible sub-mergence than Canada geese (590).

2. CO2/pH

In birds, as in reptiles and mammals, the reflex ef-fects of central chemoreceptor stimulation, followingchanges in PaCO2

or arterial pH, appear to predominateover all other receptor inputs. Cerebral perfusion and/ordenervation of peripheral receptors in ducks indicatedthat central chemoreceptors are primarily responsible forresting respiratory drive as well as reflex responses tohypercapnia and acidosis (445). As in mammals, the glo-mus tissue associated with oxygen chemoreception isalso sensitive to changes in CO2 or pH. In addition, birdspossess intrapulmonary chemoreceptors that show dis-charge rates inversely proportional to the level of CO2 ininhaled gas mixtures (553). They are located within thelung, innervated by the vagus nerve and to some extent bythe cardiac sympathetic nerve (187). These receptors aresilenced by high levels of CO2 in the airway but areinsensitive to changing PO2, and their responses tochanges in lung volume or pressure are not significantwithin physiological limits (198, 199, 553). Thus, unlikemammals, lung stretch receptor inputs are not importantin the regulation of breathing or cardiorespiratory inter-actions in birds. This relates to the fundamental morpho-logical and functional characteristics of the compact birdlung, which is ventilated unidirectionally by volumechanges in the air sacs and is not itself stretched (553).

Because some birds, like the bar-headed goose,Anser indicus, fly to extremely high altitudes, they regu-larly undertake exercise in hypobaric hypoxia (97). Theiradaptations to this environment include increased heart

size and blood oxygen affinity, compared with other birdsor with mammals. They have been found to maintainarterialized blood PO2 very close to inspired levels inhypoxia, by effective hyperventilation, with an associatedreduction in blood PCO2 and a respiratory alkalosis. This isachieved without the reduction in cerebral blood flowtypically associated with hypocapnia in mammals, andindeed, hypoxia causes a greater increase in cerebralblood flow than is observed in mammals so that bloodflow to the brain may be maintained at high altitude. Acritical difference between these high-flying birds andother birds or mammals appears to be their greater toler-ance of hypocapnia, which is likely to reside at the level oftheir central chemoreceptors in the brain.

IV. CRANIAL AUTONOMIC INNERVATION

OF THE CARDIORESPIRATORY SYSTEM

A. Mammals

1. Topography of the vagal motor column

The central origin of the motor fibers innervating theheart and airways in mammals has been well documentedby localizing the retrograde labeling following applicationof HRP or a conjugate to either the whole vagus nerve, itsindividual branches, or directly into the relevant targets.Neurons with vagally projecting axons are found predom-inantly ipsilaterally in both vagal motor nuclei, the DVNand the nA, and in the region joining these two, theintermediate zone.

The nA, as its name implies, is a diffuse region ex-tending throughout the ventrolateral medulla, from thelevel of the facial nucleus to the first cervical segment ofthe spinal column. It has been described by several au-thors, and the terminology used was somewhat confusinguntil a study in the rat (68) resulted in a description whichis beginning to be used by other authors and will be usedhere. The nuclear regions of the nA are defined on thebasis of the location of neurons projecting in the glosso-pharyngeal and vagal nerves and their branches. Thereare two major longitudinal divisions of the nucleus. Thedorsal division has three subdivisions, the compact, semi-compact, and loose divisions (rostral to caudal, respec-tively), and comprises the somatomotor innervation ofthe pharyngeal and thoracic viscera. The ventral externalformation comprises parasympathetic preganglionic neu-rons. The different subdivisions can be discerned by thesize of the neurons, their dendritic organization, and theprojection of their axons. There is less distinction in thesubregions of the DVN (206), but some differences doexist, and there are suggestions of a topographical local-ization of DVN neurons, based on target organ. Even ifsuch an organization exists, the dendritic fields of many


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DVN neurons are very extensive, often projecting intoadjacent DVN subnuclei or other medullary nuclei such asthe NTS (206, 562).

Vagal-projecting neurons are found throughout thedorsal nA and in the external division ventrolateral to theprincipal column. They are densest in the DVN and extendlateral to its boundaries into the region bordering the NTSand the reticular formation between it and the nA. Asimilar distribution of vagal-projecting neurons has beendescribed in rats (126, 340), cats (336), dogs (116), ferretsand mink (522), neonatal pigs (276), and Old and NewWorld monkeys (257). The central distribution of vagalmotoneurons includes those innervating both intratho-racic and abdominal organs, but there is no certainty thatindividual organs are represented at all sites. More spe-cific studies have examined the possibility that there is atopographic organization based on the organ of innerva-tion. Although the overall pattern of labeling is similar, thedetailed organization of the innervations do differ be-tween species.

2. Innervation of the heart

In a number of studies, tracers have been applied tothe cardiac vagal branches or to the heart itself. Althoughsome neurons in the DVN and intermediate zone werelabeled, it is clear that the region of the nA provided themajor cardiac innervation in most mammals. In rats (298,446, 479, 480, 593), cats (59, 117, 222, 223, 330, 337, 449,596), dogs (59, 274, 275, 500), and neonatal pigs (276), themajority of labeled neurons were located in the externalsubnucleus of the nA. Neurons within the compact regionof the nA, if labeled, were always in the minority. Whenthe DVN was labeled, it was usually the lateral and dorsalregions that contained the majority of labeled cells. Therelative contribution of DVN and nA to the cardiac vagiseems to vary between species. The DVN contains rela-tively more cardiac-projecting neurons in rats, and least inpigs and dogs, with cats lying somewhere in between. Inthe cat (59, 330), cardiac VPN (CVPN) are found predom-inantly in the nA, with up to 78% of cardiac neurons foundin this location. This compares with 45% of CVPN locatedventrolaterally in the dogfish and ;30% in Xenopus, indi-cating that in mammals, compared with lower verte-brates, a greater proportion of cardiac vagal motoneuronsoriginate in this division. However, the ventrolateralgroup of vagal perganglionic neurons in the dogfish are allCVPN (see sect. IVC). Only one set of studies in cats (623,624) denied the role of the nA in cardiac control, but thishas not been confirmed.

3. Innervation of the airways

Similar anatomical studies have delineated the motorinnervation of the airways in air-breathing mammals. Be-cause these have been described in detail recently (322),

only a summary is provided here. In rats, Bieger andHopkins (68) demonstrated that the compact region of thenA contained esophageal motoneurons, whereas pharyn-geal motoneurons were located in both the more caudalsemicompact formation and in a group of neurons rostralto the compact group and overlying the facial nucleus.Glossopharyngeal motoneurons were also found at thislatter site and in the external formation where laryngealmotoneurons were also localized in addition to rostralpart of the semicompact formation and the dorsal part ofthe caudal compact formation. The external and dorsaldivisions differ in that the latter innervates striated mus-cles of the esophagus, larynx, and pharynx, whereas theformer is the origin of parasympathetic preganglionicneurons. A similar localization of motoneurons innervat-ing the rat esophagus, pharynx, and cricothyroid musclehas been demonstrated (10). Preganglionic neurons inner-vating the trachea are located in the compact formation,in the area ventral to it, and in the rostral part of themedial NTS, but not in the DVN (263). This description ofthe nuclear arrangement of the rat nA is similar to thatdescribed in rabbits (296, 385, 386) and cats (242, 336, 337,478, 479). The ambigual origin of the laryngeal motorinnervation was confirmed, with some cells also beinglabeled in the rostral DVN. Neurons innervating the tra-chea overlapped those innervating the larynx in the ros-tral nA. In addition, cells in the nucleus retroambigualiscaudal to the obex also provided an innervation of theextrathoracic trachea, whereas the DVN at around obexlevel provided some innervation of the intrathoracic tra-chea. Bronchial motoneurons were found mainly in theDVN, with limited numbers in the rostral nA, whereasthose labeled following injections into lung tissue werelocated in both DVN and nA. This was partly confirmedwhen tracer was applied to the individual pulmonarybranches of the vagus in cats (59, 330). Labeled neurons inthe nA were found over a 10-mm distance spanning theobex in the external formation, but there was a trough inthe distribution of the cells projecting to the pulmonarybranches between 1 and 3 mm rostral to obex, whereneurons projecting to the cardiac branches were located(Fig. 5). These pulmonary neurons outnumbered thoselabeled in the lateral DVN. Thus, in the cat, both pulmo-nary (68%) and cardiac (78%) VPN are found predomi-nantly in the nA (330). The labeling seen in dogs, follow-ing tracers applied to the superior or recurrent laryngealnerves (638) or pulmonary branches of the vagus (57,261), is not unlike that described in cats.

B. Cyclostomes

The heart of myxinoids is aneural, that is, it is notinnervated by the vagus or the sympathetic nervous sys-tem (115, 237), whereas the heart of the lamprey (al-


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though similarly devoid of a sympathetic supply) is inner-vated by the vagus (19, 521). The cardiac fibers leave thethin nonmyelinated epibranchial trunk of the vagus andrun to the median jugular vein. In the wall of this vein, thenerve fibers form a loose network with one or two mainbundles (192).

The main effect of vagal stimulation in lampetroids isan acceleration of the heart with an accompanying de-crease in the force of contraction (191). Acetylcholineinduces an acceleration of the heart, a response uniqueamong vertebrates. Nicotinic cholinoceptor agonists,such as nicotine, have the same effect (19, 191). Theexcitatory effect of vagal stimulation or nicotinic agonistscan be blocked by nicotinic cholinoceptor antagonistssuch as tubocurarine and hexamethonium (19, 191, 405).

According to Ariens Kappers (16, 17), the CNS of thecyclostomes represents the prototype of the vertebratebrain. The hindbrain is identical in superficial appearanceto that of the rest of the vertebrates, with vagal rootletsleaving on either side to innervate the viscera. No studyhas been made of the topographical representation ofvagally innervated structures within the vagal motor col-umn of cyclostomes. In Lampetra, two separate divisionsof the vagal motor column have been identified usingnormal staining techniques: a rostral and a caudal motornucleus of X (467). The caudal motor nucleus of X, whichcannot be delineated from the spinal visceromotor cells,is thought to represent a splanchnic center, and the ros-tral nucleus is considered to be branchiomotor in nature(i.e., to innervate the branchial pouches) (5). The locationof the caudal motor nucleus in cyclostomes, which cen-ters around the obex, is similar to the region of the DVN

in the cat (59) and to the nucleus motorius nervi vagimedialis (Xmm) in the dogfish (53) in which the cellbodies contributing axons to the cardiac vagi are found.

C. Elasmobranch Fish

Innervation and control of the cardiorespiratory sys-tem in the cartilaginous elasmobranch fishes differs inimportant respects from that in the teleosts and in theair-breathing fishes. Accordingly, they are each describedseparately in the following account. The elasmobranchsare phylogenetically the earliest group of vertebrates inwhich a well-developed autonomic nervous system withclearly differentiated parasympathetic and sympatheticcomponents has been described (465). They are also theearliest group known to have an inhibitory vagal innerva-tion of the heart.

In the elasmobranch fish Scyliorhinus canicula, thevagus nerve divides to form, at its proximal end, branchialbranches 1, 2, 3, and 4 that contain skeletomotor fibersinnervating the intrinsic respiratory muscles of gill arches2, 3, 4, and 5, respectively (Fig. 1). The first gill arch isinnervated by the glossopharyngeal (IXth cranial) nerve.The vagus also sends, on each side of the fish, twobranches to the heart. One arises close to the origin of thevisceral branch of the vagus, the other from the post-trematic projection of the fourth branchial branch of thevagus (614). The two cardiac vagi pass down the ductusCuveri and then break up into an interwoven plexus onthe sinus venosus, terminating at the junction with theatrium (665). The sinoatrial node is thought to be the site

FIG. 5. Rostrocaudal distribution, with respect toobex, of vagal preganglionic motoneurons in medullaoblongata of cat. Neurons were retrogradely labeledwith horseradish peroxidase applied to cardiac or pul-monary branches of right vagus. Majority of labeledneurons are located ventrolaterally in region of nucleusambiguus, with the remainder located medially in thedorsal motor nucleus of the vagus.


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of the pacemaker in elasmobranch fishes (542, 551). Theremainder of the vagus is termed the visceral branch, andthis innervates the anterior part of the gut down to thepylorus and the anterior part of the spiral intestine (665).

Stimulation of the vagus nerve, as well as applicationof acetylcholine, has an inhibitory effect on heart rate.The effects are antagonized by atropine, implying that theeffect is mediated by muscarinic cholinoceptors as in thehigher vertebrates (99, 113, 308, 406–408, 614). Variationsin the degree of cholinergic vagal tonus on the heart, inthe absence of an adrenergic innervation (see sect. VC),serves as an important mode of nervous cardioregulationin elasmobranchs (50, 99, 614).

There are several historical studies, using classicneuranatomical techniques, of the gross location of thevagal motor nucleus in the hindbrain of elasmobranch fish(607, 658). The vagal motor nucleus was shown to consistof a continuous column of large, bipolar, tripolar, and(less frequently) quadripolar cells in conjunction with themotor nuclei of the IXth and VIIth cranial nerves (581,582). In the shark Cetorhinus and in the Holocephali,Addens (5) divided the vagal motor nucleus into separaterostral and caudal parts and suggested that the rostralportion is specialized to subserve either a visceromotor orbranchiomotor function, whereas the caudal portion rep-resents a general visceromotor or splanchnic center.Smeets et al. (582) observed that in Hydrolagus the vagalnucleus can readily be divided into a caudodorsal nucleusand a rostroventral nucleus, the latter being continuouswith the nuclei of IX and VII. In Raja, the same authorsnoted that the dorsal nucleus appeared to contain some-what smaller neurons than the ventral nucleus.

In Squalus, an area lateral to the caudal part of thevisceromotor column contains a distinct aggregation oflarge bipolar and triangular cells (581). These authorsconsidered this aggregation of cells represented a part ofthe motor nucleus of X and named it accordingly thenucleus motorius nervi vagi lateralis (Xml). The Xml ex-

tended from 2.0 mm rostral to ;4.0 mm caudal to theobex. The vagal part of the medial visceromotor columnwas designated the Xmm. The Xmm and Xml may, byvirtue of their locations, be the homologs of the mamma-lian DVN and nA, respectively (49, 581), and will be re-ferred to as such in the following descriptions of theirtopography and functional roles.

Retrograde intra-axonal transport of HRP alongbranches of the vagus nerve showed that the vagal motorcolumn of the dogfish, Scyliorhinus canicula, extendsover 5 mm in the hindbrain from 2 mm caudal to 3 mmrostral of obex (657). This agrees with the extent de-scribed by Smeets and Niewenhuys (581) for fish of sim-ilar size. Caudal to obex there appeared to be two distinctgroups of vagal motoneurons, the majority found dorso-medially, and a smaller ventromedial group, both close tothe lateral edge of the fourth ventricle. However, theventromedial group was continuous with cells in thespino-occipital motor nucleus and may constitute a for-ward extension of this nucleus, contributing axons to thehypobranchial nerve which innervates the ventral mus-cles of the orobranchial cavity (392). The majority ofvagal motoneurons caudal to obex contributed axons tothe visceral branch of the vagus including the visceralcardiac branch. Visceral cardiac motoneurons were foundsolely in the dorsomedial division of the vagal motorcolumn (i.e., the DVN).

Rostral to obex the medial motoneurons were nolonger distinguishable into dorsal and ventral divisions;instead, a single column of medial cells was found clus-tered close to the ventrolateral edge of the fourth ventri-cle (constituting the DVN). Most of the vagal motoneu-rons were found in the DVN, with the caudal one-thirdcontributing axons to the branchial cardiac branch and tothe visceral branch while the rostral two-thirds contrib-uted axons to the four branchial branches of the vagus(Fig. 6). There is a clear sequential topography in therostrocaudal distribution of the cell bodies supplying ax-

FIG. 6. Rostrocaudal distribution of vagalpreganglionic motoneurons with respect to obex inmedulla of dogfish, Scyliorhinus canicula. Majorityof labeled motoneurons are located medially in dor-sal vagal motor nucleus. A small number (8%) arelocated ventrolaterally and supply axons solely tobranchial cardiac branch of vagus innervatingheart. Medial cells supplying this nerve are indi-cated by unshaded portion of top histogram. Mo-toneurons supplying axons to branchial branches 1,2, and 3 (Br I to Br III) of vagus, innervating gillarches 2, 3, and 4, occupy rostral part of vagalmotor column, whereas more caudal motoneuronssupply axons sequentially to heart, esophagus, andstomach. [Modified from Taylor (607).]


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ons to each of the gill arches, with a small degree ofoverlap between the pools of neurons supplying adjacentbranches of the vagus (657). This sequential topographyextends rostrally so that visceromotoneurons supplyingaxons to the glossopharyngeal, IXth, facial, VIIth andmandibular, Vth cranial nerves, innervating respiratorymuscles, are distributed in discrete nuclei in a rostrocau-dal array (Fig. 2).

A clearly distinguishable group of cells was identifiedthat had a scattered ventrolateral distribution, outside theDVN, over a rostrocaudal extent of ;1 mm, rostrally fromobex. They contributed axons solely to the branchialcardiac branch of the vagus, innervating the heart (53, 49).Although the cells in this lateral division comprised only8% of the total population of VPN, they supplied 60% ofthe efferent axons running in the branchial cardiac nerve,with the other 40% supplied by cells in the rostromedialdivision. When the medial cells contributing efferent ax-ons to the heart, via the visceral cardiac branches, weretaken into account, then the lateral cells were found tosupply 45% of vagal efferent output to the heart. ThusCVPN providing axons to the branchial cardiac nerve arefound rostromedially in the elasmobranch equivalent ofthe DVN and solely comprise the lateral division or nA ofthe vagal motor column (Fig. 6). It is thought that this duallocation of CVPN has important functional implications(see sect. VIB).

D. Teleost Fish

In teleost fish, the vagus innervates the gills, theheart, and the viscera (pharynx, esophagus, stomach, andswimbladder). The cardiac branches of the vagi follow theductus Cuveri to the sinus venosus and atrium, but vagalfibers do not reach the ventricle. A ganglion in the vagalpathway lies close to the sinoatrial border and appears toconsist solely of nonadrenergic cell bodies (212, 272, 273,382, 545, 546, 664).

The vagus in teleosts is cardioinhibitory as in allvertebrates, with the exception of the cyclostomes. Thisinhibitory effect is due to the release of acetylcholineaffecting muscarinic cholinoceptors associated with thepacemaker and atrial musculature (110, 212, 272, 273, 509,516, 666). Although the negative inotropic influence of thevagi does not reach the ventricle, cardiac output is greatlyaffected by the inotropic control of the atrium, whichdirectly regulates the filling of the ventricle (307, 313),although this has recently been questioned (J. B. Graham,personal communication).

In contrast to elasmobranchs, where the branchialbranches of the vagus are solely skeletomotor (432), thebranchial branches in teleosts have both a vasomotor andskeletomotor function (493). The vagus supplies vasomo-tor fibers to the branchial circulation that have been

shown to innervate sphincters at the base of the efferentfilament arteries (470).

Early topological studies of the brain of teleosts iden-tified a single vagal motor nucleus (see Ref. 607). How-ever, application of HRP and immunocytochemistry re-vealed a lateral subnucleus of the vagal complex thatprovided axons to respiratory muscles in goldfish (452).Application of HRP to the whole vagus nerve and toselected branches of the vagus in cod (Gadus morhua)and rainbow trout revealed that vagal motoneurons werelocated over a distance of 2.8 mm in the ipsilateral hind-brain from 1.2 mm caudal to 1.6 mm rostral to obex andthat ;11% of these neurons were located ventrolaterally,whereas the others were found in a dorsomedial locationclustered close to the edge of the fourth ventricle, iden-tified as the DVN (658). The lateral group of vagal mo-toneurons was divided into two groups: a caudal groupextending for ;1 mm (from 0.75 mm caudal to 0.25 mmrostral of obex) and a more rostral group that extendedfor ;0.75 mm (0.75–1.5 mm rostral of obex). When HRPwas applied to the cardiac branch of the vagus, labeledneurons were found in the caudal lateral division as wellas in the DVN. The application of HRP to one of thebranchial branches of the vagus also labeled both lateraland dorsomedial cells, this time with the lateral cellslocated in the more rostral group of cells.

The identification of lateral CVPN in teleosts is sim-ilar to our findings in elasmobranchs. In contrast, how-ever, some branchial motoneurons are located in thelateral division in teleosts, whereas they are confined to amedial location in elasmobranchs. This may reflect theobservation that the branchial branches of the vagusserve both a vasomotor and skeletomotor function inteleosts but only a skeletomotor function in elasmo-branchs (see above) so that the medial neurons may giverise to skeletomotor fibers, whereas the lateral neuronsmay give rise to vasomotor fibers. This remains to bedemonstrated experimentally.

In teleosts, there is also a sequential topographicrepresentation of the vagus within the vagal motor col-umn. The most rostral neurons give rise to fibers supply-ing the most proximal organs (the gill arches), and thecaudal neurons give rise to fibers innervating the viscera.The cardiac neurons are located in the middle of the vagalmotor column (607). In both classes of fish in which thetopography of the vagal motor column has been studied,there is a sequential representation of the vagal branches.

E. Air-Breathing Fish

After application of HRP to the second and thirdbranchial branches of the vagus nerve in the bowfin,Amia calva (Fig. 7), retrogradely labeled cell bodies werefound in the DVN over a rostrocaudal distance of 4 mm


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either side of obex (613). There was a sequential topog-raphy in the distribution of the cell bodies innervatingbranchial nerves 2 and 3, as described in dogfish and cod(607). In addition, motor cell bodies were located in lat-eral locations outside the DVN as described in teleosts(e.g., cod) and all tetrapod vertebrates (608). In the bow-fin, some of these lateral cells were of an unusual appear-ance with large cell bodies and thick, branching den-drites. In one fish, anterograde labeling of the sensoryprojections of branchial branch 3 of the vagus was ob-served. This consisted of a diffuse array of fine dendritesand small cell bodies in the sensory vagal nucleus on thelaterodorsal edge of the fourth ventricle above the DVN,which extended for ;2 mm in the brain stem immediatelyrostral of obex.

Application of HRP to the nerve supplying the glottisand ABO revealed cell bodies in a ventrolateral location inthe brain stem and the ventral horn of the anterior spinalcord over a rostrocaudal distance of 5.3 mm, predomi-nantly caudal of obex (Fig. 7). From their location it ispossible to identify them as cell bodies that typicallysupply axons to the hypobranchial nerve (i.e., occipitaland anterior spinal nerves). Consequently, it is apparentthat the glottis and ABO are innervated by nerves of thehypobranchial complex, which provides nerves to ele-ments of musculature normally associated with feedingmovements in water-breathing fish. Given that feeding-type movements are implicated in air-breathing in bowfin(397; and see above), the observed hypobranchial inner-

vation of the glottis and ABO may imply nervous coordi-nation of air-gulping and glottal opening, which wouldensure effective ventilation of the swimbladder. Indeed,even in mammals, there are functional similarities and aclose connection between the central nervous mecha-nisms controlling breathing and those controlling swal-lowing (302).

Careful observation of the sections of bowfin brainafter application of HRP to the nerve supplying the glottisand ABO revealed an additional group of stained cellbodies that could be identified topographically as pregan-glionic vagal motoneurons in the DVN (613). This impliesthat there is a vagal element to the efferent innervation ofthe ABO, as described by Allis (8). These cell bodiesprobably provide efferent axons to smooth muscle in theswimbladder wall comparable to the vagal efferents con-trolling reflex bronchoconstriction in the mammalian lung(559). An afferent vagal supply to the ABO would seemaxiomatic but was not revealed by the study of Taylor etal. (613).

F. Amphibians

In adult air-breathing amphibians, the vagus inner-vates the hyoid apparatus and larynx, both structuresderived from the larval branchial arches. It then passes onto innervate the viscera, including the heart and lungs.The ventricle in the amphibian heart is completely undi-

FIG. 7. A diagrammatic representation of rostrocaudaldistribution either side of obex of cell bodies of pregan-glionic vagal motoneurons and ventral motoneurons sup-plying efferent axons to 2nd and 3rd branchial branches ofvagus, and to nerve supplying glottis and air-breathingorgan (ABO; swimbladder) in bowfin (Amia calva). Sen-sory projections to 3rd branchial branch of vagus are alsoshown (sensory). Horseradish peroxidase-labeled cellbodies were counted (at 60-mm intervals) from best back-fills of each branch in single preparations. Labeledbranchial vagal motoneurons were found in 2 locations(medial and lateral) in dorsal vagal motor nucleus (DVN).Labeled motoneurons supplying glottis and ABO consistedof 2 groups: a small one located rostral of obex in DVN anda much larger group of cells that was predominantly cau-dal of obex, in ventral hypobranchial motor nucleus. [Mod-ified from Taylor et al. (613).]


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vided and receives oxygen-depleted systemic blood fromthe right atrium plus oxygen-rich pulmonary blood fromthe left atrium. The proportion of the blood ejected fromthe heart at systole that enters either the pulmonary or thesystemic circuit is determined by the relative resistance toflow of each circuit, which is largely determined by thecontraction of a smooth muscle sphincter on the pulmo-cutaneous artery, innervated by the vagus nerve. Vagalstimulation both slows the heart and causes constrictionof the pulmocutaneous sphincter. Both responses are pri-marily cholinergic, although other transmitters such assomatostatin and galanin are coreleased from vagal nerveterminals at both sites (640).

The central topography of the vagal motor column inamphibians is of current interest. In the African clawedtoad Xenopus laevis, there are two cell groups in themedulla oblongata constituting the motor nuclei of thevagus and the glossopharyngeal nerves, one group in themost superficial zone of the central gray and a secondgroup more laterally in the white matter overlying thiscentral gray (468). A more recent study has confirmedthat VPN are located ipsilaterally in the hindbrain over adistance of 2.5 mm with ;32% of all cell bodies identified

in a ventrolateral location (640). Each target organ, in-cluding the heart and lungs, is innervated by VPN in boththe DVN and the nA (Fig. 8), in roughly similar propor-tions (i.e., ;2:1). The increase in the proportion of lateralVPN, over the condition described in fish, may be partiallyattributable to a change from gill to lung breathing (609).

As the amphibians metamorphose from an aquaticlarval stage to air-breathing adults, they provide an idealmodel for testing the hypothesis that progressive ventro-lateral location of VPN relates in part to the evolution/development of lung breathing (608). Of particular inter-est is the axolotl, Ambystoma mexicanum, which isneotenous. It retains larval features into the adult (i.e.,sexually mature) stage including external gills and gillclefts in the pharynx. The axolotl can be induced tometamorphose into a salamander-like animal by treat-ment with analogs of the hormone thyroxine, when theylose their gills and leave water to become committed lungbreathers. Before metamorphosis, all VPN are in a medialnucleus within the central gray representing the DVN, andthere is a clear sequential rostrocaudal distribution ofVPN supplying the first, second, and third branchialbranches of the vagus rostral of obex, reminiscent of the

FIG. 8. Rostrocaudal distribution of preganglionic vagal motoneurons either side of obex in hindbrain of the ray,Raia baetis (a); axolotl, Ambystoma mexicanum (b); clawed toad, Xenopus laevis (c); and cat, Felis cattus (d).Continuous lines indicate cell bodies in DVN; divided lines indicate cell bodies in ventrolateral nuclei associated withnucleus ambiguus (nA). There is a sequential topographic representation of vagally innervated structures in dogfish andin oxolotl, with all vagal presynptic neurons (VPN) to branchial arches sequentially distributed rostral of obex. However,in axolotl, pulmonary VPN are widely distributed through DVN. This sequential topography remains discernible inXenopus because structures derived from branchial arches (hyoid and larynx) have their VPN rostral of obex, but isvirtually lost in cat where all structures are represented over a wide rostrocaudal extent in vagal motor column, both inDVN and nA. [From Taylor (608).]


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arrangement described for the dogfish and ray brainstems, with the cardiac and gastric branches of the vaguslocated more caudally (Fig. 8). The pulmonary branch,supplying the reduced lungs, is widely distributed oneither side of the obex. After metamorphosis, there is anincrease in the number of VPN, and a proportion of them(;15%) is found in a more lateral location in the whitematter of the medulla (287, 640). Presumably, this reloca-tion of VPN has a functional relevance that may in partrelate to the switch from gill to lung breathing (609).

G. Reptiles

The vagus nerve in reptiles runs to the heart, trachea,lungs, pulmonary and coronary vasculature, thymus, thy-roid, and gut, supplying preganglionic fibers. The vagushas an inhibitory effect on heart rate (Testudines, Ref.438; Crocodilia, Refs. 217, 281; Sauria, Refs. 352, 379;Serpentes, Ref. 216), an effect blocked by atropine (e.g.,Ref. 216) and therefore cholinergic, as in all other gnatho-stomes. In addition, a tachycardial response has beenreported following vagal stimulation in some species (64,216, 352, 438). This may be attributable to the existence ofa connection between the vagus and sympathetic fibers(64, 216, 352, 438). However, in reptiles, there is little, ifany, sympathetic contribution to the cervical vagus nerve,and the sympathetic fibers join the vagus nerve near theheart in both the Crocodilia (217, 218) and the Lacertilia

(64, 352, 438). In contrast, a mixed vagosympathetic trunkhas been reported in widely different species, includingamphibians (112, 217) and mammals (134).

Control of pulmonary blood flow in reptiles isachieved by vagal cholinergic constriction of the pulmo-nary artery (86, 87, 567, 651, 652). Peripheral electricalstimulation of the vagus or intravenous injection of ace-tylcholine results both in bradycardia and an increase inpulmonary vascular resistance, which reduces pulmonaryblood flow (269). These cardiovascular changes are abol-ished by administration of atropine. Blood flow is alsounder adrenergic control. Intravenous injection of epi-nephrine causes a tachycardia and a reduction in pulmo-nary vascular resistance, resulting in an increase in pul-monary blood flow (269). Electrical stimulation of vagalafferents in the turtle results in similar cardiovascularchanges that are blocked by administration of bretylium(124), suggesting that the cardiovascular changes oftenassociated with brief periods of ventilation may be adren-ergically mediated (642). There is also evidence for in-volvement of nonadrenergic noncholinergic (NANC) fac-tors in the regulation of systemic and pulmonary vascularresistances in reptiles, which may influence patterns ofcardiac shunting (642).

Few experimental studies have investigated the cen-tral projection of the vagus nerve in the brain stem of

reptiles. It is still unresolved which fibers, pathways, andnuclei in the brain stem are specifically related to theefferent and afferent fibers and whether the informationobtained from mammals is comparable to that in reptiles.Nevertheless, some information has been obtained re-garding the central representation of the cranial nerves(IXth, Xth, XIth, XIIth) including sensory nuclei (18, 43,131, 167), motor nuclei (70, 350, 629), and both sensoryand motor nuclei (37, 38, 390).

Applying HRP techniques to some species of reptileshas revealed the central projections of a number of cra-nial nerves such as the trigeminal nerve (38), facial nerve(37), laryngeal nerve (38, 350), vagus nerve (38, 390),accessory nerve (38), and hypoglossal nerve (38, 350).Barbas-Henry and Lohman (38) described the motor nu-clei and the primary projections of different cranialnerves in the monitor lizard and found that the motornuclei of nerve IX are located ventrally in the brain stem,both medially in the glossopharyngeal part of the nA andlaterally in the nucleus salivatorius inferior, whereas themotor nuclei of the Xth nerve are represented in themotor nucleus of the vagus and in a lateral group of cellbodies. The motor nuclear complex of nerve XII consistsof a large dorsal nucleus and small ventral nucleus thatextends from the medulla oblongata into the first segmentof the cervical spinal cord.

In reptiles, early studies described two divisions (me-dial and ventrolateral) of the vagal motor column in avariety of species, which were provisionally designated asthe DVN and nA (5, 15, 18). The pattern of labeling is onthe whole similar to that observed after applying HRP tothe vagus nerve in mammals, birds, amphibians, andfishes, except for minor differences, such as degree ofrepresentation of VPN in the lateral nA or the existence orabsence of VPN in other nuclei, such as the nuclei of thespinal accessory nerve. The lateral division, althoughpresent in turtles, was more prominent in a lizard and analligator but absent from a snake (70). A nA was identifiedadjacent to the DVN in the tortoise (131), and between 36and 50% of VPN are located in the nA of the terrapin (390).Vocal control neurons are located in the nA of the gekko(350), and comparable motoneurons are present in the nAof mammals.

An initial HRP study of the vagal motor column in theagamid lizard Uromastyx microlepis (M. Al-Ghamdi andE. W. Taylor, unpublished data) revealed that the majorityof VPN are in the DVN with a small proportion (6%)ventrolaterally located in the nA. However, there was aclear separation of VPN in the DVN into two distinctgroups with a lateral group making up ;13% of the whole.Together with the cells in the nA and reticular formation,laterally displaced cells make up ;20% of the total VPN.All of these cells were cytoarchitecturally distinct fromthe cells in the medial DVN. An exploratory injection of


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wheat germ agglutinin-HRP into the heart marked a fewCVPN in the DVN rostral of obex, but none in the nA.

Electrical stimulation of the brain stem caused apronounced bradycardia, as well as vasomotor responses,in spontaneously breathing, anesthetized pond turtles,Cyclemys flavomarginata. The cardioinhibitory responsedepended on the integrity of the vagus nerves and wasparticularly marked upon stimulation of areas in the cau-dal medulla corresponding to the nA, NTS, and DVN(281).

Thus the situation in reptiles seems to vary betweenspecies, and the somatotopic representation of the vagusis not yet known. The basis of this variation is likely to bethat they are not a homogeneous group, because thepresent-day reptiles are separated by wide evolutionarydivisions (536). The chelonians (turtles and tortoises) areanapsids, a group regarded as primitive, having arisenfrom close to the ancestral reptilian stock (evolved fromprimitive amphibians). The snakes and lizards are diap-sids, from the same reptilian stock that produced thearchosaurs. These in turn evolved into the ruling reptiles(“dinosaurs”) represented today by the crocodiles andalligators and, on another evolutionary line, the birds.Mammals are recognized as having evolved from a sepa-rate, primitive reptilian stock, the synapsids. These wereremote in evolutionary terms from the lines leading to thepresent day reptiles and the birds but may have beencloser to their amphibian ancestors and to the primitivechelonians. Thus the disposition of VPN may have phylo-genetic as well as functional correlates.

H. Birds

Cranial nerves IX and X are closely related, bothtopographically and functionally, in birds. Their motornuclei lie in a continuous zone in the medulla oblongata,and they separately supply preganglionic fibers to theheart, lungs, blood vessels, and alimentary canal. An ad-jacent area in the hindbrain contains motoneurons sup-plying special visceral efferent fibers to the pharynx, lar-ynx, and palate. Their fibers leave the hindbrain by aseries of rootlets that coalesce at the proximal ganglion.This ganglion contains the cell bodies of visceral andsomatic sensory neurons which, together with cell bodiesof vagal sensory neurons in the more distal nodose gan-glion, send afferent projections into the NTS (348).

Vagal preganglionic neurons in the pigeon were lo-calized in the DVN, in an area identified in the ventrolat-eral medulla as the avian homolog of the nA in mammals(18, 71) and the region of the reticular formation extend-ing between the DVN and the nA (119, 347, 349). The DVNin pigeon is composed of 11 cytoarchitecturally distinctsubnuclei in which individual target organs have discreteand topographic representation (347, 349). Some neurons

supplying the viscera are located rostral to obex, whereasothers are located in a typically sequential position caudalto obex. A lateral subgroup projects to the heart. Similardorsoventral and rostrocaudal gradients of target repre-sentation are seen within vagal afferent projections to theNTS (14, 348). Such distinct topographic separation ofgroups of neurons innervating specific target organs hasclear implications for the central coordination of theirfunctioning.

Until recently, there were no figures available for theproportions of vagal neurons located in the medial (DVN)or lateral (nA) divisions of the vagal motor column inbirds. However, current work on the tufted duck, Aythya

fuligula, has revealed that VPN are located over a rostro-caudal extent of ;5 mm around obex in the medulla, with3% of cell bodies in the nA and a diffuse area identified asthe reticular formation. The majority (97%) of cells are inthe DVN where they are separable into subnuclei, accord-ing to their cytoarchitecture and topography (72). As yet,the viscerotopic distribution of these cells is uncertain orin dispute.

Although of particular interest to this review, cur-rently there is not a consensus on the topographic loca-tion of CVPN in birds. After electrophysiological and ret-rograde degeneration studies in the pigeon, CVPN werereportedly found exclusively in the DVN, located rostralto obex (119, 555, 556). Here they may be located with,and possibly influenced by, activity in respiratory mo-toneurons, although their central interactions remain un-known. The reported concentration of the majority ofVPN in the DVN as well as the location of the CVPNrostrally in the DVN is similar to the agamid lizard (seesect. IVG) but in sharp contrast to mammals, where over30% of VPN and the majority of CVPN are located in thenA. This may reflect the diverse evolutionary backgroundof these two homeothermic groups, referred to above.However, this conclusion was questioned by Cabot et al.(107) who demonstrated, using fragment C to tetanustoxin as a neural tract tracer, that the majority of CVPNwere in a caudal subdivision of the nA in the pigeon,which may be homologous to the ventrolateral nucleus ofthe nA in mammals. A smaller fraction (10–30%) waslocated within the ventrolateral subnucleus of the DVN.Studies on the tufted duck recorded an apparent compro-mise between the two previous studies on pigeon, since;77% of CVPN were located in the ventral subnucleus ofthe DVN, with 21% in the nA and 2% in the reticularformation (72). This distribution represents a relative con-centration of CVPN into areas outside the DVN as themean number of CVPN in the DVN represents only ;3% ofthe total population of VPN, whereas in the nA, CVPNrepresent ;30% of total VPN. It is important to our furtherunderstanding of the central control of the heart and ofcardiorespiratory interactions in birds that the exact to-pographical location of CVPN, in relation to other neu-


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rons such as the respiratory CPG, is resolved for a num-ber of species.

V. SYMPATHETIC INNERVATION OF THE

CARDIORESPIRATORY SYSTEM

A. Mammals

There is very little information on the central locationof sympathetic neurons in lower vertebrates. However,this location has been described in a number of tetrapodsand most extensively in various species of mammals. Fora comprehensive account the reader is referred to thereview by Coote (127). The advent of retrograde labelingof cell bodies with HRP and its conjugates, or fluorescentdyes applied to preganglionic areas, has provided a moredetailed picture of the location of preganglionic neuronsand their anatomical organization. These techniques havebeen utilized on the rat (13, 228, 278, 505, 506), guinea pig(426), rabbit (499, 633), and cat (507).

The sympathetic preganglionic neurons (SPN) lie inclusters in four topographically defined nuclei in the in-termediate gray on either side of the spinal cord. Thesefour nuclei, named in turn from the edge of the graymatter to the central canal, are the intermediolateralisthoraco lumbalis pars funiculus (ILF), intermediolateralisthoraco lumbalis pars principalis (ILP) or lateral horn,intercalatus spinalis (IC), and intercalatus spinalis parspara ependymatis (ICPe) or central autonomic area.Quantitatively, the majority of SPN are found in the ILP.The arrangement is likely to be the same in all mammals(127).

The rostrocaudal location of SPN in mammals islimited rostrally by the cervical segments, the last cervicalsegment being the most rostral in which these cells have

been identified, for example, cat and rabbit T1 (507, 633),rat C8 (279, 505, 506), and guinea pig C8 (540). The rostrallocation of SPN seems to be fixed at the last cervical orfirst thoracic segment, regardless of species or class.

The sympathetic neurons come to lie at these loca-tions by a process of migration. Studies in the rat usingacetylcholine transferase as a marker (494) indicate thatthe SPN arise from the ventral ventricular zone of thedeveloping neural tube, migrate radially into the ventralhorn, then are displaced dorsally, and finally, a smallernumber migrate medially to occupy sites between the ILPand central canal (413, 414). On reaching the ILP, theseneurons become increasingly multipolar and may un-dergo a change in alignment from a dorsoventral andmediolateral orientation to a rostrocaudal one (414, 506).Dendritic orientation also changes from first being dor-solongitudinally organized to more mediolaterally orga-nized as the rat matures (413, 414). There is also thedevelopment of new rostrocaudal dendrites (413, 506).

1. Topographical distribution of sympathetic

preganglionic neurons

It has been suggested that a clustering of SPN intosmall groups is related to similarity of function of theneurons (13, 492). This remains to be substantiated. How-ever, there is now good evidence that SPN projecting todifferent ganglia or to the adrenal medulla are organizedinto discrete rostrocaudally orientated columns (Fig. 9)(13, 301, 505). The idea of a viscerotopic organization ofthe cell groups has been extended to the four subnuclei(46–48, 426, 492). Thus SPN projecting to the inferiormesenteric ganglion of the guinea pig are found mainly inthe IC and ICPe (133), whereas hindlimb vasomotor neu-rons appear to mainly occupy the ILP and ILF (426). Also,those neurons supplying the hypogastric nerve in the catare located in the lower lumbar spinal cord, just medial to

FIG. 9. Schematic of basic principles of organization ofcardiovascular neurons in medulla oblongata and spinalcord of mammals. Target specificity appears to be retainedthroughout multisynaptic pathway from periphery to atleast as far as brain stem. [Based on data from Janig andMcLachlan (301), Lovick (403), McAllen (417), and Pynerand Coote (508).]


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the main portion of the ILP (46) or very medially justdorsal to the central canal in the rat (259). However, itcannot be quite as simple as this, since more recentstudies in the rat show that neurons supplying the adrenalmedulla, the stellate ganglion, superior cervical ganglion,celiac ganglion, aortic-renal ganglion, or superior or infe-rior mesenteric ganglion are represented in each of thefour subnuclei (279, 506, 591).

A further extension of the idea of functionally orga-nized specific groups of cells concerns their morphology.Two types of neurons, one with round-bodied and onewith fusiform somata are most commonly described. Athird, rather rare, larger cell type has also been observed(23, 506). These three types have been shown in theprojections to the stellate ganglion, superior cervical gan-glion, and the adrenal medulla (506). Of interest were theobservations in the rat that round-bodied somata are thesole type in the IC, and jusiform somata are the sole typein the ICPe, whereas both types are present in the ILP andILF (506). Although at present there is no strong reason toconnect this morphology with electrophysiology, it is ofinterest that cat upper thoracic SPN can be classified intothree types on the basis of their electrical properties(169). However, the biophysical codes are too few toaccount for the range of sympathetic functions.

Target specificity has also been related to chemicalcoding of these neurons. An elegant study in the guineapig revealed that substance P-immunoreactive SPN pro-jected selectively to postganglionic vasodilator neuronscontaining vasoactive intestinal polypeptide. In contrast,SPN that were immunoreactive to antibodies to calcitoningene-related peptide were found to project to postgangli-onic vasoconstrictor neurons containing neuropeptide Y(NPY) as well as norepinephrine (224, 225). Rat secreto-motor preganglionic terminals in the superior cervicalganglion are selectively immunoreactive to calretinin an-tibody (243). Using a conceptually similar approach in thecat, Krukoff et al. (367, 368) measured four peptides(neurotensin, substance P, enkephalin, and somatostatin)in SPN throughout the thoracolumbar spinal cord. Thisstudy failed to show any obvious peptide-specific pregan-glionic neurons associated with specific viscera. It alsoappears that nitric oxide synthase is specifically associ-ated with a subpopulation of SPN that projects to adrenalmedulla and viscera (244). As with the biophysical prop-erties, at present too few chemical codes have been iden-tified to account for the range of sympathetic functions.Nonetheless, this promising direction of research mightbe combined with another elegant and powerful tech-nique of transneuronal labeling with neurotropic virus(592). So far, studies on the projections to the kidney andthe adrenal medulla in rat, rabbit, and hamster have gen-erally confirmed the viscerotopic organization of the SPN(165, 333, 554).

One of the more interesting features of recent studies

of SPN has been the descriptions of their dendritic arbors,which appear to be more extensive than previously as-sumed. The dendritic arbor and its orientation have func-tional importance that is relevant to understanding theorganization of the columns of spinal neurons that aretarget specified (506). In mammals (rat, rabbit, and guineapig), primary dendrites number from six to eight andbranch extensively after passing medially, laterally, androstrocaudally (23, 279, 506, 634). It is now clear that asimilar arrangement occurs in the cat (507). The lateraldendrites pass through the bundles of descending axonsin the lateral funiculus; the medial dendrites convergefrom different clusters of neurons to cross the intermedi-ate gray matter in bundles, which on reaching the centralcanal turn and pass up and down, while some extendfurther to the lateral horn of the opposite side. The lon-gitudinally oriented dendrites are extensive, running forconsiderable distances between groups of SPN. Theseorientations may allow for reception of similar inputs byfunctionally similar SPN.

2. Sympathetic innervation of the heart

Almost all vertebrates have an excitatory sympa-thetic nerve supply to the heart. Sympathetic nerve fibersfrom the stellate ganglia innervate the atria and ventriclesas well as the sinoatrial node in reptiles, birds, and mam-mals. Sympathetic fibers travel by two pathways: a directone which mainly supplies the nonconducting tissue ofthe heart and an indirect one where a branch of thestellate ganglion joins the vagus nerve and from wherefibers travel to the pacemaker regions and conductingtissue of the heart (342). In amphibians and teleost fish,the cardiac sympathetic innervation is often in the sametrunk as the vagus (383). Cyclostomes, Elasmobranchs,Dipnoans, and some teleosts (particularly pleuronectids)lack adrenergic innervation of the heart (383). In thosevertebrates without a sympathetic innervation of theheart, the effect of circulating or locally released cat-echolamines is also excitatory (472). Cardiac cells con-taining epinephrine or norepinephrine are found in allvertebrates, including lampreys (73). This phylogeneticvariability is described in some detail below.

In amphibians, reptiles, birds, and mammals, thesympathetic excitatory influence on the heart is twofoldin that it increases both rate and force. These actions inmammals, where the most detailed studies have beenconducted, are to some extent dependent on whetherright or left sympathetic supply to the heart is activated.In the dog, monkey, and probably human, the cardiacsympathetic projection has highly localized terminal ar-bors and is capable of causing sharply discrete alterationsin the performance of segments of the myocardium (518).Broadly, stimulation of the right sympathetic nerves tothe heart in the dog, for example, causes increased heart


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rate via accelerations of cardiac pacemaker activity. Italso augments atrial inotropism. Stimulation of the leftsympathetic cardiac nerves has a major facilitatory effecton ventricular contractions and also increases conduc-tance and rate via the atrioventricular node (518, 519).

In mammals, postganglionic sympathetic axons in-nervating the respiratory and cardiac structures in thethoracic cavity are located in independent sympatheticnerves or travel to the effector with the thoracic vagusnerves, via the sympathetic branch from the stellate gan-glion (197, 341, 342, 495, 600–602). It is estimated that thethoracic vagus in cats contains ;1,500 sympathetic fibers(197, 450). In comparison, the left inferior cardiac nerve,an independent sympathetic branch of the stellate gan-glion, contains on average 2,600 sympathetic axons (374).It has been pointed out by Balkowiec and Szulczyk (28)that this large proportion of sympathetic fibers travellingwith the vagus nerve to the heart may contribute to theaxo-axonal synapses observed to occur between thesenerves (183), providing a morphological basis for theobserved cardiac vagal-cardiac sympathetic interaction(252, 366, 502, 524, 644). An electrophysiological study ofsingle sympathetic fibers in the thoracic vagus byBalkowiec and Szulczyk (28) showed they were a homo-geneous population, displaying cardiac pulse and respira-tory-related rhythmicity in their discharge pattern anddecreasing their activity in response to peripheral arterialchemoreceptor stimulation. Consequently, it was arguedthat they supply a single cardiac effector. It was assumedthat the most likely effector was the conducting tissue,because stimulation of the sympathetic fibers in the tho-racic vagus is most effective at producing increases inheart rate in dogs (520), cats (56, 341), and sheep (635).

3. Sympathetic nerve supply to airways

There is a large amount of literature detailing thephysiology and pharmacology of the smooth muscle andsecretory responses evoked by stimulation of airway au-tonomic nerves in mammals. However, these have beencomprehensively reviewed (44, 45, 300, 388), and thisreview only provides a summary of this work.

The presence and extent of innervation of the smoothmuscles by sympathetic nerves varies from species tospecies. It has been demonstrated in the trachea of guineapigs (35) and rabbits (172) as well as in bronchi of dogs(360), cats (573), and humans (152, 378, 488). It has beenfound only rarely or not at all in the bronchi of rats (27, 35,172), guinea pigs (484), rabbits (412), and humans (172).Even where an innervation has been demonstrated, it israrely very extensive.

Although sympathetic nerves modulate transmissionin enteric ganglia (659), the presence or absence of asympathetic innervation of airway ganglia has beenwidely debated. An adrenergic innervation of airway gan-

glia has been suggested in kittens (360), humans (527),and calves (299) but has been discounted in dogs (299),cats (132), guinea pigs, rats, and mice (35). Even in calves,presumed adrenergic endings were found adjacent to only10% of principal ganglion cells (299). However, in allspecies studied, adrenergic innervation of the airway vas-culature has been demonstrated, and in many species, SIFcells are present in the ganglia. It is possible that when anadrenergic innervation of the ganglion cells has beendemonstrated, the fibers arise from these SIF cells ratherthan an extrinsic sympathetic innervation.

B. Cyclostomes

The heart of cyclostomes, which is without a sym-pathetic nerve supply, contains large quantities of epi-nephrine and norepinephrine stored in chromaffin cells(2, 552). Depletion of this catecholamine store withreserpine causes a marked slowing of the heart rate inthese animals (73). Epinephrine, norepinephrine, iso-prenaline, and tyramine all stimulate the lampetroidheart, although the effects are less pronounced than theacceleration produced by acetylcholine. The effect ofthe adrenergic agonists is blocked by propranalol, sug-gesting an effect via b-adrenoceptors in lampetroids asin the higher vertebrates (19, 191, 464). The isolatedheart of myxinoids is insensitive to exogenously ap-plied acetylcholine and the catecholamines. However,injected catecholamines have marked cardiostimula-tory effects in the intact animal, whereas the b-adreno-receptor antagonist sotalol causes a markedly negativechronotropic effect. These responses have been attrib-uted to simulation of the effects of catecholaminesreleased from chromaffin stores within the heart of thenormal animal (474).

Little is known about the origin and nature of vaso-motor nerves in cyclostomes, and there is no evidence forvasomotor innervation of their branchial vasculature.However, spinal autonomic nerve fibers, containing ad-renergic elements, innervate some blood vessels in lam-preys (230), and both catecholamines and acetylcholineincrease vascular resistance in Myxine (21).

C. Elasmobranch Fish

The sympathetic system of elasmobranchs consistsof an irregular series of ganglia, approximately segmental,lying dorsal to the posterior cardinal sinus and extendingback above the kidneys (667). These paravertebral gangliaare arranged approximately segmentally, except in themost anterior part, and there are one or two gangliaconnected to each spinal nerve by white rami communi-cantes (469). The existence of recurrent gray rami com-municantes has been denied (665). The spinal autonomic


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outflow in elasmobranchs appears to occur chiefly in theventral roots of the spinal nerves (665), but a dorsaloutflow to blood vessels is not excluded (497). The seg-mentally arranged ganglia are irregularly connected lon-gitudinally and with the contralateral paravertebral gan-glia, but there are no distinct sympathetic chains of thetype found in higher vertebrate groups. There are noprevertebral (collateral) ganglia in elasmobranchs (469,473).

The most anterior pair of paravertebral ganglia ofelasmobranchs are the axillary bodies that are situatedwithin the posterior cardinal sinuses. These are made upof ganglion cells and also large masses of catecholamine-storing chromaffin cells. The axillary body ganglia receivewhite rami communicantes from several of the anteriorspinal nerves and give off the anterior splanchnic nerves.These are composed mainly, if not entirely, of postgangli-onic fibers. The left anterior splanchnic nerve crosses tojoin the right, forming a plexus along the celiac artery tothe gut and the liver (465, 665). An anastomosis betweenthe vagus and the anterior splanchnic nerves occurs insome elasmobranchs (666). The paravertebral ganglia be-hind the axillary bodies are smaller and lie in the dorsalwall of the cardinal sinuses. The suprarenal chromaffintissue is often associated with the ganglia (as in theaxillary bodies) but may exist separately (469).

A peculiarity of the sympathetic system of elasmo-branchs is that it does not extend into the head. Thiscondition is unique among vertebrates, but it is not clearwhether it is primary or the result of a secondary loss(667). Contributions to the vagi or direct cardiac nervesfrom paravertebral ganglia are, with rare exceptions (e.g.,Mustelus, Ref. 497), absent (297, 406–408, 497, 665).There are only single observations of fibers from theaxillary bodies to the heart (Mustelus, Ref. 497). As aresult, there is no direct sympathetic innervation of theheart or the branchial circulation in elasmobranchs (465),and there is no evidence for branchial vasomotor control,other than by circulating catecholamines (102, 155).

Circulating catecholamines exert a tonic influence onthe cardiovascular system in elasmobranchs under rest-ing, normoxic conditions (572). In elasmobranchs like thedogfish, which again have no cardiac sympathetic inner-vation, circulating catecholamines are important formaintaining and increasing heart rate (517). It has re-cently been demonstrated that circulating catecholaminesmodulate vagal control of heart rate in dogfish. The de-gree of inhibition of an in situ preparation of the dogfishheart during peripheral stimulation of a cardiac branch ofthe vagus was found to be modulated by circulating levelsof norepinephrine (C. Agnisola and E. W. Taylor, unpub-lished data). In addition, an adrenergic influence on theheart may be exerted by specialized catecholamine-stor-ing endothelial cells in the sinus venosus and atrium.These cells are innervated by cholinergic vagal fibers

(493, 543). The effects of epinephrine and norepinephrineon the elasmobranch heart are somewhat variable, so thepossibility of a selective cardiac control via the two nat-urally occurring amines exists, although the mechanismsof this action remain unknown (469).

D. Teleost Fish

Historically, a sympathetic cardioaccelatory innerva-tion had been generally assumed to be lacking in teleosts(510). However, the sympathetic chains extend into thehead where they contact cranial nerves, forming a vago-sympathetic trunk (225), and adrenergic fibers have beenfound to innervate the heart of some teleosts (e.g., trout,Refs. 212, 664). An adrenergic tonus on the hearts of cod(Gadus) and goldfish (Carassius) has been demon-strated, but the relative importance of the neuronal andhumoral adrenergic control of the heart remains uncer-tain (469). The positive chronotropic and ionotropic ef-fects on the teleost heart produced by adrenergic agonistsand adrenergic nerves are mediated via b-adrenoceptormechanisms associated with the pacemaker and the myo-cardial cells (111, 212, 272, 516). b-Adrenoreceptorsgenerally mediate positive chronotropy in fish and am-phibians, whereas a-adrenoreceptors mediate negativechronotropy in fish (194, 195, 469). As a whole, the te-leosts may be considered as the earliest group of verte-brates in which there is both sympathetic and parasym-pathetic control of the heart.

There is adrenergic innervation of the branchial andsystemic vascular beds in teleost and other actinoptery-gian fishes. They contain adrenergic fibers that innervatevessels in both the arterioarterial, respiratory circuit andthe arteriovenous, nutritive circulation in the gill fila-ments, possibly controlling and directing blood flowthrough these alternate pathways (454). Thus the patternsof blood flow in the gills are regulated by vagal cholinergic(see sect. IVD) and sympathetic adrenergic fibers thatincrease vascular resistance by stimulation of muscarinicand a-adrenergic receptors, respectively, or decrease it byb-adrenoreceptor stimulation (196, 469, 471, 511).

E. Amphibians

The most primitive arrangement of the sympatheticganglia in amphibians is found in the urodeles (the newtsand salamanders). Ganglionated sympathetic chains ex-tend from the level of the first spinal nerve down into thetail. Except in Necturus, the sympathetic trunk does notproject into the cranial region, although there are connec-tions with the vagus nerve in all species examined. InTriturus, the subclavian plexus gives rise to cardiac sym-pathetic nerves. In anurans, all sympathetic innervation tothe heart travels in the vagal trunk, whereas urodeles


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possess both a vagosympathetic and direct cardiac sym-pathetic nerves (94, 469). As in fish, chromaffin tissueoccurs in the walls of the posterior cardinal veins.

In anurans such as the frog (Rana pipiens) and thebullfrog, sympathetic outflow extends from the 2nd to the10th spinal nerve along the shortened spinal column. Thevagus nerve is a major pathway for postganglionic sym-pathetic fibers reaching the stomach, lungs, and heart sothat it constitutes a vagosympathetic trunk (225). Sympa-thetic preganglionic neurons in spinal segments 2 and 3innervate the first sympathetic ganglion that sends post-ganglionic fibers to heart and lungs (663), as well as upperdigestive tract and structures in the head. The pregangli-onic neurons are located between segments 3 to 8 andmainly lie in the ILP and IL in about equal numbers (277,534).

All the postganglionic neurons in the sympatheticchain of amphibians synthesize epinephrine. Epinephrineis the most important neurotransmitter of the positivechronotropic and ionotropic effects of sympathetic inner-vation on the heart, but in some species, there is coreleaseof NPY and ATP (455). In the toad and the bullfrog, theSPN are segregated into larger B and smaller C neurons(277, 454). The small C neurons, with slow conductionvelocities, contain the neuropeptides NPY and galaninand innervate blood vessels (277, 454).

F. Reptiles

The spinal sympathetic pathways of reptiles andbirds have clearly defined paravertebral chains, and someshare features not seen in other vertebrates. The sympa-thetic trunk extends craniad and probably makes exten-sive connections with cranial nerves (3). The arrangementof the sympathetic ganglia is similar in lizards and chelo-nians (270). Both have a large ganglion at the level of thebranchial plexus, which gives rise to cardiac and pulmo-nary nerves. A large ganglion in the same position incrocodilians, which corresponds to the stellate ganglionof mammals, gives rise to a prominent cardiac nerve.Catecholamine-synthesizing autonomic neurons projectfrom the paravertebral sympathetic ganglia to all cham-bers of the reptilian heart. Their nerve fibers either runwith the vagus in a vagosympathetic trunk or projectdirectly from the sympathetic chain to the heart. Thesespinal autonomic neurons exert positive inotropic andchronotropic effects on the reptilian heart, mediated bystimulation of b-adrenoreceptors (455).

In reptiles (e.g., terrapin, Tryonix sinensis), SPN arelocated in the intermediolateral gray matter of the spinalcord, with a majority of neurons in the ILP and IC cellcolumns and a smaller population dorsal to the centralcanal (389). In the lower spinal cord segments 13–18 ofthe turtle, the sympathetic neurons form a small cluster in

an area lateral to the central canal, perhaps equivalent toIC (375).

G. Birds

In birds, the sympathetic chain extends as a series ofsegmental ganglia from upper cervical to sacral levels,with the most rostral ganglion lying in the skull betweenthe origins of the glossopharyngeal and vagus nerves.However, the preganglionic neurons have a more re-stricted rostrocaudal distribution (e.g., chicken and pi-geon C14, Refs. 105, 280), and there is no cervical pregan-glionic contribution to the cervical sympathetic ganglia(225). This is despite birds having more cervical segmentsthan mammals (e.g., 14 in pigeon, 15 in chickens). Mostpostganglionic neurons in the sympathetic chains containcatecholamines and innervate structures such as bloodvessels. In contrast to reptiles, there are well-developedprevertebral ganglia in birds. Splanchnic nerves from theparavertebral chain supply a ganglionated plexus thatsurrounds the aorta and the origins of the celiac andmesenteric arteries (225).

In some avian species there is no lateral horn in thespinal cord, and the main location of SPN is in the centralautonomic area. However, a few neurons in birds arepresent in more lateral nuclei such as the IC in the pigeon;in the chick, they also appear in an area close to thelateral border of the gray matter equivalent to the ILP(106, 107, 280). Therefore, although SPN are mainly lo-cated medially in birds and laterally in mammals, reptiles,and amphibians, their distribution areas are strikinglysimilar.

In pigeons and chickens, the dendritic arbors of sym-pathetic preganglionic neurons pass medially, laterally,and rostrocaudally in the spinal cord. The lateral den-drites of the principal nucleus above the central canalconverge into bundles that traverse the entire width of theintermediate gray matter and often project into the lateralfuniculus. These bundles are like rungs of a ladder in thelongitudinal horizontal plane, similar in appearance tothose in mammals, although projecting outward (lateral-ly) rather than inward (medially). The medial dendritespass to the contralateral part of the central nucleus wherethey form a network (280).

The spinal sympathetic neurons of the upper thoracicsegments in birds innervate all chambers of the heart viathe stellate ganglia, also contributing to the intracardiacplexus formed by vagal neurons (62). As in mammals, thecardiac sympathetic neurons are tonically active andelicit both chronotropic and inotropic responses, via therelease of norepinephrine acting on b-adrenoreceptors(62, 309, 455, 628).

Little is known of the sympathetic innervation of thelungs and airways and pulmonary vasculature in birds.


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There is a sparse sympathetic innervation that is withouteffect on bronchial muscle (66) but supplies the scatteredbundles of smooth muscle fibers in the air sacs (245) andthe smooth muscle of the oblique septum separating theair sacs from the abdominal cavity (62, 245). A sympa-thetic vasoconstrictor supply to pulmonary blood vesselshas been described (60, 61, 62, 353).

VI. CENTRAL CONTROL OF

CARDIORESPIRATORY INTERACTIONS

The importance of a linkage between the mecha-nisms controlling the respiratory and the cardiovascularsystems has long been recognized, since in many physio-logical responses there are appropriate changes in bothsystems. For example, during exercise there is a closematching of the respiratory and cardiac outputs, whichgenerate the increase in oxygen uptake and transport. Inaddition, many reflex responses evoked by stimulation ofperipheral afferents evoke change simultaneously in thetwo systems. This linkage is engendered in the mecha-nisms that ensure optimal ventilation-perfusion matchingwithin the lungs of air-breathing mammals. It is nowbecoming clear that there is a similar matching of thecounterperfusions with water and blood of the gills ofaquatic animals, so (for example, in dogfish) gill ventila-tory movements and heart rate are often coordinated(548, 604). Centrally, there are also mechanisms by whichthese ventilatory and vascular control systems are cou-pled. They have been discussed in several reviews (121,135, 137, 329, 532, 605, 607). Although the modification ofcardiovascular control by the respiratory system seems todominate, it is also clear that stimulation of cardiovascu-lar afferents can modify the respiratory system. For ex-ample, when arterial baroreceptors are stimulated byrises in arterial pressure, respiratory output is depressed.Even at rest, the coupling between the respiratory andcardiovascular systems may manifest itself. Changes inheart period in phase with breathing (respiratory sinusarrhythmia) are due to respiratory modulation of the va-gal parasympathetic innervation of the heart. Similarmodulation can also be seen in the activity of manysympathetic nerves (see below), and this may, in part,explain the rhythmical changes in arterial pressure thatare sometimes observed, although mechanical changeswithin the thoracic cavity affecting venous return to theheart are also involved. In both vagal and sympatheticoutflows, the respiratory modulation of activity is due inpart to activity in the “central respiratory network” andpartly to sensory input related to lung inflation or gillventilation. For a detailed discussion of the autonomiccontrol of the heart and circulation in various vertebrates,the reader is referred to several very comprehensive re-

views (135, 194, 307, 313, 383, 457, 469, 470, 472, 570, 607,609).

A. Mammals

1. Control of heart rate

In mammals, the level of background resting activityin cardiac vagal nerves, and consequent cardiac vagaltone, appears to vary from species to species and alsowithin species. In dogs and humans, heart rate increasesmarkedly after injection of atropine, whereas in anesthe-tized cats, there is little change in heart rate when atro-pine is applied (289). In addition, in any particular organ,the relative tone in vagal and sympathetic innervationsalso varies. Even in those animals in which cardiac vagaltone is low, there is a predominant vagal tone in airwaysmooth muscle innervation, with sympathetic activityhaving little, if any, direct action here (322).

Vagal tone appears to derive from ongoing activity inperipheral sensory receptors and from other groups ofcentral neurons (Fig. 10). One important ongoing excita-tory drive to cardiac vagal outflow arises from the arterialbaroreceptors, the level of vagal drive to the heart beingrelated to the level of arterial blood pressure. Barorecep-tor denervation reduces (421) but does not abolish car-diac vagal discharge (290), implying that other inputsmust also be important. The arterial chemoreceptors mayprovide one alternative drive. They have ongoing activityat rest, and hypocapnia produced by hyperventilationproduces a tachycardia and reduction in cardiac vagalefferent activity (139, 264). The fact that anesthetics re-duce vagal tone (289) may suggest that tonic influencesalso arise from other parts of the nervous system. In thisrespect, decerebration produces a vagally mediated fall inheart rate (41), suggesting that there is a tonically activedescending inhibitory pathway. This may originate in thehypothalamic defense area, since lesions here also pro-duce cardiac slowing (402). Conversely, stimulation hereinhibits cardiac vagal activity (326). This may act via theinhibitory neurotransmitter GABA, since GABA antago-nists attenuate the tachycardia evoked by defense areastimulation (41). Vagal tone is greatly increased by stim-ulation of the superior laryngeal nerve because it inducesapnea by inhibiting both inspiratory activity and the con-sequent lung inflation. This results in an increase in activ-ity in cardiac vagal efferent fibers (329). Evidence sug-gests that superior laryngeal nerve stimulation may alsoexcite CVPN directly and via a subpopulation of postin-spiratory respiratory neurons that show firing patternssimilar to CVPN, a situation reminiscent of the synchro-nous firing of respiratory motoneurons and CVPN in theDVN of the dogfish (see sect. VIB).

In mammals, respiratory-related changes in heart pe-riod are due mainly to alterations in vagal drive to the


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heart, so it is not surprising that respiratory-related vari-ations in activity were seen in recordings from cardiacvagal efferent fibers (154, 291, 292, 303, 346, 373). Thefibers fired preferentially during expiration and were alsopowerfully excited by stimulating the arterial chemore-ceptors and baroreceptors, which would account for thecardiac-related component of their activity. The respira-tory-related activity survives section of the vagus periph-eral to the recording site and is thus of central origin.However, there is also a component due to activity inpulmonary afferents, since vagotomy does abolish therespiratory component if the animals are first hyperven-tilated to neural apnea. Koepchen et al. (362, 363) pro-posed that the respiratory modulation of vagal outflowcould be explained either by a direct respiratory modula-tion of the preganglionic neurons or if the excitatoryreflex inputs were somehow “gated” before arriving at thepreganglionic neuron, or by a combination of the two.Experiments performed in vivo using intracellular record-ings from identified CVPN in cats have demonstrated thatthese neurons do indeed receive a respiratory-related in-put. During each inspiration, their membrane potential ishyperpolarized due to the arrival of acetylcholine-medi-ated inhibitory postsynaptic potentials (226) which makesthe neurons less amenable to excitatory inputs duringinspiration.

A clear role for central respiratory drive modulatingongoing cardiac vagal drive has been elucidated. In addition,however, activity in afferents arising in the lungs also con-tributes to respiratory sinus arrhythmia (11, 12). Lung infla-tion inhibits cardiac vagal efferent activity (290, 303, 501)and evokes a tachycardia (142, 143, 211, 255). The effects oflung inflation may be so powerful that they reverse thebradycardia evoked by arterial chemoreceptor stimulationinto a tachycardia (137, 143). Unlike the actions of centralrespiratory drive, the modulatory effects of lung inflation on

cardiac vagal outflow do not appear to be imposed at thelevel of the preganglionic neurons (501).

There are several sites at which the respiratory mod-ulation of reflexes may be imposed before the pregangli-onic neurons. The NTS where many cardiorespiratoryafferents terminate is also the site of the dorsal respira-tory group, so this is one possible site. Detailed descrip-tions of the neural organization and pharmacologicalmodulation of transmission within the NTS have ap-peared (322, 323, 328, 387). Within the NTS, modulationmay occur by presynaptic actions on the sensory termi-nals themselves, or alternatively, at postsynaptic sites onNTS neurons (see Fig. 11). Afferents from the lungs andairways travelling in the superior laryngeal and vagusnerves are amenable to presynaptic influences, both fromcentral respiratory drive and from activity in other vagalafferents (39, 532). Recent studies have demonstrated thatmany NTS neurons receiving SLN input also receive con-vergent input from afferents travelling in the carotid si-nus, aortic, and vagus nerves (158, 435). Arterial barore-ceptor and chemoreceptor terminals appear to beunaffected by central respiratory activity (324, 327, 530)so that respiratory modulation of these reflexes mustoccur at a later site in the reflex pathway. This is unlikelyto be within the NTS itself since NTS neurons receivingbaroreceptor (436, 437) or chemoreceptor (433) inputsfailed to show any such modulation of the membranepotential, in phase with either central respiratory drive orlung inflation. Although laryngeal afferent inputs con-verge onto NTS cells, which also receive input from eitherlung stretch afferents (P cells, Ref. 63) or central respira-tory drive from dorsal inspiratory neurons (173), there isalso a population of NTS neurons that receives laryngealinput which do not receive any identified respiratory-related activity (158, 434, 435). Clearly, at least someafferent input can pass the NTS without being modulated

FIG. 10. A summary of possible mechanisms thatinteract at level of cardiac vagal motoneurons to evokecardiac slowing. Excitatory mechanisms are shown assolid lines, and inhibitory mechanisms are shwon asdotted lines. Lines indicate pathways of unknown syn-aptic complexity, not individual neurons. ACh, acetyl-choline; GABA, g-aminobutyric acid; HDA, hypo-thalamic defense area; PIN, subpopulation of postin-spiratory neurons; SAR, slowly adapting lung stretchreceptor afferents; SLN, superior laryngeal nerve affer-ents; ?, postulated pathways. [Modified from Jordanand Spyer (329).]


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by respiratory activity. It should not be forgotten thatrespiratory modulation of baroreceptor firing, induced bythe mechanical events of inspiration and expiration alter-ing venous return and hence cardiac filling, cardiac outputand blood pressure, is likely to be an important contrib-utor to respiratory sinus arrhythmia in humans (65, 162,627).

The effectiveness of certain cardiac reflexes is mark-edly modified by respiration. Brief stimuli applied to thearterial baroreceptors or chemoreceptors only evoke fallsin heart rate if they are applied during expiration, withstimuli given during inspiration being less effective ortotally ineffective (154, 264). Because the preganglionicneurons themselves are under respiratory control, itmight be predicted that any cardiac reflex that is mediatedby these CVPN would be modulated by respiration. In-deed, stimulation of trigeminal receptors in the facialskin, receptors in the nasopharynx and larynx, and car-diac C-fiber receptor stimulation all evoke reflex excita-tion of cardiac vagal outflow that is modified by respira-tory drive. The degree of respiratory modulation imposedby lung inflation and central respiratory drive on thebradycardia evoked by stimulation of the arterial barore-ceptors and chemoreceptors, cardiac receptors, and pul-monary C-fiber afferents has been compared quantita-tively (136, 141). The arterial chemoreceptor-evokedbradycardia was almost abolished by lung inflation andduring inspiration, whereas those evoked by stimulatingthe baroreceptors and cardiac C fibers were reduced by50–60%. Surprisingly, that evoked by stimulation of pul-monary C-fiber afferents was unaffected by respiration.Several possibilities exist. Stimulation of the pulmonary Cfibers may uncouple the linkage between the respiratoryand cardiac control mechanisms; stimulation of the dif-ferent reflexes may modify the central respiratory control

system differently, or the bradycardia evoked by onegroup of afferents may be mediated by a different groupof preganglionic neurons to those activated by the otherafferents. Comparing the respiratory responses evoked bystimulation of baroreceptors and pulmonary C fibers,Daly et al. (140) could find no evidence for differentialeffects on the respiratory pattern that would explain thedifferent respiratory modulations of the evoked bradycar-dias. With respect to the suggestion that there may be twoseparate populations of cardiac vagal motoneurons, it hasbeen demonstrated recently in both cats and rats thatC-fiber cardiac preganglionic neurons in the DVN areactivated by stimulation of pulmonary C fibers but areunaffected by the arterial baroreceptors or the respiratorycycle (315–317). The ongoing activity of these neurons israther regular, unlike those located in the nA that fire withrespiratory- and cardiac-related rhythms.

Thus, as demonstrated in the dogfish (see sect. VIB),mammals appear to have two separate groups of CVPNthat have either tonic or phasic firing patterns and may betopographically separated into groups in the DVN or thenA. This separation arises during embryological develop-ment as neurons that form the nA migrate ventrolaterallyfrom a more dorsomedial position, possibly the equivalentof the DVN, in the fetal brain stem (656). Power spectralanalysis of recordings of heart rate and breathing move-ments in human neonates revealed that respiratory sinusarrhythmia (RSA) is a major contributor to heart ratevariability (HRV) in healthy term (38–40 wk gestation)newborn infants (621). Although RSA was detected in thenear-term fetus (.35 wk), it was not discernible in thefetus before this gestational age or in early prematureneonates (,30 wk), appearing later in postnatal develop-ment (at ;33 wk). Thus the contribution of RSA to HRVvaries both with pre- and postnatal age, which may reflect

FIG. 11. Diagrammatic representation of organization of second-order neurons within NTS (shaded) that receivemonosynaptic inputs from slowly (SAR) and rapidly adapting (RAR) lung stretch receptor afferents and superiorlaryngeal nerve afferents (SLN). At least 2 discrete groups of P cell (P) are found. One receives SAR input alone, whereasthe other also receives SLN inputs. Ib neurons (a subgroup of dorsal respiratory neurons) receive monosynpatic SARinput and, in addition, an input related to central respiratory activity (CIA). Putative inputs to a group of output neurons(C), thought to be responsible for triggering a cough, are also illustrated. [Modified from Jordan (322, 323).]


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a maturational development of the underlying mecha-nisms (609). This is more likely to reflect myelination ofnerve fibers than ventrolateral migration of CVPN at thislate stage of development. However, the onset of air-breathing at metamorphosis in the axolotl was accompa-nied by ventrolateral relocation of a subpopulation ofVPN (287, 608).

2. Control of the airways

The respiratory-related modulation of cardiac vagaloutflow is not unique. Tracheal muscle tension fluctuatesin phase with central respiratory drive (448), and reflexesthat increase respiratory drive also increase tracheal ten-sion. Vagal efferent fibers innervating airway smooth mus-cle have an inspiratory pattern of firing that is augmentedwhen central respiratory drive increases and that is inhib-ited by moderate degrees of lung inflation (303, 331, 420,653, 654). The origin of the respiratory-related inputs tothe motoneuronal pools is, as yet, unknown. However,there is a close association between the ventral respira-tory group and the regions of the nA containing the VPN(67, 184). Also, because the respiratory rhythm is thoughtto be generated in the region of the rostroventral medulla(529, 585), it is possible that this is the more likely site. Infact, Mitchell and Richardson (448, 525) have argued thatthere are probably more than one “respiratory oscillator”within the brain stem. In addition to the eupneic CPG,there is also a slower, and phylogenetically older, CPG forthe branchial musculature and a faster pattern generatorinvoked during gasping (see Ref. 525 for discussion).

The organization of the afferent and efferent controlof airway smooth muscle and their central nervous inte-gration have been discussed in recent extensive reviews(45, 322, 323), and readers are directed to them for adetailed consideration. It is established that the restingtone in airway smooth muscle is due mainly to activity inthe vagal bronchoconstrictor innervation (344, 448). Theorigin of this tone is as yet undefined but, as with theheart, it is likely to be the sum of a number of competinginfluences from sensory afferents in the airways and cer-tain central mechanisms. Slowly adapting lung stretchreceptor afferents and unmyelinated airway afferents pro-vide tonic inhibitory and excitatory drives, respectively(533). In addition, both peripheral and central chemore-ceptors have ongoing activity at resting levels of arterialoxygen and CO2, and because these afferents both evokebronchoconstriction (460, 655), they may provide part ofthe resting bronchomotor tone.

Vagal parasympathetic activity is important in main-taining resting airway tone (485) and in mediating reflexbronchoconstrictions (122), airway secretion (496), andbronchial vasodilation (377). Sympathetic stimulation canevoke bronchial vasoconstriction (134), relaxation of air-way smooth muscle (104, 157), and increased mucus se-

cretion (210), but the importance of these latter effects isspecies dependent. In general, many of the effects ofsympathetic stimulation are evoked by modification ofparasympathetic activity (26, 104, 157). Activity in thesenerves shows respiratory modulation (322).

After pharmacological blockade of airway adrenergicand cholinergic receptors, responses to vagal stimulationcan still be evoked, mediated by a NANC system. Theseresponses can be inhibitory and/or excitatory dependingon the species (9, 44, 172, 246, 526, 616, 632). Indeed, inhuman airways, the NANC system provides the predomi-nant inhibitory control of smooth muscle.

3. Ongoing activity in cardiac sympathetic and

vasomotor nerves

There is a large body of evidence that sympatheticnerves supplying the heart and blood vessels in mostvertebrates studied show a continuous activity on therange of 0.1–7 Hz referred to as cardioaccelatory or vaso-motor tone (see Refs. 127, 455 for review). For example,a 2- to 6-Hz periodicity is entrained to the cardiac cycle viainhibitory feedback from the arterial baroreceptors (219).This cardiac-related inhibition is dominant in muscle andsplanchnic sympathetic vasoconstrictor nerves and prob-ably in cardiac sympathetic nerves (475).

Spontaneous activity of most sympathetic cardiovas-cular neurons exhibits a respiratory modulation. This hasbeen shown in a number of mammals such as the dog, cat,rabbit, and rat (6, 74–76, 227, 254, 482, 669–671). Themechanisms involved in the respiratory modulation ofsympathetic cardiac and vasomotor discharge are com-plex, probably depending on several components inter-acting predominantly at the medullary level (253, 531). Ingeneral terms, there are two inputs to consider: one acentral feed-forward excitatory input related to centralrespiratory drive and another peripheral feedback mech-anism related to lung inflation. This is currently a topic ofmuch interest and debate, and as yet, there is no consen-sus because of the lack of hard data. It is possible thatrespiratory neurons of the medulla make synaptic contactwith vasomotor neurons situated nearby or both groupsof neurons receive synaptic input from a common rhythmgenerator either directly or via bulbospinal pathways (22,40, 125, 504, 532, 587). These respiratory inputs may havesubstantial effects on the excitability of SPN in the spinalcord (170, 399).

At least two afferent influences are likely to be im-portant in a peripheral feedback mechanism. One isstretch receptor afferent input excited by lung inflation.During lung inflations, which were dissociated from cen-tral respiratory drive in artificially ventilated cats, themajority of SPN in the third thoracic segment were hy-perpolarized (399). However, a minority were depolar-ized. This might relate to the finding in other studies that


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lung inflation decreases sympathetic activity to the heartyet increases vasoconstrictor activity to peripheral vascu-lar beds (135). A second important peripheral mechanismis that dependent on alterations in baroreceptor afferentactivity, caused by changes in arterial pulse pressureconsequent on the fluctuations in left ventricular fillinginduced by ventilation (177, 251, 253, 627).

The evidence relating to central and peripheral influ-ences on sympathetic activity to the heart and bloodvessels has been comprehensively reviewed (135, 250,253, 415); therefore, only a brief summary will be pro-vided here. A respiratory-related discharge has been re-corded in whole cervical and abdominal sympatheticnerves in cat and rabbit (6); in postganglionic cardiac andrenal sympathetic nerves in cat (25, 345); in mixed pre-and postganglionic splanchnic, adrenal, cervical, and lum-bar nerves; and in postganglionic cardiac and renal nervesin the rat (482, 669, 670). Evidence obtained in cats anddogs supports the idea that the pattern of respiratorymodulation is linked to the function of the sympatheticneurons (74–76, 253). Recordings from cardiac sympa-thetic nerves and sympathetic vasoconstrictor nerves toskeletal muscle and to skin in the cat indicate that theinspiratory-related pattern of activity is strong in neuronsthat are involved in cardiovascular regulation (25, 28,241). Furthermore, it appears that the inspiratory influ-ence is important in determining heart rate and vasculartone. When the central respiratory drive is abolished ex-perimentally (by stimulating the laryngeal nerves), phasicactivity in sympathetic nerve fibers is abolished, and thereis a small decrease in heart rate and a substantial vaso-dilatation in hindlimb muscles, even though the tonicactivity of sympathetic fibers often increases (22).

Studies in cat and dog show that sympathetic axonssupplying the heart and pulmonary vessels have similaractivity patterns to those supplying other vascular beds(180, 239, 240, 560, 653, 655). In the case of cardiacsympathetic innervation, studies show that even thosenerves that probably have different influences on theheart, like those travelling from the right stellate ganglionbut joining the right vagus nerve to supply pacemaker andconducting tissue of the heart, have a similar cardiacrhythm and respiratory periodicity to those nerves in theleft sympathetic outflow, which mainly supply the myo-cardium and increase the force of contraction (28). Thisongoing activity appears to be largely dependent on agroup of spinally projecting neurons in the ventral me-dulla oblongata, although spinal sympathetic neurons areable to generate a small degree of “spontaneous” activityand forebrain regions may also contribute (127, 148).

The evidence showing the significance of the ventralmedullary region in mammals has been extensively re-viewed (109, 148, 403, 404, 588). In summary, the keyregion lies close to the ventral surface of the medulla,extending from the ventral portion of the inferior olive to

the caudal border of the facial nucleus. It is close to theventral group of respiratory neurons, which are anatom-ically associated with the nA wherein also lie cardiacvagal motoneurons (188, 532). Electrolytic or chemicallesion of this area abolishes sympathetic vasomotor tone(151, 419), as does application of inhibitory amino acidsrestricted to this region (160, 247, 403, 418, 537). Increasesin sympathetic vasomotor activity are obtained after ap-plication of excitatory amino acids to this region (236,403, 418, 537).

The weight of evidence favors the idea that the ven-tral medulla oblongata has separate populations of neu-rons controlling the adrenal medulla, different vascularbeds, cardiac acceleration, cardiac slowing, and ventila-tion, which in turn are connected to their specific targetsympathetic neurons in the spinal cord (508). This prin-ciple of organization, which may be present throughoutthe vertebrates, is depicted schematically in Figure 9.Each of these populations of neurons receives a variety ofcommon afferent inputs including arterial baroreceptors,arterial chemoreceptors, trigeminal receptors, and so-matosensory receptors (135, 149, 171, 201, 233, 248, 249,253, 372, 415, 417, 597, 620). It is probable that most, if notall, these afferents converge at the NTS from where theydiverge to influence the various functionally distinct pop-ulations of cardiorespiratory neurons.

Such an organization is observed in the baroreceptorreflex control of cardioacceleratory sympathetic neuronsand cardiac vagal motoneurons. Thus bilateral lesions in acircumscribed region of the ventral medulla oblongatablock the vasomotor component of the baroreceptor re-flex, leaving the cardiac vagal component intact, whereasa kynurenic acid lesion of nA blocks the cardiac vagalcomponent but leaves the vasomotor component (147,235, 236).

The question of how tonic activity is generated by themedullary cardiovascular neurons is a topic of currentinterest. In vitro studies in which intracellular recordingsare made from ventrally situated neurons in a cranial sliceof the medulla oblongata of rats show that some of theseneurons have pacemaker-like activity (343, 394). How-ever, an in vivo intracellular study of identified ventralmedulla vasomotor neurons was unable to find evidenceof pacemaker-like potentials in these cells (400), thusindicating that tonic activity was dependent on synapticinput. Some of these may be respiratory related (253) anddepend on a common cardiorespiratory neural network(532), or alternatively on an independent network oscil-lator that can become entrained to respiration (42, 219,220, 411, 475, 476, 672).

The respiratory modulation of ventral medullary va-somotor neurons, observed in cat, rat, and rabbit, is pre-served to a variable degree throughout the multisynapticpathway to the peripheral effectors (253). Some sympa-thetic outflows, like those to the heart, pulmonary vessels,


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skeletal muscle, vascular bed, and kidney, show strongerrespiratory-related oscillations in activity than those toother regions (253). A reason for this could be that therespiratory influence at the brain stem level is reinforcedat the spinal level by direct respiratory-related input toselected sympathetic neural networks (170, 227, 399, 532,673).

4. Integrative control

Stimulation of a variety of cardiorespiratory afferentsevokes changes in both respiratory and cardiovascularoutflows and, at least at the peripheral level, these havebeen carefully reviewed (256, 415, 440, 529). For example,in addition to altering heart rate and vascular resistance,arterial chemoreceptor stimulation augments respiratorydrive. Because the cardiovascular response is modified byrespiration, the overall response evoked by chemorecep-tor stimulation is complex. The precise effect on thecardiovascular system depends on the level of respiratorydrive at the time and on the magnitude of the evokedincrease in pulmonary ventilation. In some animals,tachycardia is evoked, whereas in others, a biphasic re-sponse or a bradycardia is produced. In fact, the primaryresponse to stimulating the chemoreceptors is a slowingof the heart, and this is always seen if respiration iscontrolled. However, if respiration is allowed to increase,then this may mask the bradycardia and lead to tachycar-dia. This has been extremely well documented in recentreviews (137, 138, 146, 415). Similar interactions can beseen in the airway effectors. Stimulation of pulmonary Cfibers in apneic animals evokes a constrictor response,but in animals with central respiratory activity, the samestimuli evoke an apnea and its concomitant relaxation ofthe airways, which fully masks the primary constrictorresponse (262). These interactions are not simply exper-imental curiosities; they do occur under normal physio-logical circumstances. During breath-hold diving, for in-stance, apnea is evoked by stimulation of facial receptorsinnervated by trigeminal afferents. The breath-hold leadsto a progressive stimulation of the arterial chemorecep-tors that would be expected to stimulate breathing. How-ever, the simultaneous stimulation of the facial receptorsblocks this respiratory component of the chemoreceptorreflex while at the same time augmenting the cardiaccomponent, to induce a bradycardia (96, 98, 121, 185).

We have described how in mammals there is a toniccardioacceleratory and vasomotor activity, which is cou-pled to the respiratory cycle by central and peripheralmechanisms. There are so far no studies in vertebratesother than mammals in which the patterns of sympatheticcardiac and vasomotor activity have been correlated withventilatory control, of either gills or lungs. Although stud-ies on other vertebrates are sparse, it seems likely thattonic activity in cardiac sympathetic and vasomotor

nerves is a common feature. Adrenergic blockade leads tovasodilatation of most vascular beds in fish (470, 472) andin amphibians (453). Interestingly, the branchial vesselsof fish constrict after adrenergic blockade because thesympathetic supply dilates the gill vessels via a b-adreno-receptor (470). Removal of the influence of sympatheticnerves either with reserpine or by pithing in frogs leads toa vasodilatation (455), and a-adrenoreceptor blockadecauses a decrease in heart rate in several amphibians(455). Furthermore, electrophysiological recordings fromsympathetic nerves supplying blood vessels in frogs re-veal ongoing activity that may or may not be groupedsynchronously with the heart beat (630). The main effectof sympathetic activation on the pulmonary vessels ofreptiles is a vasodilatation, brought about by noradrener-gic stimulation of b-adrenoreceptors (455). There are nostudies in other vertebrates linking sympathetic cardiacand vasomotor activity with neurons controlling ventila-tion (gill movements or lung inflation). Neither are thereany studies showing the location of presympathetic neu-rons, apart from one report on the toad (species notindicated) showing that synchronous bursts of activityand somatic or visceral afferent evoked responses areabolished only after removing the caudal part of the me-dulla (474). A review of the organization of pathwaysbetween the brain and spinal cord in amphibians andreptiles (619) did not identify respiratory or vasomotorneurons.

B. Fish

1. Cardiac vagal tone

As described previously, the heart in all fish exceptcyclostomes and in all tetrapods is supplied with inhibi-tory parasympathetic innervation via the vagus nerve. Theinhibitory effect is mediated via muscarinic cholinorecep-tors associated with the pacemaker and atrial myocar-dium (272). The heart in vertebrates typically operatesunder a degree of inhibitory vagal tone that varies withphysiological state and environmental conditions. Heartrate in the dogfish varied directly with PO2; hypoxia in-duced a reflex bradycardia, a normoxic vagal tone wasreleased by exposure to moderate hyperoxia, and ex-treme hyperoxia induced a secondary reflex bradycardia,possibly resulting from stimulation of venous receptors.All of these effects were abolished by injection of themuscarinic cholinergic blocker atropine (607). In addi-tion, cholinergic vagal tone, assessed as the proportionalchange in heart rate following atropinization or cardiacvagotomy, increased with increasing temperature of ac-climation (100, 607, 614). These data indicate that varia-tions in the degree of cholinergic vagal tonus on the heartserve as the predominant mode of nervous cardioregula-tion in elasmobranchs and that the level of vagal tone on


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the heart varies with temperature and oxygen partial pres-sure. A similar reliance of cardiac vagal tone on inputsfrom peripheral receptors has been identified in mammals(see sect. VIA).

In the teleost fish, the heart receives both a cholin-ergic vagal supply and an adrenergic sympathetic supply.Available data on the extent of vagal tone on the teleostheart give a wide range of values revealing species differ-ences and the effects of different environmental or exper-imental conditions. Variation in vagal tone affects heartrate, and a vagal, inhibitory, resting tonus has been dem-onstrated in some species (e.g., Carassius, Ref. 110). Inthe trout, vagal tone on the heart, although higher than inthe dogfish at all temperatures, decreased at higher tem-peratures. However, the cardioacceleration induced byepinephrine injection into atropinized fish increased withtemperature (660). In contrast, an inhibitory vagal tonuswas significantly greater in warm-acclimated than in cold-acclimated eels, and blocking vagal function with ben-zetimide reduced a nearly complete temperature compen-sation (558). These data indicate that adaptation of heartrate to temperature in the eel was largely mediated by theparasympathetic nervous system. Further evidence fortemperature-related changes in heart rate being deter-mined centrally was provided by work on Antarctic fishes,which indicated that the very low resting heart rates innormoxia at around 0°C are attributable to very highlevels of vagal tone (20, 607). An exception to this generalrule is the sturgeon, which exhibited no change in nor-moxic heart rate after atropinization (425).

2. Cardiorespiratory synchrony

As mentioned at the outset of this review, the match-ing of the flow rates of water and blood over the coun-tercurrent at the gills of fish, according to their relativecapacities for oxygen, is essential for effective respiratorygas exchange (498). The pumping action of the heartgenerates a pulsatile flow of blood, which in fish is deliv-ered directly down the ventral aorta to the afferentbranchial vessels. To optimize respiratory gas exchange,this pulsatile blood flow should probably be synchronizedwith the respiratory cycle, which typically consists of adouble pumping action, with a buccal pressure pumpalternating with an opercular or septal suction pump tomaintain a constant but highly pulsatile water flowthroughout the respiratory cycle. The flow is maximalearly in the respiratory cycle and declines during the lasttwo-thirds of a cycle (283, 286). Thus the supposed func-tional significance of cardiorespiratory synchrony relatesto the importance of continuously matching relative flowrates of water and blood over the countercurrent at thegill lamellae to optimize respiratory gas exchange.

A link between heart beat and ventilation in fish wasfirst noted in 1895 by Schoenlein (cited in Ref. 548), who

described 1:1 synchrony in Torpedo marmorata. Thisobservation has been repeated (604). The original obser-vation triggered numerous investigations of the occur-rence and mechanisms underlying cardiorespiratory syn-chrony in fish. Recordings of differential blood pressureand gill opacity in the dogfish revealed a brief period ofrapid blood flow through the lamellae early in each car-diac cycle (548), and because the electrocardiogramtended to occur at or near the mouth-opening phase of theventilatory cycle, this could result in coincidence of theperiods of maximum flow rate of blood and water duringeach cardiac cycle (565, 569). A clear coupling appears toexist since the heart tends to beat at a particular phase ofthe breathing cycle, for example, immediately after theopening of the mouth. The improvement in gill perfusionand consequent oxygen transfer resulting from pulsatilechanges in transmural pressure and intralamellar bloodflow (196) may be further improved by synchronization ofthe pressure pulses associated with ventilation and per-fusion. Cardiorespiratory synchrony may, by a combina-tion of these effects, increase the relative efficiency ofrespiratory gas exchange (i.e., maximum exchange forminimum work).

However, ventilation rate is usually two to threetimes faster than heart rate in experimental dogfish sothat if one ventilatory cycle coincides appropriately withheart beat, then the second or third in a sequence willoccur at a totally inappropriate phase of the cardiac cycle(565). Hughes (284) explored evidence for phase couplingbetween ventilation and heart beat in dogfish releasedinto a fish box that included a movement restrictor. So-phisticated analysis using event correlograms revealedthat in some cases the heart tended to beat in a particularphase of the ventilatory cycle for short periods. Use ofpolar coordinates revealed some significant coupling atvaried phase angles between the two rhythms, with indi-vidual fish varying in both the degree of coupling and thephase angle, during a period of observation. In the re-strained dogfish, ventilation rate was approximately twiceheart rate, and these showed a drifting relationship (604,610). Experimentally restrained dogfish show no hypoxicventilatory response (99) and no evidence of maintainedcardiorespiratory synchrony (284, 610). However, unre-strained fish show reduced normoxic ventilation rates,synchronous with heart beat, as described previously, andalso exhibit a ventilatory response to hypoxia (431).

The absence of synchrony, or even consistent closecoupling, as opposed to a drifting phase relationship, wasmost often attributable to changes in heart rate, whichwas more variable than ventilation rate in prepared dog-fish (284, 604, 610). Because they lack sympathetic inner-vation to the heart, this may be reliably interpreted asvariations in cardiac vagal tone. A decrease in vagal toneon the heart, such as that recorded during exposure tomoderately hyperoxic water, caused heart rate to rise


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toward ventilation rate (50, 604), suggesting that whenvagal tone was relatively low, a 1:1 synchrony could oc-cur. When cannulated dogfish were allowed to settle inlarge tanks of running, aerated seawater at 23°C, theyshowed 1:1 synchrony between heartbeat and ventilationfor long periods (604). This relationship was abolished byatropine, confirming the role of the vagus in the mainte-nance of synchrony. Whenever the fish was spontane-ously active or disturbed, the relationship broke downdue to a reflex bradycardia and acceleration of ventilationso that the 2:1 relationship between ventilation and heartrate characteristic of the experimentally restrained ani-mal was reestablished. Thus it is possible that the elusive-ness of data supporting the proposed existence of cardio-respiratory synchrony in dogfish was due to experimentalprocedures that increase vagal tone on the heart.

The heart in the dogfish operates under a variabledegree of vagal tone (see sect. VIB1). This implies that thecardiac vagi will show continuous efferent activity. Re-cordings from the central cut end of a branchial cardiacbranch of the vagus in decerebrate, paralyzed dogfishrevealed high levels of spontaneous efferent activity,which could be attributed to two types of unit (52, 53,611). Some units fired sporadically and increased theirfiring rate during hypoxia. Injection of capsaicin into theventilatory stream of the dogfish, which was accompaniedby a marked bradycardia, powerfully stimulated activityin these nonbursting units recorded from the central cutend of the cardiac vagus (318). Consequently, we sug-gested they may initiate reflex changes in heart rate, aswell as playing a role in the determination of the overalllevel of vagal tone on the heart, which as stated previ-ously seems to vary according to oxygen supply. Other,typically larger units, fired in rhythmical bursts that weresynchronous with ventilatory movements (607). We alsohypothesized that these units, showing respiration-relatedactivity that was unaffected by hypoxia, may serve tosynchronize heart beat with ventilation (611).

The separation of efferent cardiac vagal activity intorespiration-related and nonrespiration-related units wasdiscovered to have a basis in the distribution of theirneuron cell bodies in the brain stem. Extracellular record-ings from CVPN identified in the hindbrain of decerebrate,paralyzed dogfish by antidromic stimulation of abranchial cardiac branch revealed that neurons located inthe DVN were spontaneously active, firing in rhythmicalbursts that contributed to the respiration-related burstsrecorded from the intact nerve (51, 54). Neurons locatedventrolaterally outside the DVN were either spontane-ously active, firing regularly or sporadically but neverrhythmically, or were silent. Thus the two types of effer-ent activity recorded from the cardiac nerve arise fromthe separate groups of CVPN, as identified by neuroana-tomical studies (607).

Activity recorded from the central cut end of the

cardiac vagus, or centrally from CVPN, in the decerebrate,paralyzed dogfish is likely to be centrally generated. In theintact fish, stimulation of peripheral receptors will affectpatterns of activity. All of the spontaneously active CVPNfrom both divisions and some of the silent CVPN fired inresponse to mechanical stimulation of a gill arch, whichimplies that they could be entrained to ventilatory move-ments in the spontaneously breathing fish (607). Supportfor this idea was provided by phasic electrical stimulationof the central cut end of a branchial branch of the vagusin the decerebrate dogfish (M. J. Young, E. W. Taylor, andP. J. Butler, unpublished data). This entrained the efferentbursting units recorded from the central cut end of theipsilateral branchial cardiac branch, presumably due tostimulation of mechanoreceptor afferents (607). The fir-ing rates of the nonbursting units recorded from thebranchial cardiac were also increased, suggesting thatchemoreceptor afferents were being stimulated as well.Satchell (548) described a cyclical pattern of cardiac in-hibition in the dogfish that related to dilatation of thepharynx at each inspiration. This led to phasic increasesin vagal tone, superimposed on a tonic background ofvagal activity, which he suggested may relate to bloodpressure, although there is no evidence of baroreceptorinputs in elasmobranch fish (see above).

Consequently, normal breathing movements in theintact fish may indirectly influence cardiac vagal outflow,and subsequently heart rate, by stimulating branchialmechanoreceptors. Thus the typical reflex bradycardia inresponse to hypoxia may arise both directly, followingstimulation of peripheral chemoreceptors, and indirectly,via increased stimulation of ventilatory effort, which bystimulating branchial mechanoreceptors may increase va-gal outflow to the heart. This is reminiscent of, but oppo-site in kind to, the hypoxic response in the mammal,where stimulation of lung stretch receptors causes anincrease in heart rate (144).

These data support a previous conclusion that syn-chrony in the dogfish was reflexly controlled, with mech-anoreceptors on the gill arches constituting the afferentlimb and the cardiac vagus the efferent limb of a reflex arc(548). However, the spontaneous, respiration-relatedbursts recorded from the branchial cardiac nerve contin-ued in decerebrate dogfish, after treatment with curare,which stopped ventilatory movements, suggesting thatthey originated in the brain stem. Direct connectionsbetween bursting CVPN and RVM are possible in thedogfish hindbrain, as both are located in the DVN with anoverlapping rostrocaudal distribution (see sect. IVC). Be-cause the bursts are synchronous, the innervation ofCVPN is likely to be excitatory rather than inhibitory asdescribed for the mammal, and it is equally possible thata direct drive from a central pattern generator operatesboth on the RVM and the CVPN (607). The interactions


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that may determine the patterns of activity in dogfishCVPN are summarized in Figure 12.

These data from elasmobranchs suggest that cardio-respiratory synchrony, when present, is due primarily tocentral interactions generating respiration-related activityin CVPN located in the DVN, which are then effective indetermining synchronous heart beating when overall car-diac vagal tone, attributable primarily to activity in CVPNlocated outside the DVN, is relatively low in normoxic orhyperoxic fish. Synchrony will be reinforced in the spon-taneously breathing fish by rhythmical stimulation ofbranchial mechanoreceptors (as described above).

Confirmation that the heart may beat at a rate deter-mined by bursts of efferent activity in the cardiac vagi wasobtained by peripheral electrical stimulation of these

nerves in the prepared dogfish. Although continuous vagalstimulation normally slows the heart, it proved possible todrive the denervated heart at a rate either lower or some-what higher than its intrinsic rate with brief bursts ofstimuli, delivered down one branchial cardiac vagalbranch. At a rate several beats higher than its intrinsicone, the heart responded to alternate bursts of electricalpulses so that it began beating at half the rate of the bursts(Young et al., unpublished data). Interestingly, similarresults were obtained from a mammal. In the anesthetizeddog, electrical stimulation of the vagus nerve toward theheart with brief bursts of stimuli, similar to those re-corded from efferent cardiac vagal fibers, caused heartrate to synchronize with the stimulus, beating once foreach vagal stimulus burst over a wide frequency range(393).

Work on teleosts has stressed the importance ofinputs from peripheral receptors in the genesis of cardio-respiratory synchrony. Efferent nervous activity recordedfrom the cardiac branch of the vagus in the tench wassynchronized with the mouth-opening phase of thebreathing cycle (509). It was suggested that this activitymaintains synchrony between heart beat and breathingmovements and that both a hypoxic bradycardia and syn-chrony were mediated by reflex pathways. Randall andSmith (515) described the development of an exact syn-chrony between breathing and heart beat in the troutduring progressive hypoxia. In normoxia, heart rate wasfaster than ventilation; hypoxia caused an increase inventilation rate and a reflex bradycardia that converged toproduce a 1:1 synchronization of the two rhythms. Boththe bradycardia and synchrony were abolished by atro-pine. In addition, they were able to demonstrate 1:1 syn-chronization of hypoxic heart rate with pulsatile forcedventilation, which was clearly generated by reflex path-ways, presumably arising from mechanoreceptors on thegills, because the spontaneous breathing efforts of theintubated fish were out of phase with imposed changes inwater velocity and were without effect on heart beat(515). It is interesting in this regard that heart rate wasobserved to rise immediately upon the onset of ram ven-tilation in the trout, implying a reduction in vagal tone(607). Because this can be attributed to the effect ofcessation of activity both in the CPG and in the respira-tory apparatus, it implies that respiratory activity to someextent generates cardiac vagal tone. This is the obverse ofthe situation in mammals, where cessation of ventilation,for example during SLN stimulation (see above), in-creases vagal tone on the heart (329).

Thus we are left with an apparent conflict of evidenceon the mode of generation of cardiorespiratory syn-chrony. In elasmobranchs it may be centrally generated ininactive, normoxic, or hyperoxic fish when cardiac vagaltone is low, whereas in teleosts it appears during hypoxiaand is generated reflexly by increased vagal tone. The

FIG. 12. Diagram of possible afferent and efferent connections ofpreganglionic vagal motoneurons in hindbrain of dogfish that controland coordinate gill ventilation and heart rate. There are several estab-lished connections in nervous control of ventilation: 1) respiratorycentral pattern generator neurons (CPG) show endogenous burstingactivity that drives respiratory motoneurons (RVM); 2) RVM innervateintrinsic muscles in gill arches; 3) activity of CPG is modulated byfeedback from mechanoreceptors and possibly chemoreceptors locatedon or near gills and innervated by vagal sensory neurons (RVS). Heartrate is controlled by inhibitory input from vagus nerve that receivesaxons from cardiac vagal motoneurons (CVM), which are topographi-cally and functionally separable into 4) a ventrolateral group, some ofwhich fire continuously and may be responsible for reflex changes inheart rate (e.g., hypoxic bradycardia) and for varying level of vagal toneon heart, and 5) a medial group, which burst rhythmically and may causeheart to beat in phase with ventilation. Other more speculative connec-tions may determine activity in CVM. 6) Collaterals from neighboringRVM may have an excitatory effect on bursting medial CVM (or releasea tonic inhibiton). 7) CPG may connect directly to medial CVM. 8)Stimulation of receptors on gill arches may directly modify activity inmedial and some ventrolateral CVM. 9) Stimulation of receptors incardiovascular system close to heart, innervated by vagal sensory neu-rons (CVS), may affect vagal outflow to heart. This diagram is highlyschematic and ignores existence and possible roles of interneurons andinputs from and to higher centers in central nervous system. ‚, Efferenttermination; Œ, afferent termination; S, sinus venosus; A, atrium; V,ventricle. [From Taylor (607).]


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differences between these two groups of fish may be real,and it is of interest that branchial denervation increasesfictive ventilation rate in elasmobranchs but decreases itin teleosts. However, it is as likely that further experimen-tation will establish that both central and peripheralmechanisms are important in each group. When cod werecannulated and released into large holding tanks of nor-moxic seawater, they showed periods of 1:1 synchrony(311, 607). The importance of these observations is thatthey measured dorsal aortic blood flow, which was mark-edly pulsatile in phase with variation in buccal pressure,confirming a role for cardiorespiratory synchrony in thegeneration of concurrent flow patterns of ventilation andperfusion over the gills. Thus both unrestrained dogfishand cod can show synchrony, and as our understanding ofthe underlying mechanisms increases, it seems likely thatelasmobranchs and teleosts will share common charac-teristics with respect to the generation and potential phys-iological advantages of cardiorespiratory synchrony.

What emerges from our present understanding is thata potent mechanism for the generation of cardiorespira-tory synchrony in fish exists in the form of entrainment ofthe heart by the bursting units present in recordings ofefferent activity in the cardiac vagi, whether these aregenerated by central interactions, reflexly by stimulationof branchial mechanoreceptors, or most likely by a com-bination of central and peripheral mechanisms. Entrain-ment of the heart with the bursts of efferent, respiration-related activity in the cardiac vagi could explain the 1:1synchrony observed in “settled” normoxic dogfish andcod and in hypoxic trout. As discussed above, cardiore-spiratory synchrony may serve to optimize the effective-ness and/or efficiency of respiratory gas exchange andtransport in fish.

C. Air-Breathing Fish

Air-breathing fish use their gills for breathing waterand intermittently ventilate an accessory ABO. Usuallythe circulation to the ABO is derived postbranchially.Thus the entire cardiac output is directed toward the gills,but only a portion perfuses the accessory ABO. Selectiveperfusion may depend on sympathetic a-adrenergic con-trol (195), but because there is a reflex increase in perfu-sion of the ABO associated with each air breath, oftenwithout changes in cardiac output, some local efferentneural mechanism is likely to be important (307, 513).Lungfish intermittently breathe air, during which therecan be up to a fourfold increase in lung perfusion andincreased cardiac output associated with each breath.Control of pulmonary blood flow involves branchialshunts that are neurally regulated and cholinergic vaso-constriction of the pulmonary artery (205, 310).

D. Amphibians

A recent authoritative review considered the influ-ences of phylogeny, ontogeny, and season on central car-diovascular function in amphibians (89). The author pre-sented a detailed synopsis of our current understanding ofthe progressive development of vagal, cholinergic andsympathetic, adrenergic control of the heart in amphibi-ans, based largely on the bullfrog tadpole. Early-stage,fully aquatic larvae show no evidence of reflex adjust-ments of heart rate. Cholinergic sensitivity of the cardiacpacemaker increases during larval development, and avagal tone on the heart is first apparent at the onset ofair-breathing. At metamorphosis, there is a sharp de-crease in cholinergic sensitivity, and adult bullfrogs showno resting vagal or adrenergic tone on the heart. However,heart rate varies during intermittent lung ventilation inadult anurans (see below), and an exercise tachycardiaresults in part from b-adrenergic stimulation and a divingbradycardia from increased vagal tone. These changesduring ontogeny are summarized in Figure 13, which istaken from Burggren’s review (89).

Cardiac vagal tone varies widely with temperature insome amphibians. Injection of atropine into Xenopus

caused a doubling of mean heart rate from 6 to 12 beats/min at 5°C. At 15°C, the increase was from 9 to 35 beats/min and at 25°C from 12 to 70 beats/min (609, 612). Vagalcontrol has a major modulating effect on the temperaturedependency of heart rate with Q10 values between 5 and15°C of 1.5 and 15–25°C of 1.4 increasing to 2.8 and 2.0,respectively, after atropinization. However, the situationis complicated by the presence of a b-adrenergic tone onthe amphibian heart. When this was abolished by injec-tion of propranolol, heart rate decreased. This adrenergictone also increased with acclimation temperature. Injec-tion of propranolol plus atropine revealed the true level ofthe predominant vagal tone that increased with tempera-ture, but in a linear rather than exponential fashion (612).

Amphibians have evolved control mechanisms thatrelate to whether they are more or less committed to lungbreathing. Those that are less committed to air-breathingor have no lungs, like the lungless salamanders (Pleth-

odontidae), rely solely on sympathetic adrenergic regula-tion of cutaneous blood flow to control blood gases (195).In intermittent lung breathers like the frog and toad,control of pulmonary blood flow is achieved by a strongvagal cholinergic vasoconstriction of the pulmocutaneousartery that is extrinsic to the lung (112, 647). Vasocon-striction in the pulmonary circuit reduces pulmonaryblood flow and increases systemic recirculation of oxy-gen-poor blood from the right atrium, whereas decreasedvagal tone on the pulmonary artery is associated with theincreased pulmonary blood flow observed during lungventilation (647). Adrenergic sympathetic vasoconstric-tion of the cutaneous circulation contributes secondarily


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to increases in pulmonary blood flow (647). The extent towhich withdrawal of vagal tone versus increased sympa-thetic tone contributes to the increased heart rate andpulmonary blood flows associated with lung ventilation isnot resolved, but it may be primarily due to release ofvagal tone, because vagotomy or injection of atropinereduces or abolishes cardiorespiratory coupling (640).

Although most anuran larvae show unchanging heartrates during episodic lung ventilation (89), there is a clearcardiorespiratory coupling in adult anurans, in that inter-mittent lung ventilation is matched by intermittent in-creases in pulmonary blood flow, without compromisingsystemic blood flow (383, 566). The mechanisms underly-ing these relationships are unknown. Recent experimentsdemonstrated increases in heart rate and pulmonaryblood flow during bouts of fictive breathing in decere-brate, paralyzed and through ventilated toads, indicatingcentral control of cardiorespiratory interactions (640).These may in part arise from the overlapping centraltopography of CVPN and pulmonary VPN (see sect. IVF).Alternatively, stimulation of lung stretch receptors duringbouts of breathing may result in release of vagal tone onthe heart and pulmonary artery. Artificial inflation of thelungs in anesthetized frogs and toads elicited cardiovas-cular responses similar to those observed in normallybreathing animals, which were abolished by deep anes-thesia or injection of atropine (640). However, in con-scious Xenopus, denervation of pulmonary stretch recep-

tors did not abolish the increase in heart rate associatedwith lung inflation (190).

Some of the cardiac responses to intermittent lungventilation may be generated directly by mechanical orchemical factors (640). In anesthetized toads, artificiallung inflation caused increased pressure in the left atriumand an elevated heart rate that was not abolished byatropine injection, implying that direct mechanical effectson venous return to the heart (i.e., the Frank-Starlingmechanism) may contribute to cardiorespiratory cou-pling. An alternative mechanism has been proposed foranesthetized and unidirectionally ventilated toads, inwhich hypoxia and hypercapnia reduced pulmonaryblood flow. Some of this response may be locally medi-ated, by a direct effect on vascular tone.

The existence of phase coupling of heart beat withventilation in amphibians is contentious, although recentobservations (T. Wang, E. W.Taylor, S. Reid, and W. K.Milsom, unpublished data) indicated that coupling waspresent for periods of time in decerebrate, paralyzed, andunilaterally ventilated toads, implying generation by cen-tral interactions.

E. Reptiles

Reptiles are typically periodic breathers, and duringbouts of breathing, the degree of shunting of blood flow to

FIG. 13. Ontogeny of cardiac regulation in bullfrog, Rana catesbeiana. Horizontal bar represents an individual’s lifespan. Major developmental landmarks as well as appearance, modification, and/or disappearance of cardiac regulatorymechanisms are shown. Vertical arrows represent a single observation of indicated event. A vertical arrow combinedwith a horizontal arrow indicates onset of a continuing process. [From Burggren (89). Copyright 1995 Springer-Verlag.]


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the lung increases. Vasomotor control is important indiverting blood between the pulmonary and systemic sys-tems (662). In turtles and lizards, the net direction andmagnitude of shunt flow is affected by resistance in thepulmonary circuit, relative to the systemic circuit, byactive vagal, cholinergic regulation of pulmonary arterialresistance (268).

Reptiles show clear examples of cardiorespiratorycoupling. In the free diving turtle, Trachemys scripta,pulmonary blood flow increased more than threefold atthe onset of breathing, during recovery from breath-holdslasting longer than 5 min (641). Systemic blood flow alsoincreased during ventilation. These increases were ac-complished entirely through changes in heart rate duringventilation, with stroke volume unchanged. Systemicblood flow always exceeded pulmonary flow so that a netright to left cardiac shunt prevailed, regardless of venti-latory state. Nevertheless, because pulmonary flow in-creased markedly during ventilation, the ratio of pulmo-nary to systemic flow increased from 0.3 to 0.8. Thesecardiovascular changes associated with intermittent lungventilation in discontinuous breathers have been referredto as cardiorespiratory synchrony (e.g., Ref. 641), which isa different use of the term compared with one-to-onesynchrony in fish (see sect. VIB). In both the turtle, Pseu-

demys scripta, and the tortoise, Testudo graeca, the onsetof lung ventilation was closely accompanied by a tachy-cardia (86). As stimulation of pulmonary stretch recep-tors, arterial chemoreceptors and baroreceptors, or waterreceptors was without effect on heart rate, it was con-cluded that this ventilation tachycardia resulted from cen-tral interactions between respiratory and cardiac neuronsin the medulla. Because the breathing tachycardia wasunaffected by b-adrenergic blockade, it seems that allchanges in heart rate were mediated by alterations invagal tone. This was borne out by the observation thatefferent vagal activity decreased progressively as heartrate increased at the onset of ventilation. Injection ofatropine increased heart rate during apnea to the rateobserved during breathing, when vagal tone is low. Heartrate fell slightly before and markedly after hatching in thesnapping turtle, Chelydra serpentina, indicating the es-tablishment of a vagal tone on the heart, coincident withthe onset of lung breathing (69).

F. Birds

Neural control of the avian heart was reviewed byCabot and Cohen (108). The heart in birds is innervatedby branches of the vagus nerve that exert a cholinergic,tonic inhibitory influence on heart rate so that bilateralvagotomy causes a marked tachycardia (628). Electricalstimulation of either vagus elicits a profound bradycardiaor cardiac arrest in birds. However, there is evidence that

functional vagal input to the heart may be asymmetric,with the nerve on one side (often the right) exerting mostof the inhibitory influence over heart rate. Cardiac vagaltone is reportedly high in many birds, with bilateral va-gotomy causing a tripling of heart rate in the pigeon andduck. Direct evidence of cardiac vagal tone was obtainedfrom the pigeon, in which the majority of CVPN werereckoned to be active in the unanesthetized bird (108).This observation may now be open to question due to thecurrent debate regarding the central location of CVPN inbirds (see sect. IVG).

The nature of cardiorespiratory interactions in birdshas been elucidated to some extent by study of the re-sponses to submersion of diving species (96, 98, 589).Both central and peripheral respiratory drives are over-ridden by submersion of diving birds. Simultaneous stim-ulation of water receptors in the facial skin, innervated bythe trigeminal (Vth) cranial nerve and in the respiratorytract, innervated by the glossopharyngeal (IXth) and va-gus (Xth) cranial nerves, invokes a reflex apnea. There issome evidence that the cardiovascular responses to sub-mersion (bradycardia and vasoconstriction in most vas-cular beds) may arise, in part, directly from stimulation ofwater receptors. However, the reflex apnea, because it isassociated with cessation of central respiratory drive andphasic stimulation of lung receptors, is most likely anecessary prelude to the full development of these re-sponses. The full development of a diving bradycardia inthe mallard duck, Anas platyrhynchos, was dependent onthe cessation of central respiratory activity and of respi-ratory movements, and artificial lung inflation during sub-mersion markedly diminished the cardiovascular re-sponse (101). Ducks, in common with diving mammalssuch as seals, usually enter a dive in the expiratory phase.Consequently, their CVPN are likely (on the basis of themammalian model) to be accessible to afferent inputs,rather than refractory, as they would be if dives wereexecuted in the inspiratory phase (96). The progressivesystemic hypoxia, developed during prolonged submer-sion, then stimulates peripheral chemoreceptors, causinga profound, vagally mediated bradycardia. Penguins andwhales, however, dive on inspiration and show a rela-tively slowly developing bradycardia (96).

Clear indications of respiration-related oscillations inheart rate, similar to the respiratory sinus arrhythmiadescribed in mammals, were recorded in spontaneouslybreathing ducks. The peaks of the accelerations in heartrate were clipped off when water was poured down anorally facing tracheal cannula, suggesting that they weregenerated by the intact respiratory rhythm and lost duringstimulation of receptors normally responding to submer-sion, which induce apnea (101). This implies that inhibi-tory activity in CVPN is modulated by respiratory activity,and as this modulation reduces vagal tone, it is likely toresemble the situation described in mammals where ac-


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tivity in inspiratory neurons inhibits CVPN (see sect. VIA).There was a slight increase in heart rate on surfacing froma period of forced submersion in ducks with denervatedlungs, which was interpreted as evidence for central in-teractions between inspiratory neurons and vagal cardi-omotor neurons (101).

VII. CONCLUDING COMMENTS

As animals our lives are marked by rhythms, and therhythmical activities of ventilation and heart beat aretangible evidence of the life force in each of us. What wecannot judge by merely feeling or listening are the subtleprocesses of generation, regulation, and integration ofthese internal rhythms. Present evidence suggests that inall vertebrates, from jawless fishes to mammals and birds,innately rhythmic neuronal systems in the brain stemgenerate the respiratory rhythm. The central oscillatordriving gill ventilation in fish, initiating lung-breathingepisodes in amphibians, and reptiles and promoting ven-tilation and suckling in neonatal mammals may reside inthe reticular formation, suggesting that this center ofrhythmicity has a long evolutionary history. Fish use re-spiratory muscles, innervated by cranial nerves, for gillventilation, but can recruit hypaxial feeding muscles, intoforced ventilation. These same muscles are used to gulpair at the water surface by air-breathing fish and forbuccal and lung ventilation in amphibians. They are in-nervated by the hypobranchial nerve, comprising occipi-tal and anterior spinal nerves, which is the forerunner ofthe hypoglossal nerve, innervating the tongue of advancedtetrapods. The aspiratory, thoracic pump, characteristicof mammals and birds, which requires that the CPG in thebrain stem supplies descending fibers to innervate spinalmotoneurons, appears in reptiles but may be forshad-owed in some amphibians, whereas some reptiles retainthe use of a buccal pump. Evidence favors the existenceof separate central respiratory rhythm generators for gill/buccal cavity and ABO/lung ventilation, in air-breathingfish and amphibians, which may be the evolutionary an-tecedents of the separate areas generating inspiratoryrhythms in mammals. The relative importance of afferentinput from peripheral mechano- and chemoreceptors ininitiating and sustaining ventilation remains unresolved.This whole area presents exciting and important oppor-tunities for continued research, because the mechanismsof control of respiratory rhythms in all vertebrate groupsremain incompletely understood. It is, of course, a primeexample of an area in which an evolutionary approach tocomparative studies is likely to increase our understand-ing of fundamental mechanisms, as is illustrated by therecent advances of Feldman and his group working onneonatal mammals and Remmers and his group on thefrog brain stem (203, 429).

In mammals, the responses to stimulation of arterialchemoreceptors, baroreceptors, and lung stretch recep-tors are well characterized. Tracing their afferent projec-tions into the NTS has revealed elements of a topographicseparation of fibers innervating different organs and fromdifferent vagal branches. Slowly adapting pulmonarystretch receptor afferents (PSRA) project rostral of obex;rapidly adapting PSRA more caudally, and bronchial andpulmonary C-fiber afferents project to medial regions ofthe NTS around obex, together with arterial chemorecep-tor afferents. Afferent projections from the upper respi-ratory tract converge in the trigeminal nucleus. The de-tailed topography of these projections is likely to befundamental to their functional roles in controlling thecardiorespiratory system. Similar detail of central projec-tions from reflexogenic sites in the cardiorespiratory sys-tem is lacking for other vertebrates, and this is a fertilearea for further study.

Peripheral receptors in fish are less well character-ized. Only mechanoreceptors and peripheral chemorecep-tors sensitive to oxygen partial pressure, both diffuselydistributed on the gill arches, have been positively iden-tified by nerve transection and recording. There is strongcircumstantial evidence for oxygen content receptors inthe arterial and possibly in the venous system of fish, butthey have not as yet been localized or characterized. Bothperipheral chemoreceptors and pulmonary stretch recep-tors, which were described as slowly adapting and mod-ulated by CO2, have been identified and characterized infrogs and toads. Both of these receptor types project to anarea of the hindbrain identified as the NTS. The situationso well described for mammals seems to have a longancestry, extending back to or possibly beyond the evo-lution of air-breathing.

Central chemoreceptor control of ventilation, al-though seemingly unimportant in fish, predominates in airbreathers from amphibians, through reptiles, to birds andmammals. A clue to the origins of a functional role forcentral chemoreceptors is provided by ontogenetic stud-ies on amphibians. Fictive ventilation, measured from thebullfrog brain stem, is insensitive to hypercapnic acidosisin early larval stages but becomes progressively sensitizedas lung ventilatory bursts begin to predominate over gillbursts, during metamorphosis. This developing sensitivityis coincident with recognizable topographical changes inthe nucleus isthmi, an area of the brain stem recognizedas being associated with the integration of chemoreceptorresponses and the generation of episodic breathing inamphibians and the functional equivalent of the pons inthe mammalian brain stem. It also may relate to theventrolateral relocation of VPN at metamorphosis, notedin the axolotl. Because the ventrolateral medulla is thesite of central chemoreception in mammals, it is an en-tertaining notion that there may be a direct correlationbetween the relocation of VPN and the onset of central


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chemoreceptor drive in amphibians. Once again, this areapresents itself as ripe for further comparative studies ofthe ontogeny and phylogeny of central chemoreceptorcontrol, to further our understanding of its fundamentalnature and functional roles.

Evidence of the existence of baroreceptor responsesin fish remains controversial, and the evolution of a rolefor baroreceptor afferents and for vasomotor control,exercised via the sympathetic nervous system, in controlof the cardiovascular system, may be associated with theevolution of air-breathing. The gills of fish are neutrallybuoyant, and ventilation of the gills generates hydrostaticpressures in their dense respiratory medium that matchblood pressures in the branchial circulation so that thepressure differential is relatively low. Lungs, in contrast,are held in air that provides no support and allows thedelicate respiratory surfaces to leak tissue fluid at a ratedetermined by their permeability, which of course is high,and the pressure gradient from blood to air, which con-sequently must be closely controlled between definedlimits. Possibly because they retain gills, lungfish havesimilar, relatively low blood pressures in the respiratoryand systemic circuits. Differences in pressure betweenthe circuits appear in the amphibians and reptiles but arecomplicated by the presence of the variable cardiac shuntthat can create similar pressures with unequal flows ineach circuit. In the mammals, their requirement for a fastcirculation time to satisfy their high metabolic rate resultsin very high arterial blood pressures in the systemic cir-cuit, compared with lower vertebrates. However, thepressures developed in the pulmonary circuit are a littlelower than those measured in fish so that there is a 10-folddifference between the pressures developed in the sys-temic and pulmonary circuits. This difference is of coursemade possible by their completely separated circulatorysystem in which flows must be equal on each side whilepressures are very different. Despite this separation, it isimportant that blood pressure is maintained below a max-imum to protect against leakage from the lung or lungdamage. Consequently, there are clear roles for barore-ceptors monitoring blood pressure and vasomotor controlof peripheral resistance in lung breathers, which are notpresent in gill breathers. Control of minimum pressuresare of course equally important, particularly for kidneyand brain function, and no doubt these requirements alsovary between fish and mammals.

Regulation of heart frequency is essentially similar inmammals, birds, reptiles, amphibians, teleosts, and elas-mobranchs. With the exception of the jawless fishes, thecyclostomes, all vertebrates have an inhibitory musca-rinic, cholinergic supply to the heart via the vagus nerve.A cardioexcitatory b-adrenergic innervation is providedvia sympathetic nerve trunks in all vertebrates other thanthe cyclostomes and elasmobranchs. Vagal inhibition ofheart rate seems to predominate in most vertebrates, but

cardiac sympathetic excitation becomes more prominentin endotherms. The heart in most vertebrates operatesunder fluctuating levels of inhibitory vagal tone. Thisvaries with temperature, hypoxia, disturbance, and anes-thesia and fluctuates with the breathing cycle, the sourceof cardiorespiratory synchrony in fish and respiratorysinus arrhythmia in mammals. Sympathetic outflow to theheart and peripheral circulation, responsible for vasomo-tor tone, as well as outflow to the upper respiratory tract,also shows fluctuating levels of activity, with respiration-related components. It is interesting to hypothesize thatrespiration-related rhythmicity in the nervous supply tothe cardiovascular system may serve to optimize its func-tional integrity, as well as respiratory gas exchange andtransport. These possibilities would seem to invite furtherfunctional studies.

The central origins of fluctuations in vagal tone onthe heart, and the consequent variability of heart rate,together with the origins of fluctuations in vasomotortone, in the different vertebrate groups have been a cen-tral theme of this review. Central interactions appear tooriginate partially as a result of the convergence of sen-sory projections noted above, and the specific, and some-times overlapping, distribution of preganglionic and vis-ceral motoneurons in the brain stem and spinal cord. Forexample, comparative neuroanatomical studies have re-vealed that the distribution of VPN between the DVN andthe ventrolateral nA varies between groups. In elasmo-branch fish, only 8% of VPN are in the nA, but they are allCVPN. This ventrolateral group of cells seems to deter-mine the reflex responses of the heart to external stimuli,such as hypoxia, whereas the CVPN in the DVN showrespiration-related activity, which may generate cardiore-spiratory synchrony. This topographical and functionalseparation of CVPN has since been found to be reflectedin the brain stem of mammals, in which two functionallyseparate populations of CVPN have been identified, onlyone of which responds to pulmonary stretch receptorinputs. The most recent evidence suggests that, as indogfish, these are topographically separated between thenA and DVN, indicating that functional separation of VPNmay be fundamental to their control functions. This clearlink between the primitive elasmobranch fishes and themammals is bridged by an intriguing phylogenetic pro-gression. In bony fishes, ;12% of VPN are located ventro-laterally outside the DVN; these are predominantly CVPN,but some cells supply axons to branchial (respiratory)branches of the vagus. This proportion rises to 15, 20, andeven 30% in the different classes of amphibians with theventrolateral relocation of VPN outside the DVN occur-ring at metamorphosis, concurrent with the onset of epi-sodic lung breathing and central chemoreceptor re-sponses. This proportion stabilizes at 30–40% inmammals, with up to 80% of CVPN located in the nA,together with respiratory motoneurons, from which they


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receive inhibitory inputs, generating respiratory sinus ar-rhythmia, an arrangement established during embryolog-ical development. However, this neat progression is con-fused in the markedly polyphyletic reptiles, with theturtles and some lizards having high proportions of VPNin the nA, and other lizards and alligators having ,5% ofVPN in this location. This alternate pattern characterizesthose near ancestors of the dinosaurs, the birds, with ,3%of VPN found in the nA of the duck. Interestingly though,a large proportion of the VPN in the nA of the duck areCVPN. Separate functions have yet to be assigned to theCVPN in the dual locations in the brain stems of amphib-ians, reptiles, and birds. Further study of this area seemslikely to be of very great interest and of importance to ourunderstanding of the development and evolution of thecontrol systems associated with air-breathing. The am-phibians should be a primary target for these studiesbecause they metamorphose from committed gill breath-ers to facultative lung breathers, and we already knowthat this process is accompanied by topographicalchanges in appropriate regions of the CNS. A combinationof neuranatomical, neurophysiological, and functionalstudies of the kind previously applied to mammalian spe-cies should uncover new and fascinating insights into thisexciting area of study as amphibian ontogeny, at least inpart, recapitulates vertebrate phylogeny.

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