Brain Stem Catecholamine Mechanisms in Tonicand Reflex Control of Blood Pressure

DONALD J. REIS, ANTONIO R. GRANATA, TONG H. JOH, CHRISTOPHER A. Ross,

DAVID A. RUGGIERO, AND DONG H. PARK

SUMMARY Neurons of the lower brain stem maintain resting levels of arterial pressure (AP),mediate reflex responses from cardiopulmonary receptors, and are an important site of the hypoten-sive actions of a2-adrenergic agonists. Details of the pathways and transmitters that mediate tonic andreflex control of AP are emerging. Afferent fibers of cardiopulmonary receptors in the ninth and tenthnerves terminate bilaterally in the nucleus of the tractus solitarius (NTS). Although some neuronscontain substance P, the primary neurotransmitter appears to be the excitatory amino acid L-gluta-mate (L-glu). Neurons in rostral ventrolateral medulla, which most probably comprise the Cl groupof epinephrine neurons, are also critical in AP control. Cl neurons project to innervate cholinergicpreganglionic sympathetic neurons in the spinal cord. Stimulation of the Cl area electrically or withL-glu increases AP, while lesions or local injection of the inhibitory amino acid gamma-aminobutyricacid (GABA) lowers AP to levels comparable to spinal cord transection. Lesions of Cl neurons or theirpathways abolish vasodepressor reflexes from baroreceptors and vagal afferents. In contrast, norad-renergic neurons of the caudal ventrolateral medulla, the Al group, project rostrally to innervate, inpart, vasopressin neurons of the hypothalamus. Stimulation of Al neurons lowers AP, while lesions orGABA elevates it. We propose that Cl neurons comprise the so-called tonic vasomotor center of thebrain stem and also mediate, via a projection from the NTS, the vasodepressor limb of baroreflexes.The NTS-C1 projection may be GABAergic. (Hypertension 6 (Suppl II): II-7-II-15, 1984)

KEY WORDS • adrenergic • adrenaline neurons • noradrenergic neuronsbaroreceptor reflexes • blood pressure * nucleus of the tractus solitarius

IT has long been recognized that neurons within thelower brain stem, which comprise the medullaoblongata and pons, are critical for the tonic and

reflex regulation of systemic arterial pressure (AP).1"3

Neurons in the lower brain: (1) maintain tonic back-ground drive to sympathetic preganglionic neurons,thereby maintaining normal resting levels of AP2"4; (2)are the site of termination of cardiopulmonary affer-ents, which includes those from high and low pressurebaro- and other cardiopulmonary receptors5"8; and (3)are the major targets of those centrally acting a-adren-ergic agonists that act as antihypertensive agents, mostnotably, clonidine and a-methyldopa.9"12 Indeed thatthese agents, which act on receptors in the brain nor-mally stimulated by catecholamines, produce cardio-vascular actions by stimulation of baroreceptors," n

From the Laboratory of Neurobiology, Department of Neurol-ogy, Cornell University Medical College, 1300 York Avenue, NewYork, New York 10021.

Address for reprints: A. R. Granata, Lab. of Neurobiology, 411E. 69th St., New York, New York 10021.

raises questions about the relationship between thecentral networks responsible for maintaining AP andthe central catecholamine neurons.

This paper reviews recent research from our labora-tory directed toward clarifying the networks in thelower brain stem that are responsible for maintainingnormal levels of AP and mediating barorefiex re-sponses. Our findings suggest an important new rolefor catecholamine cell groups of the lower medulla insuch control. We review these studies with the presentknowledge of control of the circulation by the brainstem.

Nucleus of the Tractus Solitariusand Arterial Pressure

The nucleus of the tractus solitarius (NTS) is themajor site of termination of afferents of the ninth andtenth cranial nerves. As such, the NTS is the majorrelay nucleus for information arising from barorecep-tors and cardiopulmonary afferents.

Interestingly, recognition that the NTS is critical forbaroreceptor reflex function is relatively recent and has

1-7

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11-8 HYPERTENSION SUPPL II VOL 6, No5, SEPTEMBER-OCTOBER 1984

been elaborated on only over the past 20 years. Theevidence for its role in control of AP stems from avariety of physiological and anatomical studies.5"8 Inbrief: (1) The NTS has been demonstrated by retro-grade transport techniques to be the site of terminationof afferents that arise from cardiopulmonary receptors.(2) Neurons in the NTS can be demonstrated to re-spond monosynaptically to stimulation of baroreceptorafferents and also to fire in synchrony with the arterialpulse, which indicates that they are locked into thebaroreceptor reflex chain. (3) Electrical stimulation ofthe NTS can, with stimuli of appropriate frequency,simulate the baroreceptors, while (4) lesions of theNTS have been demonstrated to abolish cardiopul-monary reflexes.13 Indeed, lesions of the NTS, pro-duced either by destruction of local neurons or byappropriate drugs, have been shown to result in neuro-genic hypertension.14-l5

The cardiovascular portions of the NTS are abun-dantly innervated by inputs from a variety of brainareas as well as from branches of the ninth and tenthnerves. These areas include the area postrema, para-brachial nucleus of the pons, various monoamine brainstem nuclei of pons, paraventricular and lateral hypo-thalamic nuclei, amygdala, and forebrain.16"18 Theseareas contain a wide variety of peptide and monoaminetransmitters.18 The transmitter of the primary afferentinput is uncertain. Studies from this laboratory over thepast several years have demonstrated that the baro-receptor response may be mediated by the excitatoryamino acid L-glutamate19"23 and not by monoaminergicnor cholinergic inputs,23"27 although these agents maymodulate the response (as may the various peptidesinnervating the area). On the other hand, there is histo-chemical and immunochemical evidence that sub-stance P also is contained in baroreceptor afferent fi-bers that innervate the NTS.28 Whether substance Pacts to mediate baroreflex responses or to modulatethem is uncertain, and the results of application of thisdrug locally to the NTS have been variable dependingon species and investigators.29"31

Ventrolateral Medulla and Cardiovascular ControlAlthough neurons in the NTS relay all information

arising from cardiopulmonary receptors to other cen-ters in the brain, the pathways by which such informa-tion is relayed, particularly those that signal an inhi-bition of vasomotor tone — the hallmark of thebaroreceptor vasodepressor response — until recentlyhave been unknown. Attention has focused on the ven-trolateral medulla as the area of importance in control-ling tonic and reflex control of AP. The ventrolateralmedulla can be separated into a rostral zone, the rostralventrolateral medulla (RVL), and a caudal zone, thecaudal ventrolateral medulla (CVL), which, as will bediscussed, differ functionally with respect to their ac-tivities in regulating the circulation.

Rostral Ventrolateral MedullaStudies have documented that bilateral lesions of the

RVL,32"34 c o o l ing of the area,35 or local application of

drugs such as gamma-aminobutyric acid (GABA),pentobarbital, or clonidine,10 36~38 reduce AP, some-times to a magnitude comparable to that produced byspinal cord transection. In contrast, electrical stimula-tion or local administration of excitatory amino acidsto the region has been observed to elevate AP.34 Suchevidence suggests the RVL may be responsible formaintaining tonic levels of AP. The region also maymediate vasodepressor responses to baroreflex stimu-lation: baroreflex responses disappear after bilaterallesions of, or application of kainic acid to, the area.39- ^

Anatomical studies have also supported the viewthat the RVL is important in control of AP; evidence isavailable that neurons in the RVL project into regionsof the spinal cord that contain preganglionic autonomicneurons41^3 and that RVL receives projections fromthe NTS.44"17

Caudal Ventrolateral MedullaThe CVL differs from the RVL with respect to its

actions on AP. Electrical or chemical stimulation ofneurons in the region under appropriate conditionslowered AP,48-49 while lesions of the area resulted inelevations of AP.49"5' Neurons in the CVL do not pro-ject to the spinal cord (see next section). Thus, infunctional terms, the RVL and CVL appear to haveopposite actions on AP. What has not been determinedare the identity of the neurons and their transmitterswithin each of these areas that are responsible for thecardiovascular effects. That it is different sets of cate-cholamine neurons within these regions that accountfor the functional differentiation has been suggested bysome recent studies, largely from this laboratory.

Catecholamine Neurons in RostralVentrolateral Medulla: Cl Group

It has long been known that the areas of the ventro-lateral medulla that have functionally been establishedas controlling AP contain neurons that synthesize andrelease catecholamines. In their pioneering studies,Dahlstrom and Fuxe52"53 described a group of histo-fluorescent neurons in the ventrolateral medulla thatwere presumed on the basis of their histofluorescenceto contain norepinephrine. These, the Al neurons,were believed to project to the spinal cord.

It should be emphasized that histofluorescence can-not differentiate, with certainty, between dopamine,norepinephrine, or epinephrine. It required the intro-duction of immunocytochemical techniques for the lo-calization of catecholamine biosynthetic enzymes toprovide a tool that could establish which catechola-mine a neuron could synthesize. Thus, neurons thatcontained only tyrosine hydroxylase had only the ca-pacity for synthesizing dopamine. The presence of ty-rosine hydroxylase and dopamine-/3-hydroxylase indi-cated that the neuron could synthesize norepinephrine,while the presence of the enzyme phenylethanolamineN-methyltransferase (PNMT), the enzyme that con-verts norepinephrine to epinephrine, indicated thatsuch a cell was adrenergic. In 1974 Hokfelt et al.,54

using an antibody to PNMT, discovered that a subpop-

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ulation of neurons called the Cl group, which weresituated in the most rostral portion of the Al group,contained this enzyme. The ventrolateral Al grouptherefore was not homogeneous, but consisted of twoparts: a rostral adrenergic Cl group and a caudal nor-adrenergic Al group with admixing in between."

Further evidence that the Al and Cl neurons differhas come from examination of their projections. Usingtracer techniques, it has been established that the Alneurons do not, as first believed, project to the spinalcord but rather send their axons rostrally, innervatingin large measure magnocellular neurons of the para-ventricular and supraoptic nuclei of the hypothala-mus—56~58 neurons that synthesize vasopressin andproject into the posterior pituitary. In contrast, a largepopulation of Cl neurons also send their axons cau-dally to innervate almost exclusively the intermedio-lateral column of the spinal cord (Figure I).59"61 In-deed, the major catecholaminergic innervation of thespinal cord originating in the medulla oblongata isadrenergic.59

Possible Function of Cl Adrenergic Neurons in the TonicControl of AP

It has long been known that electrical stimulation ofthe RVL will elicit elevations of AP and heart rate.3

Whether these effects are mediated by the C1 cells inthe RVL, however, remained to be established.

A144Medulla

FIGURE I. Autoradiographic demonstration of projectionsfrom the Cl region to the intermediolateral column (ILC). 10= inferior olive; IVN = inferior vestibular nucleus; MVN =medial vestibular nucleus; NTS = nucleus of the tractus soli-tarius; PP = nucleus prepositus; RPa = raphe pallidus; STN= spinal trigeminal nucleus; STT = spinal trigeminal tract.(From Ross et al.60)

In a recent series of experiments by combining elec-trical and chemical stimulation techniques along withcareful correlation with the anatomy of neurons stain-ing for PNMT, we39-w have demonstrated an extreme-ly tight correlation between the responses elicited fromthe Cl area and the distribution of neurons and theiraxonal processes, which contain the enzyme PNMT.In summary, electrical stimulation of the Cl area orwithin the axonal pathways elicited a powerful eleva-tion of arterial pressure and heart rate (Figure 2A).Such stimulation also elicited a release of adrenal med-ullary catecholamines and arginine vasopressin (AVP)from the hypofhalamus. The response to electricalstimulation was dependent on the stimulus frequencyin so far as the response was elicited with frequenciesof more than 2 Hz and reached a maximum at stimulusfrequencies greater than 100 Hz. The response wasgraded with respect to the stimulus intensity. Thethreshold for the response was less than 15 piAmp at 5times the threshold that elicited an elevation of AP inexcess of 80 mm Hg. The pressor response to electricalstimulation of the Cl area was dependent on stimula-tion of intrinsic neurons as elevations of AP of compa-rable magnitude could be elicited by the microinjectionof very small amounts of the excitatory amino acid L-glutamate (L-glu) into the area. Because L-glu did notexcite fibers of passage, we concluded that it was exci-tation of intrinsic neurons in the C1 area that caused thesympathetic neurons to discharge.

In contrast to the effects of excitation, interferencewith the activity of neurons in the Cl area resulted in acollapse of AP to levels comparable to those producedby spinal cord transection. Thus, small electrolyticlesions (Table I),62"63 the introduction of tetrodotoxin(Figure 2B),60 or the inhibitory amino acid GABA39 alllowered arterial pressure. The effects of such distur-bances were graded: unilateral lesions only producedpartial reductions of AP.62 Comparable reductions ofAP to those produced by lesions in the Cl cell bodyarea could also be produced by transecting lesions inthe brain stem that affect the fiber bundle stained forPNMT (unpublished observations).

These experiments therefore suggest that neurons inthe RVL are tonically active and that these neurons aretonically inhibited by GABA. These studies are entire-ly consistent with the view that the Cl neurons of theRVL provide tonic vasomotor tone.

Role of the Cl Area in Baroreceptor Reflexes

That the RVL participates in baroreceptor reflexresponses has been suggested by two lines of evidence:(1) Neurons in the RVL have been shown to be inner-vated by inputs from the NTS44"46; (2) bilateral lesionsof the RVL or the application of drugs to neuronssubadjacent to it3- *° abolished vasodepressor responseselicited by electrical or natural stimulation of cardio-pulmonary afferents (Table 1). Physiological studies,however, have been interpreted with difficulty becauselesions or drugs may often drop blood pressure to lev-els below that reached by maximal stimulation of baro-receptors.

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PNMT Label

TS

-200

-150

lOOmmHg

LOSEC triln

FIGURE 2a. Cardiovascular responses elicited from the Cl region in chloralose-anesthetized, paralyzed, artifi-cially ventilated rats. a. A single electrode tract is seen passing through the ventrolateral medulla (right side ofillustration). At each point, the animal was stimulated for 10 seconds with a square-wave pulse of 20 fxAmp, 100Hz. Note that the pressor responses are highly localized to regions that correspond with the distribution of cellslabeled for phenvlethanolamine N'-methyltransferase (PNMT) at the same level of the brain stem (left side ofillustration).

200

MEANARTERIAL ) m

PRESSURE(mmHgl

0

200

ARTERIALPRESSURE 100(mmHg)

0

600

HEART RATE(beats/mi n)

400

200

TETRODOTOXIN

INJECTION

AFTER SPINALTRANSECTION

TTX TTX lOmin lOntin

lmin

FIGURE 2b. Cardiovascular responses to bilateral injections of tet rodo toxin (lOpmolellOO nl saline) into the Clarea. The first injection (TTX), indicated by an arrow on the bottom of chart recording, produced a partialreduction of AP, while injection into the contralateral side (second arrow) resulted in a collapse of AP to le\'elscomparable to that produced by subsequent spinal cord transeclion. CST = corticospinal tract;10 = inferior olive; IVN = inferior vestibular nucleus; MVN = medial vestibular nucleus; NA = nucleusambiguus; NTSr = nucleus tractus solitarius pars rostralis; PP = nucleus prepositus; RPa = raphe pallidus;STN = spinal trigeminal nucleus; STT = spinal trigeminal tract; TS = tractus solitarius. (From Ross, et al.60)

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TABLE I. Effec ts upon Resting and Reflex Changes in Arterial Pressure and Heart Rate ofLe\ion(s) ofCI Area Alone or Combined with aUnilateral Lesion of the NTS*

Treatment

Bilateral Cl area lesions

Contralateral NTS and ipsilateralCl area lesions

N

4

4

Before

Control

MAP

98.5±8.2

96.9±6.6

HR

380.8±30.2

368.0±15.2

lesion

Vagal stimulation(mean change)

MAP

-32.5±3.1

-36 2±2.5

HR

-50 5±5.0

-29.8±5.4

After

Control

MAP

50.5±5.0t

89.4±7 1

HR

220.5±20.6t

399.6±26.9

lesion

Vagal stimulation(mean change)

MAP

-1 .3±1 0*

-2 .2±1.0*

HR

-1 .5±1.1*

-1 .8±0.8*

*From Granata et al.62 By permission of the American Heart Association+p < 0 025.%p < 0.01. when compared with controls (before lesion).NOTES: Unilateral vagal stimulation performed with pulse of 2-msec duration. 5 Hz and 10 times threshold current intensity; 10-sec train of

stimulus.Values are expressed as means ± SEM, N = number of experiments. MAP = mean arterial pressure (mm Hg), HR = heart rate (beats/min);

NTS = nucleus of the tractus solitarius.

That the Cl neurons of the RVL may mediate thebaroreflex response was suggested to us by our findingthat the Cl area was heavily innervated, largely unilat-erally, by a projection of the cardiovascular portions ofthe NTS.64 To test the hypothesis that the NTS-C1projection mediates the vasodepressor response frombaroreceptor afferents, we devised an experimentalmodel. The model has been based on the facts that theprojections from cardiopulmonary afferents of theninth and tenth nerves are distributed bilaterally8; thatthe projection from NTS appears primarily unilateral64;and that lesions of a single Cl area only partially re-duce resting AP (unpublished observations). We there-fore used a preparation in which the left vagus nerve istransected and stimulated electrically, and a lesion isplaced in the right NTS, thereby isolating the reflex arcfrom the vagal afferents or carotid sinus afferents onthat side to a single loop of the left NTS-left Cl area.A lesion then placed in the left Cl area should totallyinterfere with the reflex arc, but as the right Cl arearemains undamaged, background arterial pressure

should be maintained. Conversely, a lesion of the rightCl area would have no effect on reflex responses as theafferent loop of information from the left vagus andcarotid sinus nerves innervating the right Cl has beeninterrupted by the unilateral lesion of the right NTS.

We have discovered that (1) lesions of the right NTSresulted in a slight elevation of resting AP and in par-tial interference with the magnitude of the vasodepres-sor response to electrical stimulation of the left vagusnerve or stretch of the left carotid sinus region; (2) theaddition of a lesion of either the right or left Cl arearesulted in a lowering of AP to a level comparable tothat in the unoperated anesthetized rat (Table 1); (3) alesion of the left Cl area totally abolished reflex re-sponses elicited by electrical stimulation of the leftvagus nerve (Table 1) or carotid sinus (Table 2); (4)electrolytic lesion of the right NTS combined with alesion of the right Cl area had no further effect onvasodepressor responses than did the NTS lesionalone; (5) if kainic acid was injected into the left Clarea rather than placement of an electrolytic lesion, a

TABLE 2. Effects upon Cardiovascular Responses to Carotid Sinus Stretch of Le.sion(s) ofCI Area Alone or Combined with a UnilateralLesion of the NTS*

Treatment

Bilateral Cl area lesions

Contralateral NTS and ipsilateralCl area lesions

N

4

5

Before

Control

MAP

98.9±8.5

95.8±10.5

HR

346±20.8

355.0±10.1

lesion

Carotid sinus stretch(mean change)

MAP

-27.8±6.1

-29.8±6.7

HR

-27.2±7.1

-30.5±7.5

After

Control

MAP

51.01-±8.1

89.9±7.5

HR

233.3t±25.0

340.5±16.0

lesion

Carotid sinus stretch(mean change)

MAP

- 1 . 5 *±1.3

-1 .8± 1 . 1 *

HR

- 1 8*± 1.4

- 1.5± 1 . 1 *

*From Granata et al.62

tp < 0.025.*p < 0.01 when compared with controls (before lesion).NOTES: The carotid sinus baroreceptors were stimulated naturally (stretched) by pulling the ligature looped around the common carotid

artery downward toward the heart for 12 sec. In all cases, ipsilateral and contralateral are referred to the side of the vagal stimulation or carotidsinus stretch.

Values are expressed as mean ± SEM; N = number of experiments; MAP = mean arterial pressure (mm Hg); HR = heart rate (beats/min);NTS = nucleus of the tractus solitarius.

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comparable abolition of baroreceptors was obtained,which indicated that the effects of electrolytic lesionsare on neurons in the region rather than on fibers ofpassage.63 Most recently we have obtained evidencethat lesions restricted to the axonal bundles of PNMT-containing fibers that project dorsally and then descendinto the spinal cord produce effects comparable tothose obtained with electrolytic lesions of the cellbodies (unpublished observations).

These observations raise the question as to whetheror not Cl neurons may be important in the expressionof several forms of hypertension. That a unilateral Cllesion reduced the significant elevation of arterial pres-sure produced by NTS lesions, demonstrates that itsintegrity is necessary for the expression of at least theneurogenic hypertension produced by bilateral lesionsof the NTS (NTS hypertension).

Contrasting Roles of Al Neurons of the CaudalVentrolateral Medulla in Cardiovascular Function

Electrical stimulation of the A1 area in the rabbit48 orrat49 resulted in changes of AP that were very differentfrom those elicited from the Cl area. Electrical stimu-lation of the region with low-frequency stimuli (5-15Hz) or the microinjection of the excitatory amino acidL-glu resulted in graded reductions of AP. Electricalstimulation with higher frequencies resulted in a pres-sor response. In the rabbit the vasodepressor responsewas accompanied by bradycardia; in the rat, by tachy-cardia.

Primary afferents(Glu)

Carotidsinus

Medulla

Preganglionicsympatheticneuron (Ach)

Thoracic cord

HeartAdrenal medulla

Postganglionicsympatheticneuron (NE)

Lesions of the Al area produced effects entirelydifferent from that produced by lesions of the Cl area.Thus, electrolytic lesions or the introduction of kainicacid into the Al area of rabbit50"51 or rat49 resulted inelevations of AP, which led inevitably in the rat andoften in the rabbit, to fulminating pulmonary edemaand death. The microinjection of GAB A into the Alarea also resulted in an elevation of arterial pressure.48

Lesions of the Al area, in contrast to those of the Clarea, did not substantially alter the magnitude of thevasodepressor response to maximal stimulation of va-gal afferent fibers or to carotid sinus stretch.49 Chron-ically, lesions of the A1 area, however, may impair thegain of the baroreceptor reflex curve.50

The hypertension produced by Al lesions was sub-stantially, but not totally, the result of an increase inthe release of AVP from the pituitary.49"50 Thus, inter-ference with Al function by electrolytic lesions orkainic acid elevated AP, and the response to hyperten-sion was significantly reduced by treatment with anAVP antagonist.

The Neuroanatomical Substrate of the Tonic andBaroreceptor Reflex Control

From these considerations and previous work fromour laboratory, we constructed a working diagram ofthe neuroanatomy of the baroreceptor reflex arc (Fig-ure 3). In brief, afferent information arising from baro-receptors projects into the NTS. From here it engagesneurons that project to the Cl area; Cl neurons project

FIGURE 3. Diagrammatic representa-

tion of proposed pathways and neuro-transmitters that mediate baroreceptorreflex activity. Afferent fibers of theninth (IX) and tenth (X) nerves termi-nate in the nucleus of the tractus solitar-ius (NTS) with a proposed neurotrans-mitter being L-glutamate (Glu). Herethey synapse on neurons that relay intothe Cl area. The transmitter of theseneurons may be gamma-aminobutyricacid (GABA). These neurons, whichsynthesize epinephrine (E), innervatecholinergic neurons in the intermedio-lateral (IML) and inter mediomedial lev-els of the spinal cord, which then relayeither into the adrenal medulla or intosympathetic ganglion where they con-tact noradrenergic postganglionic neu-rons, which in turn innervate noradren-ergic sympathetic neurons (NE), whichinnervate blood vessels, the heart, orboth. Also shown are neurons in thedorsal motor nucleus (DMX) of the \<a-gus and in the nucleus of Nosaka (N),which provide efferent innervation ofthe heart and nucleus ambiguus (NA).

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into the intermediolateral column of the cord, withneurons of that region projecting directly to the adrenalmedulla or to sympathetic ganglia, which make con-tact with those ganglionic neurons that innervate theblood vessels and the heart.

A provisional statement can be made about the neu-rochemistry of this loop. The neurotransmitter of theprimary afferent fibers is still not completely estab-lished. As described previously, there is substantialevidence to suggest that these fibers may contain L-gluand that the release of this amino acid transmits infor-mation from baroreceptors onto neurons of the NTS.Because, however, afferent fibers contain substance P,they may exert some yet unknown function on thereflex response.

The transmitter of the NTS-C1 projection is notyet clearly established; however, the abundant evi-dence66"67 that (1) GAB A is essential in mediatingbaroreceptor reflex responses on heart rate and also onblood pressure, (2) the site of action seems to be in theventrolateral medulla, and (3) neurons in the NTS willrelease GABA in vitro (Meeley MP, Reis DJ, unpub-lished observation), makes this a reasonable candidatefor this limb of the reflex arc.

Excitation of the Cl area was necessary to medi-ate the tonic vasomotor and reflex vasodepressor re-sponses, and hence the transmitter in this limb could beepinephrine. Whether or not it is epinephrine that isreleased to act on preganglionic neurons in the spinalcord to lower arterial pressure remains to be estab-lished. That the microiontophoresis of epinephrine inthe area of preganglionic neurons purportedly reducestheir activity rather than elevates it is a perplexingparadox.68"*9 That Cl neurons have been discovered tocontain other neuropeptides, however, such as neuro-peptide Y,70 raises the possibility that the release ofsome agent other than epinephrine may produce theeffect. The transmitter from the preganglionic sympa-thetic neuron to the ganglion cells is presumably ace-tylcholine, although these neurons may contain co-transmitters, and finally, the effective transmitterreleased from noradrenergic neurons on blood pressureis norepinephrine.

We must emphasize that the neurochemical wiringdiagram of the baroreceptor reflex arc acting on bloodpressure is provisional and a working hypothesis. Suf-ficient surprises have emerged from studies of neuro-transmitter systems over the last decade to makeenthusiastic statements premature in identifying trans-mitters).

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D J Reis, A R Granata, T H Joh, C A Ross, D A Ruggiero and D H ParkBrain stem catecholamine mechanisms in tonic and reflex control of blood pressure.

Print ISSN: 0194-911X. Online ISSN: 1524-4563 Copyright © 1984 American Heart Association, Inc. All rights reserved.

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