role of epinephrine in acute stress

Role of epinephrine in acute stress

Jacobo Wortsman, MDDepartment of Medicine, Southern Illinois University School of Medicine,

3128 Temple Dr., Springfield, IL 62704, USA

It has been more than 70 years since Walter B. Cannon described an adre-nal response to threatening environmental stimuli (physical or psychological)

which resulted in the release of ‘‘sympathin,’’ a humoral agent [72]. Cannon

further characterized the subsequent behavioral response as consisting of the

‘‘fight-or-flight’’ reaction, which is expressed broadly throughout the animal

kingdom [72]. The next big advancement in this area was the recognition by

Selye of a consistent multiorgan involvement that ensued upon acute and pro-

longed exposure to harmful but widely heterogeneous physical agents [152].

As described, a notable component of this response to damaging stimuliwas change in morphology and secretory activity of the adrenal glands,

alteration later extended to other elements of the neuroendocrine system

[151–152]. Subsequently, a large number of investigators have contributed

to characterize the mechanisms for the damage induced by most noxious

agents or ‘‘stressors,’’ and the resulting biological reaction or ‘‘stress res-

ponse’’ [12,95,117]. The intermediate steps or progression mechanisms that

would ultimately lead to the specific behavior pattern (fight-or-flight) have,

however, remained elusive. To evaluate this phenomenon (i.e., the sequentialposition of stress reactants in the chain of events and their relevance), consid-

erationmust be given to the implied physical damage to the stressed subject in

either a fight or flight response. Because the potential for such an outcome,

that is, the development of a pathologic condition, the definition of any com-

ponent part of the stress response must involve careful separation from its

direct pathologic and/or physiological involvements. This separation

becomes necessary, because organs and functions involved in the stress

response also are affected by the processes of growth, development, reproduc-tion, cycles of wakefulness and sleep, and other nonstressor activities of nor-

mal life. Once the participation of a specific stress reactant has been defined,

its detection in turn can be used to quantify stress intensity.

For the purpose of classification, physical stress results from the action of

stressors that interact directly with a living organism to threaten the stability

of the internal environment. Conversely, psychological stress is produced by

Endocrinol Metab Clin N Am

31 (2002) 79–106

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stressors that change the external environment (including societal position)

without material interaction with the stressed subject.

Neuroendocrine response to stress

The hormones detected in response to stress are assumed to represent the

intrinsic components of a nonspecific preprogrammed process, although

the involvement of a given hormone in the process also can reflect a specific

reaction to the stressor itself. For example the secretion of corticotropin

(ACTH) may be a component of the stress response, or its release may bedirectly driven by cytokines as is the case in inflammatory disorders [117].

Thus, the involvement of a hormone in the stress response implies its release

by an orderly process (after CRH secretion in the case of ACTH) following

stressor recognition. If the sequential steps were not to follow the same pro-

gression, the highly coordinated behavior of the ‘‘fight-or-flight’’ reaction

would rapidly disintegrate without becoming effective. Because the stress

response normally is programmed in the hardware of living organisms,

the critical step for eliciting the response becomes the process of stress recog-nition. Moreover, since the end point, the behavioral response, may vary

with different stresses, the recognition phase (in psychological stress) must

involve the lowest degree of awareness of stressor presence and the potential

impact of its interaction with the stressed subject. The factors involved in

the setting of the threshold for stressor recognition remain to be defined

precisely.

Hormonal responses

Once a stress has been recognized, the circulating blood is enriched with a

host of hormones from the pituitary and adrenal glands. These include pitu-

itary proopiomelanocortin (POMC)-derived peptides comprising ACTH,

b-endorphin andmelanotropins, prolactin, growth hormone, and vasopressin[12]. The adrenal contributions are represented by cortisol, epinephrine and

norepinephrine [117]. The latter also is derived of blood spillover from sym-

pathetic stimulation [50,111] (another component of the stress response).

Categorization of the stress response

To determine the functional relevance of the complex heterogeneous hor-

monal mixture, it becomes necessary to assess the relative contributions made

by the specific hormonal components. To approach this problem in a human

model, using a natural setting where the stress response would be developed

fully (maximally) would be optimal. Because physical stresses lend themselvesto more precise quantification than psychological stresses, a physical model

80 J. Wortsman / Endocrinol Metab Clin N Am 31 (2002) 79–106

would ensure both consistency and reproducibility. Within that framework it

becomes apparent that cardiac arrest would represent truly maximal stress

[202], since, if left unattended, it has a mortality of 100%. It also offers the ad-

vantage of providing a model for the process of stress development over anextremely short period, limiting the confounding effect of secondary (compen-

satory) reactions. This is equivalent to the alarm reaction described by Selye

[152]. Moreover, the blood flow obtained during cardiopulmonary resuscita-

tion (CPR) [186] would prevent significant hormone blood removal. When

such a study was conducted [202], the experimental conditions were standar-

dized by including only patients from the intensive care unit (ICU) developing

cardiac arrest while undergoing continuing monitoring. The blood samples

were drawn by an observer familiar with the workings of the resuscitationteam, but who was not a current member. This provision assured completely

unobstructed work by the resuscitation team [202].

The main quantitative plasma hormonal responses to cardiac arrest were

(ratio of mean cardiac arrest/upper limit normal): ACTH 2.0; b-endorphin2.5; cortisol 2.5; prolactin 2.0; norepinephrine 18; vasopressin 25; and epi-

nephrine 111 [114,200]. Thus, the most prominent hormonal responses to

cardiac arrest are those of epinephrine, vasopressin, and norepinephrine that

are elevated by one to two orders of magnitude. Moreover, and as antici-pated, the epinephrine response produced the highest recorded level for a

non-neoplastic adrenal disorder. In contrast, the levels of ACTH, b-endor-phin, cortisol, and prolactin were merely twice the upper limit of normal. This

would be expected, since ACTH, cortisol, b-endorphin, and prolactin

require preserved hypothalamic-pituitary or pituitary-adrenal circulation,

which would be impaired in cardiac arrest. As regards growth hormone, this

stress hormone was not measured, but its release and subsequent activa-

tion (measured as IGF-1 production) [179] are likely subject to the samelimitations. In additional studies chromatographic characterization of

b-endorphin immunoreactivity showed identical profiles in cardiac arrest

and ICU patients [203] and there was a high correlation between plasma

chromogranin A and plasma norepinephrine [36]. These investigations,

together with the attainment of resuscitation in some of the patients, con-

firmed that the hormonal responses of the cardiac arrest model did not

represent a postmortem (autolytic) phenomenon.

Thus, it is notable that many years after the original postulation by Can-non, past- and ongoing-research in this area has added only vasopressin to

the original sympathin (a mixture of epinephrine and norepinephrine) [72] as

main mediators for the fight-or-flight response.

Afferent pathways of the stress response

Because psychological and physical stress share the same neuroendocrine

response [48], it would seem that they also would share similar pathwaysafter recognition to trigger qualitatively identical responses. Such a common

81J. Wortsman / Endocrinol Metab Clin N Am 31 (2002) 79–106

response-starting center would have to be located in the central nervous

system (CNS) the place for integration of psychological stress, and also

the source for neuroendocrine mediators. More specifically, this common

center must be the hypothalamus, recognized as the command center inte-grating and regulating pituitary endocrine secretion [66]. The hypothalamus

is also the site of production of vasopressin, and it is the most proximal CNS

center from where adrenomedullary secretion and sympathetic activation

can be stimulated consistently [66]. The central pathways involved in recogni-

tion of several experimentalmodels of stress have been reviewed recently [121].

In the hypothalamus, numerous CNS connections may provide information

on recognition of multiple types of physical or psychological stressors [66].

In human cardiac arrest mean peak plasma epinephrine reaches approxi-mately 10,000 pg/mL (normal range: 34± 2 pg/mL) [102,202]. Extraordinary

activation of the same neuroendocrine response has also been reported in

canine, porcine and rodent models of cardiac arrest [81,86,98,148,185].

Whether it is from the cessation of blood flow or the absence of pulsatile cir-

culation, cardiac arrest probably stimulates cardiopulmonary receptors

[34,106] to produce an extremely rapid response of sympathetic activation

and adrenomedullary secretion. In dogs, marked sympathetic discharge is

already detectable at 20 to 30 seconds after the onset of ventricular fibrilla-tion [1]. Of note, coronary occlusion per se does not have this effect [1]. Also,

CPR itself does not contribute to the adrenal medullary response, since

plasma epinephrine levels do not differ between dogs resuscitated with con-

ventional CPR or with cardiopulmonary bypass [204]. High spinal anes-

thesia does not block the renin response to cardiac arrest [141].

Efferent pathways

The existence of central command neurons (i.e., neurons with dual func-

tion regulating sympathetic and adrenomedullary activity) has been con-

firmed in studies with a double-virus transneuronal labeling technique

[83]. At least in the rat, these ‘‘command neurons’’ are located in the

hypothalamus and brainstem [83], and endogenous excitatory amino acids

may be involved in their stimulations [84]. From the hypothalamus, sympa-

thetic and adrenomedullary stimuli can be dissociated experimentally with

specific stressors or with pharmacological manipulation [20,29,41,110,162].There are also long connections between the hypothalamus and spinal cord,

but their participation in the response to stress has not been determined

[146]. Nevertheless, it seems likely that the efferent pathway interphases with

sympathetic preganglionic neurons, after traversing at least one relay station

in the brainstem (raphe palidus and raphe obscuris nuclei, and ventromedial

and rostral ventrolateral medulla) [115,165].

Neural stimulation comes to the adrenal medulla through the splanchnic

nerves [178]. Innervation is principally cholinergic by preganglionic sympa-thetic fibers originating in the intermediolateral cell column of the thoracic


spinal cord ipsilateral to each gland. Direct nerve stimulation results in

higher adrenal catecholamine secretion than produced by exposure to stress

[54]. For example, in cats, the strongest stimulus (asphyxia) results in an out-

put of 2 to 3 lg/kg/per minute (resting level 0.1 lg/kg/min), although underdirect nerve stimulation (10 impulses/s) the maximal secretory capacity

reaches 5 lg/kg/per minute [54]. In the dog, maximal secretion is 200-fold

the basal levels at the frequency of 10 Hz [38]. It has been postulated that

in the adrenal medulla, secretion would be regulated by nicotinic receptors

(short latency) at lower stimulation levels, and at high stimulation levels by

muscarinic receptors (long latency) [178].

In each chromaffin adrenomedullary cell there are approximately 10,000

granules, of which 2% are in a ‘‘release ready pool’’ [10]. After a train of sti-mulations, the initial fast release is followed by a further slow release of 4000

granules (>20% of total). If only 5% of all available granules were released,

the expected plasma concentration would reach approximately 200,000 pg/

mL. The time constant for release by exocytosis is 150 to 1000 lsec, compared

with 0.2 to 1.2 lsec for release from synaptic vesicles [10]. Because the rate-

limiting step for catecholamine secretion from adrenal medullary cells during

exocytosis is the dissociation of catecholamines from the vesicular matrix at

the cell surface, the greater that number of granules that are mobilized thegreater the number of catecholamine molecules that will be secreted [194].

Connection of the adrenosympathetic system

to other hormonal stress responses

It is unclear whether the ‘‘command center’’ neurons are already involved

at the earlier phase of stress recognition. Nevertheless, once the stress

response has been triggered, there are a number of hypothalamic connec-

tions mediating release of vasopressin and of trophic factors for the pituitary

gland [66]. Coordination of the response is probably a function of intrahy-

pothalamic connections; for example, in the supraoptic nucleus, a significantproportion of axon terminals appear to be intranuclear or otherwise of local

origin [66]. It is therefore thought that local circuit neurons may act to syn-

chronize activity of a neuronal group and thus integrate its components into

a functional unit [66]. From the hypothalamus, neurosecretion has easy

access to the pituitary gland, which receives most of its blood flow from the

local portal system [66]. There is also some direct arterial supply to the pitui-

tary entering primarily the capsule and fibrous core of the gland [62].

Plasma epinephrine concentrations in acute severe stress

In cardiac arrest, the mean concentration was found to be 10,300 ± 2900

pg/mL [202]. The highest spontaneous value in a surviving patient who didnot received epinephrine reached 36,000 pg/mL, whereas a concentration


of 273,000 pg/mL was detected in a successfully resuscitated patient who

had received epinephrine [202]. Another clinical series reported that after

treatment with epinephrine, successfully resuscitated patients have mean

plasma epinephrine concentration of 136,300 pg/mL (2700-fold the normalresting level of 49.6 ± 35.2 pg/mL). Interestingly, in this setting, plasma epi-

nephrine did not correlate with blood pressure, heart rate, plasma lactate, or

glucose concentrations [130]. By comparison, in dogs successfully resusci-

tated from cardiac arrest, basal plasma epinephrine was 2300 pg/mL; during

cardiac arrest reached 44,300 pg/mL and postepinephrine treatment rose to

2,326,000 pg/mL [86]. In pigs, plasma epinephrine increased from 3000 pg/

mL to 94,000 pg/mL at 6 minutes post arrest [98].

Another acute setting, head trauma is associated with elevated plasmacatecholamines in humans [91]. Experimentally induced brain death in rats

(with an intracranial balloon) also increases plasma epinephrine, by 149-fold

(to approximately 11,000 pg/mL) at 30 seconds [73]. The experimental rein-

duction of anaphylaxis produced very high epinephrine levels only in

patients who developed shock, with plasma concentrations of up to 6500

pg/mL [181]. In a recent series of patients with pheochromocytoma (165

cases), median (range) plasma epinephrine was 97 (0 to 3608) pg/mL in

the cases without complications and 190 (0 to 4927 pg/mL in those withcomplications [127]. In a single patient with hemorrhagic pheochromocy-

toma developing pancreatitis and cardiomyopathy, plasma epinephrine

was approximately 20,000 pg/mL [46].

Epinephrine actions

Acting through a- and b-receptors, epinephrine has mainly cardiovascularand metabolic actions [77]. In contrast to the high plasma epinephrine levels

detected in acute, severe physical stress, the concentrations that trigger its bio-

logical activities are relatively low. Thus, at concentrations ranging from 150

to 500 pg/mL there are significant increases in heart rate, systolic blood pres-

sure, stroke volume, ejection fraction, and cardiac output. In addition, there

is decreased systemic vascular resistance [166]. These hemodynamic actions

can be reproduced by exercise when it is sufficient to increase epinephrine to

the same levels [13,53,166]. Epinephrine metabolic actions are also expressedfully at the same concentration range as the hemodynamic effects and include

increments in blood glycerol, free fatty acids, plasma glucose, blood lactate,

b-hydroxybutyrate, and decrements in plasma insulin [11,33]. There are also

increases in oxygen consumption reflected in enhancements in the respiratory-

exchange ratio and metabolic rate [160]. The lipolytic action of epinephrine is

thought to be mediated mainly by increases in adipose tissue blood flow, with

additional changes in adipose tissue hormone-sensitive lipase and lipoprotein

lipase [144,145]. Epinephrine has glycogenolytic effects in muscle, apparentlybecause of selective stimulation of type 1 (slow-twitch) fibers [64]; epinephrine


also impairs peripheral glucose metabolism and enhances hepatic glucose

production [11]. Other effects include activation of the innate immune system,

with increases in natural killer cells and granulocytes [18] and increases in

prostacyclin and thromboxane [136]. Epinephrine inhibition of macrophageNO production, [154] together with its effects on the cytokine network, result

in a net anti-inflammatory action (attenuates production of proinflammatory

tumor necrosis factor-a. [TNF-a]. and potentiate production of anti-inflam-

matory interleukin-10 [IL-10] [182].

Psychological stress produces highly variable plasma epinephrine levels, for

example the color word test is associated with a mean value of approximately

100 pg/mL and, public speaking (among medical personnel) 400 pg/mL

[42,43]. During exercise, plasma epinephrine also increases in proportion withexercise intensity as would be expected [13,53,166]. The epinephrine exercise

response is enhanced by hypoxia [110]. Hypoglycemia is a powerful stimulant

for epinephrine secretion, producing levels of up to 5000 pg/mL, depending on

its severity [35]. It is also thought that epinephrine secretion during exercise is a

component of a redundant mechanism to prevent hypoglycemia [108].

Epinephrine actions in cardiac arrest

As mentioned previously, epinephrine has a- and b-receptor activity.

Through its a1- and a2-adrenergic effects, epinephrine increases systemic vas-

cular resistance and arterial blood pressure, and therefore perfusion. Thus, it

increases coronary perfusion and myocardial blood flow [122,188]. The

b-activity of epinephrine accounts for its chronotropic and inotropic effects,

increasing myocardial contractility, heart rate, and automaticity [122,188].

These b-mediated actions are unimportant during cardiac arrest and arebelieved to be detrimental by increasing myocardial oxygen consumption

and energy demands. They evenmay be responsible for producingmyocardial

ischemic injury andmyocardial dysfunction, with shortening of postresuscita-

tion survival [44,87]. Still, experimental studies have confirmed that despite the

massive endogenous secretion, epinephrine administration improves survival

after cardiac arrest [61,79,148].

Plasma kinetics of epinephrine

In humans, infusion of epinephrine that results in levels less than 100 pg/

mL has produced mean plasma residence times (half-life) of 1.68 ± 0.16 to

1.71 ± 0.04 minutes (depending on the mathematical model used) [140]. Epi-

nephrine clearance is prolonged in cardiac arrest [81,130]. Most, if not all

plasma epinephrine, is derived from direct adrenomedullary secretion [51].

In resting humans, epinephrine spillover from extra-adrenal tissues contrib-utes only 9% to plasma levels [47]. The liver is important in epinephrine


clearance, removing 32% of plasma concentration (most of it by extraneuro-

nal uptake) [47]. Plasma removal may, however, be concentration dependent

since tissues such as the adipose tissue that do not remove significant

amounts of epinephrine at rest exhibit nonetheless notable extraction ofthe catecholamine from plasma during epinephrine infusion [144]. Among

epinephrine metabolites, the main one, metanephrine, has 91% of its resting

plasma level produced within the adrenal glands [47].

The onset of epinephrine action has been related to its plasma concentra-

tions in a number of studies that have defined the ‘‘thresholds’’ for the

expression of its actions. Termination of epinephrine action may not corre-

late with the removal of the stimulus or the return of plasma levels to base-

line concentrations, and a phenomenon that some have called ‘‘depo-effect’’may become apparent [172]. This refers to the unexpected persistent effect of

high levels on subsequent plasma or tissue kinetics. Thus, after cessation

of strenuous exercise that increases plasma levels by 50-fold, 50% persists

at 5 minutes, and the epinephrine levels may remain elevated still 2 hours

later [13]. Also, after an epinephrine infusion that elevated plasma concen-

tration to 400 pg/mL, its effects on heart rate, basal metabolic rate, plasma

lactate and blood glucose were noted to persist long after epinephrine had

returned to basal levels [52]. Whether this phenomenon accounts for para-doxical effects such as delayed appearance or unexpected persistence of epi-

nephrine toxic actions is not known. Lastly, the epinephrine response to a

given stimulus can be modified by other concomitant factors. For example,

the epinephrine response to hypoglycemia in sheep is eliminated by cortisol

or dexamethasone, while the same treatment does not affect the epinephrine

response to dog barking [94].

Epinephrine toxicity

The reactions to high epinephrine levels (derived from exogenous admin-

istration or endogenous secretion) can be classified into cardiovascular andmetabolic, depending on the main clinical effector. It must, however, be

recognized that overall, most human subjects will exhibit signs of mixed

involvement, although with selective predominance according to the under-

lying health status of the individual being evaluated.

Cardiovascular toxic effects

Early studies performed in dogs in 1919 demonstrated that injection of

large epinephrine boluses produced intense vasoconstriction in somatic

and splanchnic areas [49]. With very large doses producing maximal con-

striction, the effect outlasted the injection period for up to 2 hours [49]. Sub-

sequent studies in 1941 showed that infusion of high doses of epinephrineproduced shock from decreased plasma volume [55]. because of increased


vascular permeability. More recently, a similar model showed development

of glomerular crescents and renal arterial and tubular necrosis [107].

Most striking are epinephrine effects on the heart affecting mainly electric-

al activity and myocardial function [16,69]. Thus, epinephrine causes mem-brane depolarization and induction of automatic activity (production of

spontaneous action potential) [69]. Moreover, the doses required to produce

these two effects have been found to be very close in a preparation of guinea

pig ventricular muscle cells (2.5 · 10)6 mol/L vs. 6.4 · 10)6 mol/L) [69]. As

regards the inotropic effects, at ‘‘usual epinephrine concentrations’’ (prob-

ably <1,000 pg/mL) they are mediated by b1 and b2 adrenoceptors to pro-

duce positive chronotropic and inotropic actions, [58] and perhaps by the

not yet fully characterized b4 adrenoceptor which is also cardiostimulant[58]. High catecholamine concentrations, however, activate the b3 adreno-

ceptor, which decreases cardiac contractility in a response that remains pre-

sent in the failing heart after the b1 and b2 positive inotropic effects have

become attenuated [58]. High doses of epinephrine also produce pulmonary

edema, and are used as the causative agent in a highly reproducible experi-

mental model [133,149,153]. Pulmonary A-V shunting and hypooxygenation

are other effects of epinephrine, [19] and it has been postulated that ara-

chidonate metabolites may play a major role in producing this involve-ment [133].

A dilated reversible cardiomyopathy has been noted after administration

of large doses of epinephrine or in patients harboring pheochromocytomas

[27,56,105,199]. In a rodent model of cardiac arrest, epinephrine administra-

tion increased the severity of postresuscitation myocardial dysfunction and

decreased the duration of survival [173]. It has been reported that epineph-

rine in vitro, at concentrations 10)9 to 10)3 M, is not directly cytotoxic for

myocardial cells. Plasma from rats injected with epinephrine (5 mg/kg),however, is highly cytotoxic, in particular when collected from blood drawn

at 30 minutes post injection [116]. Thus, within 60 seconds of incubation

with myocardial cells, membrane microblebs and microvilli are present,

and intracellular adenosine triphosphate (ATP) concentration falls signifi-

cantly. At 180 seconds of incubation, extensive membrane damage is notice-

able [116].

Metabolic toxic effects

As would be expected, metabolic toxic effects are represented by exag-

geration of the epinephrine actions demonstrable at lower levels. Thus,

the elevation of lactic acid may rise to overt lactic acidosis, which may pose

a difficult therapeutic challenge [78,96]. This complication was reported in a

23-year-old male morphine addict who self-injected 20 mg of epinephrine

intravenously (estimated plasma concentration: 1,000,000 pg/mL) [92]. Lac-tic acidosis even has been noted after coronary artery bypass graft surgery


in patients receiving epinephrine as a vasopressor agent [57]. Epinephrine

administration also was associated with the development of hyperglycemic

hyperosmolar nonketotic coma in a nondiabetic child [26].

Epinephrine toxic effects in patients with preexistent heart disease

Patients with prolonged QT interval syndromes are predisposed to the

development of ventricular tachycardia, ventricular fibrillation, and tor-

sades de pointes [171,176]. In the hereditary variants, the result of an ion

channelopathy, the effect of adrenergic stimulation on cardiac electrical

activity is thought to be critical for triggering potentially malignant arryth-mias [171]. In these cases, the mainstay therapeutic approach is represented

by antiadrenergic drugs (b-blocker agents), to which left cardiac sympa-

thetic denervation may be added [176]. Interestingly, in what was noted to

be the first example of this condition, a young girl experienced sudden car-

diac death while being admonished at school [176]. There are two forms of

this hereditary syndrome the Jervell and Lange-Nielsen syndrome, asso-

ciated with deafness; and the Romano-Ward syndrome, associated with nor-

mal hearing [171]. Nevertheless, even individuals with a normal heart, whengiven epinephrine, frequently develop ectopic arrhythmias unrelated to dose

(0.2 or 0.3 lg/kg/min), heart rate, or blood pressure responses [100].

Patients with coronary artery disease (CAD) have been known to develop

the clinical and electrocardiographic manifestations of angina when under-

going psychological stress or given epinephrine. In fact, the latter was used

as a diagnostic test for the presence of CAD as early as 1930 [101]. In more

recent studies, an S-T elevation greater than 1 mm during epinephrine infu-

sion (0.03 to 0.3 lg/kg/min) in patients with chest pain had a sensitivity of87% and specificity of 100% to predict CAD [147]. In another study of epi-

nephrine infusion that included 8 patients with normal coronary anatomy

and in 23 with CAD, CAD patients had more frequent ventricular arrhyth-

mias (55% versus 25%), chest pain (50% versus 13%) and ischemic EKG

changes (73% versus 13%) [169]. The epinephrine-related ischemic thresh-

olds ranged from 652 to 3362 pg/mL [169]. Hemodynamic responses to epi-

nephrine between groups were similar, although CAD patients had lesser

increase in cardiac contractility and decrease in end systolic ventricularvolume [169]. In a similarly studied group of 14 patients with CAD sympto-

matic myocardial ischemia developed in 4 of the 14 patients; arterial plasma

epinephrine concentrations were up to 572 pg/mL [112]. The epinephrine-

induced increased heart rate persisted for up to 30 minutes after the end

of the infusion [112]. In two patients with severe anaphylactic reactions

receiving epinephrine 0.3 to 0.5 mg intravenous over approximately 3 min-

utes, nonsustained idioventricular rhythm and ventricular tachycardia were

noted. Myocardial ischemia was noted in one additional case, and clinicalmyocardial infarction was noted in a 34-year-old healthy male subsequently


discovered to have stenosis of several coronary artery branches [14,80,168].

In conscious dogs epinephrine administration increased the susceptibility to

malignant arrhythmias, ventricular fibrillation and cardiac arrest during

electrical stimulation [126].

Epinephrine toxicity in cardiac arrest

There is extensive experience on the effect of epinephrine in cardiac arrest

and its relation to postresuscitation complications. The use of very high

doses of epinephrine (0.2 mg/kg), as opposed to the conventional dose of

1 mg, [123] has been related to either lack of effect on outcome, or to wor-sening rates of survival [25,161]. In fact, high epinephrine doses adminis-

tered during CPR are associated positively with impairment of systemic

oxygen consumption (VO2) and oxygen delivery (DO2) in the post resusci-

tation period, probably because of impairment of the microcirculation

[139]. Acute renal failure (ARF), which is common after cardiac arrest

[109] is also partly dependent on epinephrine dosage [107] (mean epinephr-

ine dose ARF: 1.81 ± 0.36; no ARF: 0.9 ± 0.18 mg) [109]. Higher epinephr-

ine doses also have been associated with worse neurologic outcome, [17].although it is unclear whether this action maybe related to the selective neu-

ronal loss in the thalamic reticular nucleus reported in human cardiac arrest

[142]. In an experimental porcine model of ventricular fibrillation, high-dose

epinephrine (200 lg/kg) induced severe vasoconstriction of cortical cerebral

blood vessels [59].

Miscellaneous

In patients with panic disorder and social phobia, epinephrine infusion

producing expected levels of 600 pg/mL had panicogenic effects [184].

Patients developing panic attacks also had exaggerated epinephrine-related

falls in transcutaneous Pco2 and cardiovascular responses (cardiorespiratory

sensitivity) [183]. Tremor is also common, being reported in 16 of 17 chil-

dren who received epinephrine, achieving plasma levels of up to 2000 pg/

mL [156]; this effect likely is related to increased muscle sympathetic nerve

traffic [175].To summarize, the main toxicity of epinephrine is represented by its effects

on the cardiovascular system. This becomes important in individual with pre-

existent overt or subclinical syndromes of cardiac hyper excitability in whom

psychological stress, especially when severe, may trigger a potentially lethal

arrhythmia. In patients with CAD, the same type of stimulation can result

in the production of a myocardial infarction. Most healthy subjects without

underlying cardiac pathology nevertheless will develop only transient and

full reversible cardiac arrhythmias. High plasma epinephrine levels (meanvalue 10,600 pg/mL) achieved acutely from pharmacologic administration


concentrations similar to those spontaneously found in cardiac arrest have

limited cardiac effects [134]. In this setting, epinephrine does not impair myo-

cardial perfusion and may result in short bursts of non sustained ventricular

tachycardia [134]. Concerning the effect of epinephrine in experimental myo-cardial infarction, studies in a porcine model have shown that epinephrine

improves systolic shortening without affecting infarct size [90].

Significance of epinephrine in the response to stress

It is apparent that all cardiac and metabolic epinephrine actions are fully

expressed at concentrations of approximately 1000 pg/mL. However, physi-

cal stress (cardiac arrest) results in levels that are greater by 10-fold ormore, and severe hypoglycemia can also elicit concentrations far greater

than 1000 pg/mL. In regards to psychological stress, the tests used to eval-

uate epinephrine responses to this type of public speaking, or even para-

chute jumping do not represent situations where the external environment

of the tested subject will change in a significant manner. A more appropri-

ate, if somehow unethical, setting for testing would be to determine the same

responses in individuals facing stimuli that definitely will change the external

and social environment (e.g., facing a court of law and sentenced to a jailterm or worse yet, to death). Alternatively, the same process could be repre-

sented in civil life by the sudden action of termination of employment, or of

receiving a diagnosis of cancer. The affected individuals may perhaps

develop values one or greater orders of magnitude than the concentrations

of less than 1000 pg/mL found in most experimental models studied. This is

related to the obvious higher intensity of those real-life stimuli. Further-

more, most real-life psychological stresses are preceded by an important

anticipatory phase. This is best illustrated by a careful study in volunteersexperiencing their first parachute jump that clearly showed two stages in

the epinephrine response. Immediately before the stress, there was an initial

rise in the phase of anticipation (of an expected outcome). Additionally,

during the stress itself, the levels rose further [135]. The significance of the

anticipation phase is that it probably will activate the adrenal medulla trans-

locating the reserve pool of adrenomedullary catecholamine granules to the

rapidly releasable pool, a process also accomplished with direct stimulation.

Hence, following anticipation, a larger number of granules would becomeavailable for secretion and, depending on outcome, result in potentially

extraordinarily high plasma concentrations. The anticipation phase is prob-

ably involved in the expression of ‘‘stress-induced analgesia’’ [3], and related

to the cognitive component of stress. This is the likely explanation for the

results of a study of six patients with acute myocardial infarction (MI)

and unstable angina who were transported by helicopter to a referral center

[177]. None of the patients experienced hemodynamic changes during the

transfer, yet mean plasma epinephrine that was 841 pg/mL preflight roseto 3455 pg/mL during the flight [177]. Similarly, in 35 children admitted


for burns, there were significant correlations between the affected surface

area and a number of hormones (vasopressin, renin, angiotensin II, aldos-

terone, norepinephrine, dopamine and atrial natriuretic factor), although

the same correlation with plasma epinephrine was nonsignificant [158].Interestingly, blockade of beta adrenergic stimulation in that setting attenu-

ates hypermetabolism and reverses muscle protein catabolism [74]. Even in

rats, where anaphylaxis caused by egg albumin induced a large and rapid

increase of epinephrine, the increase was far more pronounced in awake

compared with anesthetized animal, despite a lesser decrease in blood pres-

sure in the former [67]. In cardiac arrest, patients are unconscious; their cog-

nitive component is absent, and the epinephrine secreted represents the

maximum available (i.e., the readily releasable pool), while the reserve poolis not mobilized.

Assuming that real-life severe psychological stress produce plasma epi-

nephrine levels as high or even much higher than the cardiotoxic concentra-

tions of maximal physical stress, the question arises as to the target for such

a response. A logical effector for psychological stress would be the (CNS),

however, the blood-brain barrier is almost completely impermeable to epi-

nephrine [24,118]. In fact specific testing was performed for the possibility

that CNS permeability to epinephrine would transiently increase duringstress, [201] since areas of extravasation appear in the brain of experimental

models of cardiac arrest injected with dyes intravenously [7,128]. Neverthe-

less, epinephrine concentration in cerebrospinal fluid remained unchanged

in canine cardiac arrest, in spite of the extraordinarily high gradient estab-

lished with the plasma levels [201].

Against that evidence, data accumulated over many years clearly demon-

strate central actions for plasma epinephrine. For example, plasma epi-

nephrine increases cerebral blood flow and cerebral oxygen consumptionin humans and experimental animals [37,89]. It also increases electroence-

phalogram (EEG) wave frequency and amplitude in humans and cats

[22,60], and produces analgesia in humans and dogs (raising the response

threshold to electrical stimulation of dental fillings), [82]. It inhibits hypo-

thalamic secretion of LHRH (rat) [21]; and decreases the level of sedation

during anesthesia producing an arrousel efffect (humans) [4]. Furthermore,

the haloperidol induced catalepsy (rats) is attenuated by stress (handling,

immobilization or cold exposure to 3�C), or by intravenous infusion of epi-nephrine [32,206]. In rats and mice epinephrine affects memory improv-

ing retention performance in a wide range of tasks [195]. Also, in female

mice, intravenous epinephrine decreases sexual receptivity, but not embryo

implantation [40].

There are additional peripheral changes during stress that are media-

ted directly by epinephrine or, by other neuroendocrine components of the

same response, namely vasopressin and the sympathetic system. Thus, stress

is associated with vasoconstriction necessary for the maintenance ofblood pressure, antidiuresis, bronchodilation, and decreased gastrointestinal


motility [197], and also, with increases in renin and decreases in plasma

aldosterone because of decreases in serum potassium, a change reproducible

in humans by infusion of epinephrine to levels of approximately 600 pg/mL

[93]. At least in tissue culture, epinephrine changes the shape of pituicytes(neurohypophysial astrocytes), consistent with posterior pituitary secretory

response [70]. Also, in rats the intracerebroventricular or intracerebral

administration of epinephrine produces a secretory surge of CRH-41 in

the median the eminence [15]. The latter effect is restricted to the central den-

dro-perikaryal region of CRH-41 producing neurons, since it has no effect

on the nerve ending of these neurons [15].

The plethora of central effects indicates access of the catecholamine to the

CNS. This would be possible only in areas devoid of blood-brain barrier.There are two hypothalamic structures with these properties; one is the med-

ian eminence, [66] and the other is the organum vaculosum laminae termi-

nalis [65]. Although it is the glial sheath that envelops brain capillaries

that may confer special permeability properties, there are significant regio-

nal differences in the structure of perivascular spaces in the brain. For

instance, there is enhanced efficacy of drainage of interstital fluid in the basal

ganglia compared with the cortex, a property that could contribute to a

higher frequency of lacunae in the basal ganglia [129].Actual demonstration that plasma epinephrine could enter the brain was

provided by Axelrod et al, who showed in cats that plasma 3H-epinephrine

is concentrated in the hypothalamus at up to 10% to 15% of the plasma level

[189]. Other brain areas took up approximately 2%, except for the medulla

oblongata, which retained approximately 5% [189]. 3H-norepinephrine also

is concentrated only in the hypothalamus, at approximately 16% of the

blood level [190]. It must be noted that in another brain area also devoid

of blood-brain barrier, the area postrema, there is selective paucity of b-adrenoceptors in astrocytes [5]. This in turn suggests that catecholamines

entering through blood vessels� fenestrations can diffuse more freely through

greater distances.

Once epinephrine molecules reach the hypothalamus, they cannot be

removed easily; as yet there is no evidence for a specific epinephrine trans-

porter in mammals, as it exists for norepinephrine [6]. Some of the

plasma-derived hypothalamic epinephrine nevertheless could go back to

the hypophyseal portal blood network or to the pineal gland, since epi-nephrine contents of those locations decrease after adrenalectomy [119,

125]. The hypothalamus itself is a rich source for epinephrine, having the

highest concentrations in the brain in most species [103]. Whereas the bio-

synthetic machinery for the manufacturing of epinephrine is available

locally, its cellular localization is dissociated from the epinephrine store sites

[113]. In humans, the hypothalamus has high density of binding sites for epi-

nephrine, with dissociation constant (KD) in the nanomolar range [191].

This suggests that local receptors could be activated at the concentrationsfound in very severe stress (5000 to 10000 pg/mL or greater), even if only


15% of the plasma level were to reach the receptors. The adrenergic recep-

tors present in the hypothalamus include a1-a2-, and b-adrenoceptors [2]. Of

particular interest are the b receptors since epinephrine is the natural ligand

for the b2 adrenergic receptors. Of note, b-adrenergic receptors exist in twointerconvertible conformations in rat and human brain [8]. Guanine nucleo-

tides and sodium shift high-affinity receptor sites into low-affinity sites.

Overall receptor number often fails to reflect changes in functional respon-

sivity [8].

At least in the rat brain cortex, b-adrenoceptors are localized predomi-

nantly on glial cells, not in neurons [163–164]. In fact, stimulation of b-adre-noceptors produces a cAMP response that is blocked by the gliatoxin

fluorocitrate (selective for glial cells), whereas the neurotoxin kainic acid(selective for neurons) is without effect [164]. Nevertheless, b receptor stimu-

lation induces neuronal activation with expression of c-fos (an immediate

early stress gene) [164]. This suggests that b-adrenergic receptor activation

is followed by sequential actions, and that glial cells represent the key target.

One possibility for direct interaction with the b2 receptor in neurons is

through activation of the Ca2+ channelv1.2, which is colocalized with G-pro-

tein coupled receptors [39]. Colocalization of receptors with their ultimate

targets in macromolecular complexes implies that signaling is specific andfast [39]. Thus, application of albuterol (a b2 adrenergic receptor agonist)

to the cell surface does not activate the Ca2+ channel, which results only

from direct application to the channel [39]. Expression of this action would

therefore require very high extracellular concentrations or highly targeted

delivery to become evident. Activation of the Cav1.2, an L-type class C cal-

cium channel, results in modulation of nerve impulses in brain neurons [97].

There is also signaling to the nucleus with stimulation of gene expression

mediated by a calmodulin complex activating the RAS/mitogen activatedprotein kinase (MAPK) pathway [45].

Glial cells are adendritic elements derived from the mesoderm, and they

outnumber neurons in the mammalian brain [182]. The typical glial cell of

the brain cortex is the astrocyte, which is metabolically very active [167].

Astrocytes are situated in close proximity to blood vessels, are more numer-

ous in the hypothalamus, [192]. and have high density of adrenoceptors

[192]. Norepinephrine, for example, increases CO2 production in astrocytes

but not neurons [167]. Functional interactions between neurons and astro-cytes seem to play a major role in brain function. In addition to b-adrenergicreceptors, a2 adrenoceptors also are expressed widely in the brain, with high

concentration in the median eminence [187]. Affinity for all three a2-receptorsubtypes (A,B,C) is as great or greater for epinephrine than norepineph-

rine [104].

Therefore, following recognition of a significant physical or psychological

stressor, perhaps in the hypothalamus itself, an immediate neuroendocrine

reaction ensues that includes adrenomedullary secretion of mostly epine-phrine and some norepinephrine, sympathetic stimulation that results in


norepinephrine overflow into the circulation, and pituitary release of vaso-

pressin. Secreted plasma epinephrine almost simultaneously reaches the

heart and the hypothalamus itself, and subsequently the muscle and adipose

tissues, targets of its vascular and metabolic actions. Although the centraleffects of very high plasma levels (5000 to 10,000 pg/mL) would result from

direct hypothalamic stimulation through receptors that would become acti-

vated at those concentrations, lower or intermediate levels could gain similar

access through an alternate route. Thus, at least in rats, the effect of systemic

epinephrine of inducing amygdala (involved in encoding of emotional mem-

ory) norepinephrine release can be prevented by lidocaine anesthesia of the

nucleus of the solitary tract [196]. This suggests that vagal branches may act

as accessory receptors for plasma epinephrine to then transfer the informa-tion to the CNS. Upon reaching the central level, epinephrine actions

primarily should result in glial activation that only secondarily would

involve the neurons. Thus during stress, epinephrine would not participate

in the generation of new information (a neuronal function) that would place

further demands on brain processing capability. Rather, it would only

change information flow increasing considerably its rate of transfer. Visual

evidence obtained in cultured mouse superior cervical ganglion cells has

shown that epinephrine at concentrations as low as 10)8M increases axoplas-mic particle flow through microtubules after interacting with b2-adrenergicreceptors [170]. A mathematical model based on the effect of catecholamines

increasing neuronal responsivity to excitatory and inhibitory inputs, showed

that the changes induced improve the signal detection performance of the net-

work as a whole [150].

In reviewing the actions of epinephrine, it becomes apparent that because

of the myriad receptor types for which it is a ligand, dichotomy of its effects

can be evident, resulting occasionally in opposing activities. For example,systemic plasma epinephrine has a central analgesic effect, whereas if applied

locally at low concentrations to neuromas, it produces hyperalgesia [28].

Moreover, plasma epinephrine produces hypertension and tachycardia; how-

ever, if administered directly intracerebroventricularly, it produces hypoten-

sion and bradycardia in anesthized and awake animals [68]. Even in a single

tissue organ such as the myocardium, the inotropic effects of a- or b-adrenor-eceptors are not additive; instead there is inhibitory interaction between the

two adrenergic receptor populations [157]. Experimental epinephrine-induced cardiac arrhythmias can be prevented with phenytoin given intrathe-

cally but not intravenously (dogs) [71]. In rats, angiotensin II given intracer-

ebroventricularly but not intravenously increases the threshold (inducing

resistance) to intravenous epinephrine-induced cardiac arrhythmias [132].

Similar central and/or peripheral dissociation has been noted on the hyper-

tension of a rat model with transplantable pleochromocytoma [131]. In these

tumor-bearing rats, blood pressure decreased with clonidine (a central acting

blocker of sympathetic tone), but the same drug is ineffective in rats madeacutely hypertensive with norepinephrine infusion [131].


Although the sympathetic and adrenomedullary responses to stress most

often are coordinated, activation of the two systems can be dissociated experi-

mentally. Thus, specific afferent stimuli (stressors) or efferent pathway mani-

pulation (surgically or pharmacologically) can separate the responsesproducing predominance of one system over the other [20,29,41,110,146,

162]. This intersystem relation becomes more complex when considering the

effect of direct interactions, that is, epinephrine action increasing plasma

norepinephrine concentrations. It has been postulated that this epinephrine

action could result from an effect on prejunctional b2-adrenoreceptors or

from uptake on the nerve ending themselves [23,63,180] although epinephrine

is not released later as a cotransmitter. The possibility that sympathetic stimu-

lation could represent a central action of epinephrine [205] was addressedevaluating the correlations between plasma epinephrine and norepinephrine

in cardiac arrest patients who had received high doses of epinephrine. In these

patients, plasma epinephrine increased 3000- to 12,000-fold over the resting

levels [205], with the individual correlations between the catecholamines being

segregated into very high values or low values in a nonuniform distribution

[205]. These results suggest and all-or-none phenomenon, more consistent

with a single epinephrine central site of action (viable or nonviable), rather

than multiple (variable affected) peripheral nerve ending targets [205]. More-over, the span of epinephrine concentrations associated with norepinephrine

responses suggests that receptor saturation levels had not been reached [205].

Thus, a process such as diffusion may have allowed only a fraction of epi-

nephrine molecules to reach the site of action. Such a mechanism is again

consistent with epinephrine entering the CNS, being transported locally

according to a mass action effect, and cause direct central sympathetic sti-

mulation.

Once triggered by a severe stress with real-life anticipatory stimulationand an outcome that would result in profound changes in the external or

internal environment, the adrenomedullary, sympathetic, and vasopressin

responses become clustered to streamline motor activity. The coordinated

enhancement of cardiac ino- and chronotropic activities, bronchodilation

with increased oxygen availability, and the release into the blood of energy

substrates (glucose, free fatty acids, glycerol and lactate) all facilitate brain

and muscle perfusion and metabolism. The favoring of platelet aggregation

and enhancement of innate immunity provide the necessary infrastructure tominimize physical injury. In addition to the sympathetic effects on the gas-

trointestinal tract decreasing motor activity and producing sphincter con-

traction, the specific actions of epinephrine include gastric dysrhythmia

(bradygastria) suppression of appetite and perhaps, inhibition of defecation,

[88,99,193]. In the rat, high intraperitoneal doses of epinephrine produce

hypophagia through taste aversion similar to normal satiety [9]. Bad taste,

dygensia, is also a known side effect of epinephrine, at least in chil-

dren [155]. At plasma concentrations of approximately 740 pg/mL, epineph-rine also causes unpleasantness, tension, and restlessness [75]. Sympathetic


stimulation produces detrusor relaxation in the bladder with sphincter con-

traction, while epinephrine inhibits water intake (in thirsty rats treated with

hypertonic saline or polyethylene glycol) [143]. Neither norepinephrine nor

isoproterenol show the latter effect [143]. Thus, added to the antidiureticeffect of vasopressin, decreased need for fluids or micturition represents

another accompaniment of the same response. As far as effects on sexual

function, epinephrine disrupts receptivity in female rats [40]; in human males

adrenergic stimulation produces penile detumescence [85].

Therefore, the effects of the neuroendrocrine response to stress amount to

coordinated suppression of endogenous bodily input to the CNS, with

analgesia, suppression of appetite and perhaps of defecation, thirst avoid-

ance with decreased micturition, and suppression of sexual urge. Thus,the removal of this endogenous noise allows unimpeded CNS flow of

high-priority information that, when processed, results in a specific reaction:

fight-or-flight, for which the motor system is already prepared. According

to this model, ‘‘adrenaline rush’’ represents a syndrome characterized by

enhanced vigilance with increased environmental awareness and profound

suppression of input processing of endogenous stimuli. Because it appears

that epinephrine plasma concentrations of up to 10,000 pg/mL would act

predominantly on glial cells and not neurons, the information contentwould not be distorted. Only its rate of flow would be affected (enhanced).

It is possible that epinephrine may increase information flow rate not just by

the removal of endogenous input, but directly, through stimulation of axo-

nal particle transport. That epinephrine would not distort perceptions is

documented in a study of normal volunteers who received epinephrine in-

fusions or saline while exercising. Plasma epinephrine at a mean level of

2400 pg/mL did not affect the rating of perceived exertion [198]. Thus, at

the most basic level, the neuroendocrine response prioritizes the informationto be processed by the CNS and facilitates the information processing func-

tion; outside the CNS, it prioritizes motor activity.

Although this model can account for most effects of stress caused by a

stimulus severe enough to generate epinephrine levels of up to 10,000 pg/

mL, the question remains on the possible activity of concentrations that

are even higher. In this regard, maybe at those levels epinephrine could reac-

tivate the action of catecholamines on ontogenesis [124]. Such embryonic

and fetal activity has been demonstrated for the catecholamine biosyntheticenzyme tyrosine hydroxylase [207], and for norepinephrine [174]. The find-

ing of adrenergic receptors secluded within ion channels in neurons that pre-

sumably can be reached only at extremely high extracellular concentrations

[39] and the persistence in the brain of neural stem cells after cortical neuro-

genesis is complete [120] would support this tantalizing prospect.

As would be expected from epinephrine action as only a facilitator of

the response to stress, gene-targeted mice lacking endogenous epinephrine

or norepinephrine show minimal phenotypic effects [31]. These animals havesmaller size and increased cardiac contractility with enhanced contractile


response to the b1 adrenoreceptor agonist dobutamine (catecholamine

supersensitivity) [31]. Contrasting with acute stress, chronic severe stress

(hemodynamically unstable patients and septic shock), where adrenocortical

cortisol secretion is thought to be important or critical for the outcome,there is high incidence of adrenal dysfunction [137,138]. This frequently is

detected only with specific stimulation tests, and the outcome improves with

glucocorticoid therapy [138]. It thus appears that cortisol is more important

for outcome in chronic stress.

It cannot be ignored that many of the important human addictions are

mediated by agents that increase plasma epinephrine. These include alcohol

[76], smoking [35], and exercise, especially if strenuous. Moreover, the re-

creational drug amphetamine enhances catecholamine release from the adre-nal medulla [159,208], and cocaine produces a dose-dependent increase of

plasma catecholamines through a central mechanism [30]. It is therefore

possible that epinephrine suppression of endogenous inputs could be one

of the reward mechanisms leading to development of addiction.

Summary

This article presents the likely pathway of stimuli generated by the recog-

nition of high-intensity stressors to ultimately produce a fight-or-flight

response. A key element is the recognition that psychological stressors that

do not directly alter the internal environment represent the most important

etiology of a fight-or-flight response. Adrenomedullary secretion is a critical

component of that response; impromptu stimulation of the adrenal medulla

can produce plasma epinephrine concentrations greater than 10,000 pg/mL.When these plasma levels reach the hypothalamus to act on the CNS, the

result is facilitation of the decision making, and decision execution processes

(fight-or-flight), and perhaps further sympathetic stimulation and vasopres-

sin release. Subjects with underlying cardiovascular and/or metabolic patho-

logy may be particularly susceptible to potentially lethal reactions to this

neuroendocrine response. Additionally, since this biological reaction may

be triggered by sudden changes in the social environment, the coordinated

actions of epinephrine, sympathetic stimulation and vasopressin must bedirected at not only optimizing the chances for survival, but also at attaining

maximal preservation of the individual environmental and social domains.

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