SYMPATHOADRENAL MEDULLARY SYSTEM AND STRESS

I. J. Kopin, G. Eisenhofer, and D.

Goldstein” National Institutes of Health
National Institute of Neurological and Communicative Disorders
and Stroke
*National Heart, Lung, and Blood Institute
Bethesda, Maryland 20892

HISTORICALINTRODUCTION
Claude Bernard, in 1879, introduced the concept that as organisms
evolved to become more independent of their external environment, they
developed more complex means of preserving their internal environment, the
milieu interieur. He wrote that “all vital mechanisms, however varied they may
be, have only one object, that of preserving the conditions of life in the internal
environment.“ Modern concepts of stress stem from this tenet.
The neuroendocrine determinants of stress responses were first
indicated by Oliver and Shaffer, who, in 1895, described the remarkable
physiological changes produced after injection of adrenal extracts. These
observations led to the isolation and characterization of epinephrine (or
adrenaline) by Abel in 1899. The similarity of effects of epinephrine to those of
sympathetic nerve stimulation suggested to Elliott in 1905 that an
epinephrine-like substance might be a chemical mediator released from
sympathetic nerve endings. Almost a half-century later, von E u ler
discovered that the transmitter was norepinephrine.
Walter Cannon, in 1929, summarized a generation of work which
centered on the theory that the sympathoadrenomedullary system reacts in
various emergency situations, such as pain, bleeding, exposure to cold, and
rage, by secre tio n of e pi ne ph r i n e int o I he b Io o dstrea m, a nd t h
at sympathoadrenomedullary activation plays an important role in preserving
the milieu interieur. Cannon coined the term "homeostasis" to describe “the
coordinated physiological reactions which maintain the steady states of the
body“ by integrated cooperation of wide range of organs.
Selye proposed that stress is a specifit response pattern elicited
regardless of the stimulus and allowing the organism to adapt and to re-
establish normally (see Selye, 1983). He did not view stress as necessarily
damaging or unpleasant-- he used these characteristics to define distress.
Selye defined stages of the stress reaction: an initial “alarm reaction ”,
characterized by an immediate sympathoadrenomedullary discharge; a
subsequent "stage of resistance", characterized by activation of the
hypothalamic-pituitary-adrenocortical axis; and a syndrome of adrenal
hypertrophy, gastrointestinal ulceration, and thymic and lymphoid shrinkage,
which he called the "General Adaptation Syndrome", which could proceed to
the last stage, exhaustion and death. During the stage of resistance,
derangements in hormonal responses and abn ormal tissue changes were
proposed to result in "diseases of adaptation". Although Selye’s early
concepts were expressed in terms of biological processes, they were

11
G. P. Chrousos et al. (eds.), Mechanisms of Physical and Emotional Stress
© Springer Science+Business Media New York 1988
extended to include psycholog ical, interpersonal, and even sociocultural
processes (see e.g., Jenkins, 1979).

HOMEOSTASIS AND DISTRESS

Stress defies easy definition. Cannon would have defined stress in
terms of stimuli--in particular, noxious stimuli or stressors--which are
countered by activation of physiological systems including the
sympathoadrenomedullary system. Selye defined stress in terms of a specific
reaction pattern, with emphasis on the pituitary-adrenocortical system. In this
presentation, stress is defined neither by the stimuli nor the responses, but as
a state in which expectations--whether genetically programmed or acquired--
do not match current or anticipated perceptions of the internal or external
environment. Stress responses evolved because they were advantageous in
natural selection, providing means to anticipate and react rapidly to threats to
the survival or well-being of the organism, preserving the internaI milieu by
short-term adjustments in activities of several systems. When these
responses do not maintain homeostasis and resistance fails due to
inadequate, inappropriate, or excessive activation of the compensatory
systems, physical and psychological damage results. This condition, often
associated with emotional experiences such as anxiety, fear, or anger, is
distress; avoidance of distress is one of the main objectives motivating
learning. In contrast, successful homeostatic responses usually are
unconscious.
Homeostatic and distress responses also differ in that homeostatic
responses are stimulus-specific, producing changes which are appropriate for
adaptation to the disturbance, whereas distress responses usually are more
generalized and can be precipitated when the homeostatic mechanisms are
overwhelmed. Homeostatic responses are relatively predictable within a
relatively narrow range of individual variation, whereas distress responses
can differ markedly among individuals, depending on constitutional factors as
well as the conditioning history of the organism. Both homeostatic
mechanisms and distress responses include activation of the
sympathoadrenomedullary system.
Homeostatic responses generally are mediated by nerve networks, such
as the sympathoneural and parasympathetic systems (Table 1), whereas
distress responses often involve hormones such as epinephrine, adrenal
corticosteroids, and vasopressin. Challenges which throughout evolution have
posed direct threats to well-being, such as cardiovascular collapse,
hypoglycemia,

Table 1. Stimuli Which Evoke Autonomic Responses

t' •!• -*fi›ecif ic Responses Generalized Responses

(Autonomic Nervous System) (Sympathoadrenomedullary)

Orthostasis, Exercise (C.V.S.’, Lung) Exhaustion, C.V.S.*

Collapse Temperature (C.V.S.”, Lung, Sweat) Pain
Food Intake, Waste Discharge Hypoglycemia
(GI Motility, Secretion)
Fluid Balance (G.U.“*, Renal, Bladder) Hypovolemia, Hemorrhage
Alertness (C.V.S.*) "Fight or Flight“ (Fear,
Rage Anxiety, Depression)
”C.V.S. = Cardiovascular ‘*G.U. = Genitourinary
12
asphyxiation, hemorrhage, and fig ht/flight situations, require and are
countered by global, metabolic responses determined mainly by elaboration
of hormones, even at low intensities of stimulation. The organism invariably
appears to be distressed. As the intensity increases, sympathoneural
responses also can occur. Stimuli such as orthostasis, altered environmental
temperature, and food ingestion tend to elicit more regionally specific
responses of nerve networks, causing complex adjustments of glandular
secretion and blood volume distribution. The organism often is unaware of
these responses, but if the intensity of stimulation overwhelms the
homeostatic mechanisms--e.g., with forced prolonged standing or exercise to
exhaustion --mo re generalized responses are elicited and the organism
experiences distress.

RELAXED

AROUSED
FLIGHT FIGHT

ALARMED IRRITATED

AFRAID ANGRY, AGGRESSIVE

Failure of Behavioral Responses

Inevitability
Awareness of Bodily Changes

PANICKY ENRAGED
Fig. 1 Arousal States in Response to Environmental Stimuli or Internal Needs

Arousal states resulting from environmental stimuli or internal needs may be

conceptualized in terms of continua (Figure 1). The organism strives to attain
a safe, sated state. Alerting reactions can evolve to alarm or irritation and
then panicky fear or aggressive rage, the physiological and biochemical
concomitants of distress becoming progressively more intense. Failure to
escape, avoid, or reverse the disturbance can lead to extreme states where
behaviors and physiological responses no longer achieve the desired goals.
Persistent or chronically repeated distress responses such as these can lead
to a variety of psychosomatic syndromes.

DETERMINANTS OF SYMPATHOADRENOMEDULLARY FUNCTION

The neuronal modulation of sympathoadrenomedullary outflow began to
be unfolded when von Euler discovered in 1948 that although epinephrine is
the hormone released from the adrenal medulla, the precursor of epinephrine,
norepinephrine, is the neurotransmitter released at peripheral sympathetic
nerve endings. Axelrod and co-workers defined the metabolism and
disposition
of catecholamines (Axelrod, 1960), demonstrated the importance of reuptake
as
a mode of terminating the actions of the neurotransmitter (Hertting and
Axelrod, 1961), and showed that a wide variety of psychoactive drugs act by
altering catecholamine disposition or metabolism.
 Release of epinephrine from the adrenal medulla and of norepinephrine
from sympathetic nerve terminals depends on nerve impulse outflow from the
spinal cord via preganglionic cholinergic neurons whose cell bodies are
located in the intermediolateral gray matter of the thoracic and upper Iumbar
segments. At each level, myelinated axons from the preganglionic neurons
emerge in an anterior root of a spinal nerve, fo rm the white ramus
communicans, and enter the corresponding ganglion of the sympathetic
chain. In the ganglia the fibres may form synapses (usually many) with
postganglionic (noradrenergic) neurons or traverse the ganglia without
forming synapses, continuing to merge into the greater or lesser splanchnic
nerves which supply the adrenal medulla or synapse with neurons located in
ganglia clustered around the branches of the abdominal aorta (coelic or aorta-
renal ganglia). Preganglionic fibres from the upper thoracic segments ascend
along the sympathetic chain to terminals in the stellate or cervical sympathetic
ganglia; preganglionic fibres from the lower thoracic or lumbar segments
descend to sympathetic ganglia of the lower lumbar or sacral spinal nerves.
The spinal sympathetic ganglia send postganglionic unmyelinated fibres, via a
gray ramus communicans, to the spinal nerves and thereby reach various
areas of the peripheral tissues. Unmyelinated fibres from the cervical ganglia
are distributed via branches of the vagus to reach the thoracic viscera and via
plexuses on the carotid artery and its branches to reach the eye and blood
vessels, glands, and muscles of the head and neck.
Immediate (within seconds or less) changes in the rates of
catecholamine release from sympathetic terminals or the adrenal medulla
depend mainly on altered rates of release of acetylcholine from the
preganglionic neurones, but regulatory processes have been implicated at
various levels. The release of NE at postganglionic nerve terminals and of
epinephrine from the adrenal medulla are subject to modulatory effects
mediated by presynaptic receptors for angiotensin, dopamine, prostaglandins,
and other substances. The density of such receptors may be modified slowly
(requiring hours or days). This may be determined by genetic factors or be
responsive to physiological “resetting“. Release of acetylcholine and its
efficacy in depolarizing postganglionic neurons can also be modulated
physiologically.
The regional localization and pharmacologically-induced alterations of
norepinephrine in the hypothalamus and mesencephalon led Martha Vogt
(1954) to sug gest th at catecholamines are also centraI nervous system
neurotransmitters. Carlsson (1959) first suggested that dopamine, the
precursor of norepinephrine, was also a distinct brain neurotransmitter.
Subsequent development of methods for assay of catecholamines and the
metabolites, for determining localization of catecholam ine-synthesizin g en
zymes usi ng immunohistochemical method s, and for fluorescence
histochem ical demonstration of catecholamines in tissues (Falck, 1962)
allowed definitive localization of catecholaminergic neurons and their
projections in brain as well as studies of the effects of exposure to various
stressors. These techniques, and newer methods for tracking neuronal
pathways by axonal transport of fluorescent dyes or horseradish peroxidase,
as well as for immunohistochemical demonstration of peptides and other
neuromodulators, promise to enable more complete descriptions of the
central neural regulation of sympathetic outflow. It already is clear that
regionally specific responses determining physiological adaptations and more
generalized activation are under complex neurological regulation involving an
array of neurotransmitters (see below).
There appear to be several intraspinal and supraspinal mechanisms for
influencing the outflow of nerve impulses to the adrenal medulla and to
various segments of the sympathetic innervation fields. These are modulated
via spinal reflexes, reflexes from baroreceptors, and by descending pathways
from various brain areas. Many of the neurotransmitter substances thought to
be involved are listed in Table 2. The roles of growth factors, genetic
determinants and neuronal plasticity in long term modifications of responsivity
are poorly defined.
14
 Table 2 Neurotransmitters in fibres terminating in region of
spinal preganglionic sympathetic neurones

ñ/eurotransm/tter (Descending from) Local SR )fiaI Neurotransmitter

Serotonin (Raphe) Substance P

Norepinephrine (Ay, A5› Enkephalin
Epinephrine (C ) Somatostatin
Oxytocin-neurophysin (Paraventricular N) Neurotensin
TRH (? Paraventricular N) GABA
Substance P (Medulla) Glycine
Enkephalin (Medulla) Glutamate
Aspartate

Table 3 Physiological Responses to Sympathoadrenomedullary Activation

Tachycardia Hyperventilation,Bronchodilation
Vasoconstriction Sweat
GI Tract
Kidney Piloerection
Spleen
Cutaneous Hyperglycemia, Hyperlipemia,
Inhibition of GI Proptosis, Pupillary Dilation
Tract Motility
Secretion Renin-angiotensin-aldosterone System
Activation
Vasodilation Platelet Activation
Skeletal muscle

PHYSIOLOGICAL INDICES OF SYMPATHO-ADRENOMEDULLARY RESPONSES TO

STRESS
Physiological components of the generalized response to stressors
include cardiovascular, renal visceral, cutaneous, and metabolic responses,
each of which may by itself be a homeostatic mechanism. These are listed in
Table 3. Th e cardiovascul ar responses to assu ming an erect p ostu re
include vasoconstriction and increases in heart rate. These sympathetically
mediated
15
responses are imperceptible but are required to counter hydrostatic pooling
Of blood in the legs and maintain cardiac output, blood pressure and cerebral
perfusion (Bannister, 1983; Goldstein et al., 1982). Adrenomedullary
secretion, however, is stimulated only slightly if at all during orthostasis (Burke
et al., 1977; Robertson et al., 1979) whereas sympathetic nerve activity to leg
skeletal muscle is increased (Wallin and Sudlof, 1982). Similarly, in mild
exercise sympathetic neuronal activation, rather than adrenal medullary
secretion, predominates. When homeostatic mechanisms fail, e.g., with
orthostatic hypotension attending drug-induced blockade of adrenergic
receptors, more generalized responses are observed, with adrenal medullary
secretion, marked tachycardia, peripheral vasoconstriction, sweating, and
hyperglycemia.
Gastrointestinal responses also may be homeostatic or a component of
generalized stress responses. Postprandial increases of visceral blood flow at
the expense of coronary and cerebral perfusion may account for episodes of
angina pectoris or orthostatic hypotension in susceptible elderly individuals.
Splanchnic vasoconstriction during exercise or during exposure to high
temperature are homeostatic responses. Inhibition of gastrointestinal activity
and sphincter relaxation, however, are characteristic responses in acute
distress.
Cutaneous responses to extremes of environmental temperature
promote body cooling (vasodi lation and sweating) or conserve heat
(cutaneous vasoconstriction and piloerection). Metabolic responses to stimuli
such as lowered blood glucose, exposure to cold or exercise, involve both
sympathetic and adrenal medullary responses, but the latter predominate
when extremes (hypoglycemia, hypothermia, exhaustion, etc.) ca use
insufficiency of the homeostatic mechanism.
The physiological changes attending the generalized stress response
may be viewed as an integrated adaptive response necessary to preserve life,
preparing the organism for "fight or flight" (Cannon, 1929). Thus, cutaneous
and visceral vasoconstriction with associated decreases in skeletal muscular
vascular resistance results in shunting of blood flow to support extraordinary
muscular efforts. Similarly, increments in blood glucose and free fatty acids,
as well as enhancement of oxygen delivery by bronchodilation and increases
in cardiac output (sustained by tachycardia and splenic contraction), support
increased energy needs. Other stress responses have also received
teleological explanations: piloerection provides insulation from cold or
disguises small size; proptosis and pupillary dilation attend increased
vigilance; platelet activation and cutaneous vasoconstriction limit blood loss.
Cannon (1929) emphasized the advantages of anticipatory sympatho-
adrenomedullary responses in the evolution of emotional behaviors: ”But fear
and ag gressive feeling, as anticipatory responses to critical situation, make
ready for action and thereby have had great survival values. And the
remarkable system of internal adjustments which attend these emotions and
which mobilize the forces of the body are such as to have had great survival
values. Thus the bodily changes may be reasonably interpreted”. Although
sympatho-ad renomed ullary stress responses have survival value, repeated
or severe stress may result in inappropriate persistance of increased
sympathetic nerve activity (e.g., Johnson et al., 1983). Such persistent
responses have provided the basis for several hypotheses relating stress to
subsequent psychosomatic disorders.
MEASUREMENTS OF URINARY AND PLASMA CATECHOLAMINES AS INDICES
OF ACUTE RESPONSES TO STRESSORS
Cannon’s observations on the physiological responses that prepare the
organism for "fight or flight" were attributed to sympatho-adrenal medullary
discharge of catecholamines, but it was not until 1954, after new, sensitive
fluorimetric methods were introduced, that stress responses were
demonstrated to produce increases in urinary catecholamine excretion. It was
shown that during anxiety of airplane flight pilots and passengers excretea
increased amounts of catecholamines (Euler and Lundberg, 1954). Elmadjian
(1963)
reviewed the various early studies that showed normal subjects excrete
increased amounts of catecholamines during a variety of situations
associated with anxiety or aggression. In general, in these situations
increases in epinephrine were more striking than those of norepinephrine.
Often there has been poor agreement among physiological responses,
subjective feelings, and changes in catecholam ine excretion. Frankenhauser
(1971) noted th at epinephrine excretion was more closely related to the
intensity than the quality of an emotion. Increased tension, expectancy
(pleasant or unpleasant), and demand for concentration also were associated
with higher epinephrine excretion rates.
During the interval between 1955 and 1970, there were several
important discoveries regarding the disposition and metabolism of catech
olamines. Accurate methods for measurements of catecholamine metabolites
in urine became available, and later, sensitive and specific radioenzymatic
assays for catecholamines in plasma were introduced. The main urinary
metabolites of both epinephr ine and norepin ephrine were found to be 3-
methoxy-4- hydroxymandelic acid (vaniIIyIman delic acid, VMA) and 3 -me th
oxy-4- hydroxyphen ylglycoI (MHPG). Assay of these meta bol ites could not
descriminate adrenal medullary from sympathetic responses. The hope that
MHPG excretion might be an index of brain norepinephrine metabolism
fostered many studies in psychiatric patients, but the subsequent discovery
that VMA largely is formed from MHPG, made interpretation of such studies
tenuous

Table 4. Stress Research

ANIMAL MODELS
Slight Disturbances (turn on light, open cage, handle, transfer)
(alerting reaction)
Major Stressors
Physical (temp. extremes, elec. shock, immobilization, etc.)
Psychological (threat, natural or experimental, alarm)
Pharmacological (ether, 2-deoxyglucose, insulin, etc.)
Tissue Damage (fracture, hemorrhage, chemical injury, etc.)

HUMAN VOLUNTEERS
Laboratory Experiments (mental activity, cold, centrifugation, etc.)
On-the-job (workers, aviators, air traffic controllers, etc.)
Opportunistic
Patients (trauma, surgical operations, acute or chronic
illness) Psychological Stressors (patient relatives, near

disasters, etc.)
(see review by Kopin, 1985). The ability to measure precisely both
epinephrine and norepinephrine by radioenzymatic assays and, more
recently, by high performance liquid chromatography with electrochemical
detection (HPLC-ED) stimulated hundreds of studies in which a variety of
stimuli were used to evoke changes in plasma catecholamines in
experimental animals and in humans (see Table 4).
Increases in catecholamines in plasma were found with relatively mild
stimuli associated with usual daily activities (Figure 2). Thus standing up
doubles
plasma norepinephrine without greatly affecting epinephrine. Drinking coffee,
smoking, or mental activity elevates both norepinephrine and epinephrine,
whereas public speaking (medical residents presenting grand rounds)
produces proportionately larger changes in epinephrine than norepinephrine.
The effects of some experimental procedures used in humans to evoke
catecholamine responses are shown in Figure 3. Considering the discomfort and
cardiovascular effects of immersion of the hand and forearm into ice-cold
water, the plasma catecholamine responses to the cold pressor test
seem surprisingly small. Mild exercise, in contrast, evokes larger increases in both
norepinephrine and epinephrine. Mental challenge requiring increased
alertness is attended by a sympathetically mediated cardiovascular response,

SITTING
STANDING

MENTAL ARITHMETIC

PUBMC SPEAKING

COFFEE

SMOKING

PERCENT BASAL ILYING)

Fig. 2 Effects of Usual Activities on Plasma Catecholamines

STANDING

GRIP +

STD COLD
•VARIES WITH DEGREE OF EFFORT ANOXGLUCOS AVAILABILITY. ETC.
PR.

MOD. EXER.“

GLUC-N

STRENUOUS“

GLUC€@ 0 1fXI 2IXl 3tXI 4tXI

PERCENT BASAL LEVEL

Fig. 3 Evoked Increases in Plasma Catecholamines

but performance of a non-distressing mental task does not appear to

produce elevated plasma epinephrine levels (Eisenhofer et al., 1985;
Goldstein et al., 1987).
 With decreases in blood glucose. or strenuous exercise the relative
increases in epinephrine exceed those of norepinephrine, as is the case for
public speaking. A similar difference in the sympathoadrenal versus
adrenomedullary responses is seen with diabetic ketosis, acute myocardial
infarction, and hemorrhagic shock (Fig. 4). Such severe stressors evoke
proportionately greaterresponses in epinephrine than in norepinephrine,
whereas durin g extensive surgery or in the post-operative state, the
norepinephrine response is often relatively greater. Sympathetic neuronal
responses appear to regulate blood volume and distribution of the blood to
various tissues, whereas epinephrine release from the adrenal medulla is a
hormonal response to metabolic disturbances, preparation for emergencies,
situations requirin g vigilance or lacking predictability, or failure of
sympathoneural homeostatic mechanisms. The hormonal response especially
influences cardiac output, both by positive inotropic and chronotropic effects
and by skel etal muscle vasodilation.

BASAL
EPINEPHRINE
SURGERY NOREPINEPHRINE

POST-OPER.
• VARIES
DIABETIC KETOSIS WIDELY WITH
SEVERITY

HEM.-SHOCK

PERCENT BASAL LEVELS

Fig. 4 Plasma Catetholamine Levels In Catastrophic Illness

The validity of venous plasma norepinephrine as an index of sympathetic

neuronal discharge has been questioned (Brown et al., 1981). Differences in
overall sympathetic activation or in sympathetic activity in other regions may
not be reflected adequately by changes in catecholamine levels in plasma
obtained from blood in the antecubital vein, the usual site of sampling. The
concentration of norepinephrine in the ven ous blood of any region is
determined by the concentration of the catecholamine in arterial blood,
extraction of the catecholamine from the blood during its passage through
the tissues, and the overflow of the neurotransmitter released from the
sympathetic nerve terminals in the tissue. The arterial concentration of
norepinephrine is the result of the levels in mixed venous blood after
removal of a portion of the
catech ol amine during passag e of blood through the lungs. Thus, the
norepinephrine concentration in venous blood of any particuiar tissue
would not necessarily reflect the overflow of norepinephrine into blood
throughout the body.
In a recent study (Goldstein et al., 1987) of plasma catecholamines during a
mental challenge of playing a video electronic game, increase in plasma
norepinephrine in antecubital venous blood bore no relationship to increments
in cardiac output or systolic blood pressure. Arterial norepinephrine
responses correlated weakly (r = 0.48) with increments in cardiac output,
and were not related to responses of systolic blood pressure. There were,
however, significant correlations between changes in tota I body n
orepi nephrine spillover (determined by isotope dilution methods during
constant infusion of 3 H-f'- norepinephrine) and changes in cardiac output
(r = 0.68) or systolic blood pressure (r = 0.60). Furthermore, while there was
a linear relationship between forearm clearance of norepinephrine and blood
flow, the slope and intercept of the regression line relating the forearm
clearance and blood flow were such that at low flow rates as much as 70-
80% of the arterial norepinephrine was extracted, whereas at faster flow
rates only 30-40% was extracted. Thus regional hemodynamics, activity
of norepinephrine removal systems, and regional differences in sympathetic
activity interact in determining changes in antecubital venous
norepinephrine levels and diminish reliability of such changes as an
index of sympathetic activity.
CONSEQUENCES OF CHRONIC INCREASES IN SYMPATHOADRENAL MEDULLARY
ACTIVITY
Stimulation-evoked increases in neurohumoral secretion occur almost
instantaneously and may be maintained for short intervals, during which
the stores of catecholamine provide a reserve for continued responses.
With frequently repeated or prolonged exposure to a stressful stimulus,
mechanisms are brought into play to adapt to the stressor. Increased
demand for the production of catecholamines results in increased levels of
tyrosine hydroxylase (TH), the rate limiting enzyme in catecholamine
synthesis, as well as of dopamine-§-hydroxyIase (DBH) and
phenyIethanoIamine-N-methyl transferase (PNMT)) (see Kvetnansky, 1980)).
In the adrenal medulla, TH and DBH are mainly a result of neuronally
involved catecholamine release. Increments in TH levels subsequent to
repeated immobilization, hypoglycemia, or cold exposure, are prevented by
denervation (which also blocks release of epinephrine). Adrenal DBH
decreases during exposure to stressful stimuli, because it is released by
exocytosis, along with epinephrine and other vehicular contents,. Restoration
of DBH becomes increasingly rapid with repeated stress responses and levels
of the enzyme become greater than normal during a subsequent interval
without exposure to stress. PNMT, the enzyme that converts norepi
nephrin e to epinephrine, mai n Iy is u nd er h o rmo n a I control.
Glucocorticoids in high concentration from the adrenal cortex bathe the
medullary cells and maintain PNMT levels. This enzyme decreases after
hypophysectomy and increases slightly when adrenal cortical secretory activity is
enhanced. The increments in enzyme levels in the adrenal medulla during
chronic or repeated stress serve to maintain the ability of the gland to
secret increased quantities of epinephrine. Similar increments in TH and
DBH have been found in sympathetically innervated tissue. Basal levels of the
enzymes and presumably their regulatory mechanisms (synthesis and
degradation) are under genetic control (Ciaranello, 1977). Responses to
stimuli are likely to vary among individuals, as they do among inbred
strains of rats (McCarty & Kopin, 1978), on the basis of such genetically
controlled factors as enzyme synthesis and degradation and responsivity
of the neuronal systems modulating catecholamine release.
The physiological responses to released catecholamines are dependent
also on the receptors and receptor activated mechanisms. With repeated
exposure, receptors are frequently down-regulated so that enhanced
catecholamine release ovet a prolonged interval might elicit responses of
lesser magnitudes. Variability in responsiveness to adrenoceptor
stimulation bj/ administered catecholamines has been cited as a possible
explanation for differences among individuals or groups in adrenoceptor-
mediated responses to some stressors (Eisenhofer et al., 1985). The health
consequences of prolonged of chronically
repeated distress are being explored actively. The availability of biochemical
indices of the magnitude of distress should aid these studies.
SUMMARY
The sympatho-adrenomedullary system plays an important role in stages of
stress responses and in turn is subject to regulatory processes which are
modulated by the neuronal and hormonal responses to exposure to
stressors. Homeostatic mechanisms which prevent marked physiological
changes in the course of daily life and psychological alerting are mild
stimuli. As described by Cannon the homeostatic mechanisms enlisted for
rapid alterations of bodily functions in preparation for “fight or flight” are
mediated mostly by sympathoad renomed ul lary disch arg e of
catecholamin es. S uch in itial neurohumorally mediated bodily
changes are included in the early alarm reaction in stress, as defined by
Selye. Norepinéphrine is rel eased from sympathetic nerve terminals into
the neuroeffector junction and then into blood; epinephrine is discharged
directly into the circulation from the adrenal medulla.
When homeostatic mechanisms fail to correct the effects of a disturbance,
or when psychological alerting produces emotional reactions, an alarm
reaction begins with general activation of the sympathoadrenomedullary
system and recruitment of additional neurohumoral systems (e.g.,
hypothalamic - pituitary - ad ren al co rt icaI, vasopress i n, ren in -an gi oten
s i n) . C ate c h o Iami ne neurotransmitters in the central nervous system
as weII as peripheral catecholamines are likely to have an important role in
regulating these stress responses but exactly how is unknown. With repeated
or prolonged exposure to stressors, a phase ensues where there are Zhang
es in catech olamin e biosynthetic enzymes and receptor responsivity; other
biochemical responses may result in a variety of pathological changes .
Changes in norepinephrine
release during homeostasis (e.g., local changes in blood flow,. gIandular
secretion, fat pad metabolic activation) may not be reflected in altered plasma
levels of the catecholamine in antecubital venous blood. Increases in arterial
concentrations of catecholamines and in their urinary excretion occur when
sympatho-adrenomedullary activity is sufficient to produce significant
increases in overflow of norepinephrine from the neuroeffector junctions into
the circulation or when epinephrine is discharged from the adrenal medulla.
Massive increases in catecholamine discharge are readily detected in plasma
even from antecubital vein blood, but less generalized responses may be
masked unless regional spillover rates are assessed using isotope dilution
methods.

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