Brief Review
Epinephrine and the Genesis of Hypertension
John S. Floras
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Several lines of evidence suggest a psychophysiological link between stress, adrenomedullary
activation, and the genesis of hypertension. Experimental data support four important
concepts: 1) epinephrine stimulates prejunctional ft-adrenergic receptors that facilitate
norepinephrine release from sympathetic nerve endings; 2) epinephrine can be converted into
a cotransmitter by neuronal uptake and on subsequent release augment the simultaneous
discharge of norepinephrine; 3) exogenous epinephrine can induce sustained hypertension in
rats; and 4) there is a period of critical sensitivity to endogenous epinephrine in a genetic model
of rat hypertension. Plasma epinephrine concentrations are elevated in many young subjects
with borderline or mild hypertension. The hypothesis that intermittent surges in epinephrine
could initiate or promote the development of primary hypertension by amplifying peripheral
neurotransmission, both directly (facilitative effect) and indirectly (cotransmitter action), is
supported by reports that hemodynamic and noradrenergic responses to sympathetic activation
can be augmented by increases in endogenous epinephrine or by its local or systemic (up to 30
ng/kg/min) infusion. Such responses have been documented in both normotensive and
hypertensive subjects and can be blocked by propranolol. Although the weight of evidence
(mostly indirect) indicates that epinephrine can augment norepinephrine release in humans,
the epinephrine hypothesis, itself, remains unproven. Expression of hypertension by this
mechanism may be restricted to a specific epinephrine-sensitive subset of individuals with a
genetic predisposition to high blood pressure. (Hypertension 1992; 19:1-18)
A
decade ago, it was proposed that the primary
abnormality in essential hypertension may
L. be increased release of epinephrine from the
adrenal medulla.1 According to this hypothesis, small
repetitive increases in circulating epinephrine cause
hypertension indirectly, rather than directly, by stimulating prejunctional ft-adrenergic receptors that
facilitate exocytotic norepinephrine discharge from
sympathetic nerve endings (Figure 1). An episodic or
sustained increase in norepinephrine release could
then initiate, permit, or promote the development of
high blood pressure.
Folkow2 has identified "excitatory psychoemotional influences" as one of two environmental stimuli that may reinforce or sometimes precipitate primary hypertension in those with a genetic
predisposition for high blood pressure. The concept
From the Division of Cardiology and the Centre for Cardiovascular Research, Toronto General Hospital, University of Toronto,
Toronto, Canada.
Supported by grants-in-aid from the Heart and Stroke Foundation of Ontario. J.S.F. is the recipient of a Career Scientist Award
from the Ministry of Health of the Province of Ontario. The
opinions expressed in this review are those of the author and not
of the Ministry.
Address for correspondence: Dr. John S. Floras, Division of
Cardiology, 12 EN-234, Toronto General Hospital, 200 Elizabeth
Street, Toronto, Ontario M5G 2C4, Canada.
Submitted March 5, 1991; accepted in revised form Jury 16,
1991.
that episodic increases in plasma epinephrine, if of
sufficient magnitude, could act as the physiological
link between such "stressful" environmental influences and the development of hypertension in predisposed individuals is intuitively attractive. Thresholds for epinephrine's cardiovascular and metabolic
actions are at plasma concentrations that can be
replicated by mental stress.3"8 Early hypertension in
many subjects is associated with a pattern of enhanced autonomic cardiovascular drive at rest and
increased sympathoadrenal reactivity, analogous to
the hypothalamic defense reaction, in response to
mental stress but not in response to physical tasks.5-79
In the mind of the lay public, "stress" has long been
associated with "adrenaline" and the genesis of
hypertension. This concept has been reinforced by
reports of hypertension after the stress of battle10 or
exposure to noise,1112 descriptions of relations between stress, personality, and blood pressure and
plasma epinephrine concentrations,2-513-15 and documentation in prospective studies of environmental
changes that promote or protect against primary
hypertension.1617
A facilitative effect on peripheral noradrenergic
transmission has been observed both during and after
exposure to epinephrine. Aftereffects of epinephrine
are presumed to be through conversion of epinephrine from a hormone to a cotransmitter since this
catecholamine can be incorporated into postgangli-
Hypertension
Vol 19, No 1 January 1992
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FIGURE 1. Schematic representation (much simplified) of prejunctional and postjunctional adrenergic receptors at the
sympathetic neuroeffector junction in the peripheral nervous system. Left panel: Low level nerve stimulation releases norepinephrine
(NE), which has a higher affinity for inhibitory ar than facilitative firadrenergic receptors. Center panel: Direct activation of
prejunctional Pradrenergic receptor by circulating epinephrine ([EPI]) facilitates neurotransmitter release. Right panel: Sustained
aftereffects of [EPIJ incorporated into sympathetic varicosity (neuronal uptake) and converted from hormone to cotransmitter.
Positive feedback loop by which activation of prejunctional ^-receptor by neurally released [EPI] facilitates NE release and
augments effector cell response. Effector cell responses to facilitation of norepinephrine release are increased vascular contraction
(a/) and increased heart rate (f),).
onic sympathetic nerves and released, with norepinephrine, up to 24 hours after its uptake.18-23
Through this local positive feedback mechanism,
endogenous epinephrine, within the synaptic cleft,
could augment norepinephrine release both during
episodes of sympathoadrenaJ activation and afterwards when plasma concentrations have returned to
basal levels18*24-32 (Figure 1). The sustained, indirect
aftereffects on norepinephrine release of brief, repetitive increases in plasma epinephrine concentrations
may be of greater functional importance in the
genesis of hypertension than its immediate direct,
and often brief, cardiovascular actions as a circulating hormone.1'15-20-28-33
In addition to these actions at the neuroeffector
junction, stimulation of ft-adrenergic receptors by
epinephrine also facilitates hypothalamic34 and adrenal28-35 catecholamine release. As both norepinephrine and epinephrine are released from these tissues,
these observations suggest a potential positive feedback loop that would allow epinephrine to augment
its own release via "autoreceptor" stimulation. In
this way, a relatively small increase in epinephrine
could amplify neurotransmission through several
closely linked central as well as peripheral 0-adrenergic mechanisms.
Although these two components (facilitative and
cotransmitter) (Figure 1) of the epinephrine hypothesis are supported by a number of studies in isolated
tissues, intact normotensive animals, experimental
models of hypertension, and in humans, not all
experimental data are consistent with the epinephrine hypothesis. A review of these experimental data
will be piesented briefly with principal emphasis on
evidence for facilitated release of norepinephrine
and induction of experimental hypertension by epinephrine. Review of investigations in humans will
focus on 1) evidence for increased circulating epinephrine in primary hypertension, 2) evidence for
enhanced prejunctional /^-responsiveness in early
hypertension, 3) evidence for facilitated release of
norepinephrine by epinephrine in normal and hypertensive humans, and 4) the functional significance of
augmented sympathetic neurotransmission by epinephrine as it relates to circulatory regulation.
Experimental Evidence for Facilitated Release of
Norepinephrine by Epinephrine
Direct Effects of Epinephrine on
Norepinephrine Release
Evidence that epinephrine and other /3-adrenergic
receptor agonists can facilitate exocytotic norepinephrine release from sympathetic varicosities by stimulating prejunctional /^-receptors (Figure 1) has been
extensively reported and reviewed.18-24-26-28^0-32^6-46
Facilitative prejunctional ft-receptors have also been
described.47"49 Functionally, one could consider three
potential roles for such receptors: as autoreceptors50
activated by neuronally released norepinephrine, as
"heteroreceptors"50 activated by epinephrine, as a
circulating hormone, or as autoreceptors stimulated
by epinephrine transformed from a hormone to a
neurotransmitter by its uptake and storage in sympathetic varicosities (Figure 1). There is little evidence
that the neurotransmitter norepinephrine potentiates
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Epinephrine and Hypertension
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LOG CONCENTRATION OF ISOPROTERENOL, »
FIGURE 2. Line plots show comparison of the effects of increasing concentrations of isoproterenol on the contractile responses of
human and canine saphenous veins to electrical activation of the adrenergic nerve endings (left panel) and exogenous
norepinephrine (right panel). Data are expressed as percent of the maximal contractile response to the stimulation used and are
shown as mean±SEM. Numbers indicate how many preparations from different donors were used at each concentration. In the
canine vein, the effect of isoproterenol was comparable during contractions evoked by electrical stimulation and exogenous
norepinephrine, except that at 3xlO~6 M, the depression in the presence of the latter was significantly larger. 'Change caused by
isoproterenol is statistically significant from control (p<0.05). Reproduced with permission.30
its own release.28'45-50 Rather, epinephrine, whose
affinity for ft-adrenergic receptors is more than 200fold greater than that of norepinephrine,51 appears to
be the "natural agonist" for these receptors in humans.26-47-52^3 Prejunctional ft-adrenergic receptors
may respond preferentially to circulating as opposed
to neurally released catecholamines.54
Facilitated release of [3H]norepinephrine from tissues preloaded with the labeled neurotransmitter has
been documented in vitro at epinephrine concentrations in the range of 10"10 to lO^M.42 This is within the
physiological range of plasma epinephrine concentrations.55 At higher concentrations (more than 10"8 M),
epinephrine, like norepinephrine, acts on prejunctional
aradrenergic receptors to inhibit sympathetic neurotransmission20-3942^3 (Figure 1). That this facilitative
action is a nonspecific effect of epinephrine is unlikely
since it is abolished or attenuated by ft-adrenergic
receptor blockade.18-20-26^32-42-44 Although prejunctional ft-adrenergic receptor-mediated facilitation of
norepinephrine release appears due to increased Ca2+
entry into nerve terminals, resulting in increased intraneural cyclic AMP,28-56-58 the exact mechanism by
which a2-receptor stimulation inhibits neurotransmitter
release has not been established.56'57'59
The maximal enhancement of norepinephrine release by epinephrine is relatively small (from 13 to
133%, depending on tissue and preparation) when
compared with the effect of atj-adrenergic receptor
antagonists on stimulated norepinephrine release,42'45 and the functional consequence of ft-
adrenergic receptor stimulation varies from species
to species.2^33-36'39'42'4759-61 The facilitative effect of
isoproterenol on electrically stimulated norepinephrine release from adrenergic nerves of saphenous
veins is greater in humans than in the dog and is
associated with an augmented (human) as opposed
to a diminished (canine) contractile response when
these two interventions are combined30 (Figure 2).
Such quantitative differences make it difficult to
predict responses to epinephrine in humans from
experimental observations in other species.
Inhibitory prejunctional a2-receptors and facilitative ft-adrenergic receptors have been documented
in a number of human vascular tissues, including
omental arteries and veins, digital arteries, and saphenous veins,41-42'53'62-64 and functionally important
ft-receptors n a v e been demonstrated in the human
heart.65 Whether prejunctional inhibitory aradrenergic receptors (autoreceptors) must first be blocked
to detect the facilitative effects of ^-adrenergic receptor (heteroreceptor) stimulation on norepinephrine release in humans66 will depend on a number of
factors (such as the ratio and sensitivity to agonists of
prejunctional a^ft-adrenergic receptors and the
width of the junctional cleft) that vary from tissue to
tissue.4567 The strength of negative feedback regulation by a 2 - a dr e n e r gi c receptors, for example, is inversely proportional to the width of the junctional
cleft.45-67 It should not be surprising, therefore, to
find variations in the effects of epinephrine on neu-
Hypertension
Vol 19, No 1 January 1992
retransmitter release or neurogenic vasoconstriction
in different vascular beds in humans.41'42"53-64
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Sustained Aftereffects of Epinephrine on
Norepinephrine Release
In 1932, Burn68 observed augmented neurogenic
vasoconstriction in vivo both during and after exposure to epinephrine, but the latter response fatigued
after successive nerve stimulation. Burn suggested
this effect of epinephrine was due to its storage and
subsequent release.
The affinity of neuronal uptake-1 for epinephrine
is about half that for norepinephrine.23 In the mouse,
about 35% of injected epinephrine and about 55% of
injected norepinephrine appear to be taken up and
released by this neuronal mechanism.69
Myocardial extraction and stimulated release of
epinephrine have been documented in dogs and in
human subjects.22-70 Approximately 75% of this extraction can be blocked by desipramine.70 In dogs,
the ratio of epinephrine to norepinephrine released
on stellate stimulation is comparable to the ventricular content of these catecholamines.22-70 Esler and
his colleagues70 have documented cardiac epinephrine spillover, averaging 2 ng/min or 2% of the
corresponding norepinephrine spillover, in six patients with untreated congestive heart failure (but
not in resting healthy volunteers), and higher levels
of neuronal epinephrine release from their gut, liver,
lungs, and kidneys. Approximately 25% of the total
plasma epinephrine appearance rate in these patients with heart failure could be attributed to regional overflows from these organs.
In marked contrast to its plasma half-life, measured in minutes,71 the half-life of neuronal epinephrine is approximately 4 hours.20 Since the release of
epinephrine may be detected up to 24 hours after its
neuronal uptake,18-21-47 the potential for neurally
released epinephrine to increase the simultaneous
discharge of norepinephrine by stimulating prejunctional /32-adrenergic receptors, and thereby augment
neurogenic vasoconstriction at the neuroeffector
junction, should persist long after a surge in endogenous epinephrine subsides and its local concentration returns to basal levels.20-26 To illustrate this
concept, Majewski et al72 demonstrated in anesthetized rabbits a 50% increase in norepinephrine spillover into plasma after an epinephrine infusion. This
was at a time when tissue epinephrine concentrations
were elevated, but plasma epinephrine concentrations were not. These effects on norepinephrine
release could be attenuated by propranolol and abolished by prior uptake-1 blockade (desipramine).72
Whether neurally released epinephrine exerts such
positive feedback in humans remains controversial.41-42 Molderings and colleagues41 could not detect
any facilitate aftereffect of newly taken up (tritiated) epinephrine (10 nmol/1) on norepinephrine
release from human saphenous veins.
Rat Models of Hypertension
Several groups29-48-73-74 have shown that infusion or
depot implantation of epinephrine in doses that do
not increase its plasma concentration can cause
sustained elevation of blood pressure in normotensive rats. This conclusion has been challenged by
others.75 The increase in blood pressure in two of
these protocols could be blocked if metoprolol was
coadministered.29-48 These particular experiments
suggested that a threshold uptake into atria of 46
pmol epinephrine/g tissue was sufficient (but 14
pmol/g insufficient) to generate an autofacilitative
feedback loop.29 Stress-induced hypertension (immobilization) in normal rats appears also critically dependent on the presence of epinephrine.76
Spontaneously hypertensive rats (SHR) are similar to humans with primary hypertension in that
neurohumoral alterations and excitatory psychosocial stimuli reinforce their genetic predisposition to
high blood pressure.2 SHR display several characteristics of augmented sympathoadrenal activity.
Plasma and ganglionic epinephrine concentrations,77-78 epinephrine synthesis,79 sympathetic ganglionic ft-receptor concentrations,78 and adrenergic
responses to stress80 are all increased when compared with Wistar-Kyoto (WKY) rats, and central
epinephrine concentrations and PNMT activity rise
in parallel with blood pressure.81
Surgical resection of the adrenal medullae of 4-6week-old SHR attenuates the development of hypertension without affecting these animals' growth or
heart rates.52 This is the period of most rapid growth
and development in this strain; increased vascular
resistance is already established by 4 weeks of age.82
The pressor response to neurally released norepinephrine in these experiments was reduced in the
isolated perfused mesenteric bed of demedullated
rats and could be augmented by adding epinephrine
to the perfusate. In contrast, there was no apparent
difference between sham and demedullated SHR in
postjunctional responsiveness to norepinephrine or
epinephrine in this vascular bed.52
The antihypertensive effect of demedullation could
be abolished by selective ft-agonists or epinephrine
depot implants and restored by concurrent selective
ft-adrenergic receptor blockade.83 Because these
observations52-83-84 contradict an earlier report that
adrenal demedullation does not affect established
hypertension in adult SHR85 and are inconsistent
with a large body of evidence for reduced sensitivity
and responsiveness of postjunctional /J-adrenergic
receptors in SHR (particularly older SHR 86 ),
Borkowski52 has proposed that /^-adrenergic receptor-mediated facilitation of norepinephrine release
by epinephrine contributes to the development (rather than the maintenance) of hypertension in this
model during a period of "critical sensitivity."
A number of other approaches have been used to
detect prejunctional facilitation of norepinephrine
release in SHR. These include quantitation of neu-
Floras Epinephrine and Hypertension
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rotransmitter release or neurogenic vasoconstriction
in pithed rats or in isolated vascular beds. In one such
study, acute bilateral adrenal demedullation reduced
pressor responses in pithed SHR, whereas the subsequent infusion of epinephrine (50 ng/min) enhanced pressor responses to nerve stimulation without affecting those induced by norepinephrine. This
potentiation by epinephrine could be abolished by
pretreatment with ICI 118,551 (a ^-selective antagonist) but not by atenolol.87
Several groups have described facilitated norepinephrine release and augmented neurogenic vasoconstriction by /3-adrenergic receptor agonists in the
mesenteric,61-88 renal,36 and portal vascularure89 of
SHR and WKY rats; responses in the mesenteric
vascular bed were potentiated in SHR.6188 Interpretation of responses in isolated vascular beds is complicated by tissue and species variation in prejunctional p- and a-adrenergic receptor distribution,
density, or responsiveness to agonists. At low concentrations (5.5 nM/1), epinephrine potentiates electrically induced norepinephrine overflow from mesenteric sympathetic nerves of SHR and augments the
pressor response to this stimulus in this vascular bed
but has the opposite effect in normotensive WKY
rats.90 Both effects of epinephrine are antagonized by
propranolol. At higher doses (14 nM/1), epinephrine
decreases norepinephrine spillover in both strains,
but this attenuation is muted in SHR and can be
reversed by administration of the prejunctional a2receptor antagonist yohimbine.90
Feldman86 has reviewed evidence for reduced
postjunctional ft-adrenergic receptor sensitivity and
responsiveness in adult SHR. Whether a parallel
reduction in prejunctional ^-adrenergic receptor
responsiveness occurs with age and stage of hypertension is unclear. Prejunctional responsiveness to
the infused ft-receptor agonists salbutamol and procaterol can be demonstrated at concentrations below
those at which their postjunctionally mediated vasodilator effects become apparent.91 That prejunctional
^-responsiveness decreases with age is supported by
two observations. Facilitation by isoproterenol of
electrically stimulated norepinephrine release is
greater in superfused spleen strips of SHR than
WKY rats at 5 weeks of age but is similar in
preparations obtained from 15-week-old animals.92
Second, isoproterenol-induced vasodepressor responses are intact in 6-8-week-old SHR (i.e., in the
developmental stages of hypertension) but are attenuated in 16-week-old SHR.93
Epinephrine would therefore appear to play an
important role at a critical stage of enhanced &adrenergic receptor responsiveness in the initiation
and development (but not in the maintenance) of
spontaneous hypertension in rats.
Plasma Catecholamine Concentrations in
Primary Hypertension
Investigation of the contribution of the sympathetic nervous system to the initiation and mainte-
nance of primary hypertension has focused principally on indirect measures of sympathetic traffic such
as venous plasma norepinephrine concentrations.
This is despite recognized limitations of this approach.94-96 Although few clear-cut differences between normotensive subjects and patients with high
blood pressure have emerged from these studies,97
virtually all group comparisons in subjects 40 years or
younger have demonstrated increased venous plasma
norepinephrine concentrations in those with primary
hypertension.98"100 Organ-specific evaluation of sympathetic activity by the radiotracer kinetic technique
has also documented increased total and regional
(cardiac, renal) norepinephrine spillover into plasma
in young hypertensive subjects.101 More recently,
microneurographic studies have demonstrated increased sympathetic traffic to muscle in young subjects with borderline hypertension.102-104 These observations suggest an important sympathoneural
contribution to the initiation of hypertension in many
of these young subjects.
What is the evidence that epinephrine release,
either intermittent or sustained, is increased in
younger subjects during the developmental stages of
hypertension or that increased plasma norepinephrine concentrations and the augmented norepinephrine spillover in these subjects are a consequence of
facilitated neurotransmitter release by epinephrine?
In normotensive subjects, plasma epinephrine concentrations remain stable or decrease with age,
whereas norepinephrine concentrations tend to
rise 98-io5 The positive correlation between age and
norepinephrine is absent in hypertensive subjects.106
If epinephrine release were relatively enhanced in
young individuals genetically predisposed to hypertension, its central and peripheral actions could
explain several of these age-related observations. A
central action34 could augment efferent sympathetic
outflow,102-104-107 its facilitative effects at the adrenergic terminal could augment norepinephrine spillover, and its action on adrenal ft-receptors could
autofacilitate its own release.28-35
Elevated venous plasma epinephrine concentrations have been documented in borderline hypertension,36-100-108 in hypertensive subjects with rapid resting heart rates,98 and in many subjects with wellestablished essential hypertension, at rest, in
response to mental stress, and during activities such
as submaximal exercise and the cold pressor
test.7-98-108-112 Although these increases in resting
venous plasma epinephrine concentrations are modest, with average values of 13 pg/ml or about 30%
above those recorded in normotensive subjects, they
are reported in most studies.98
Kjeldsen and his colleagues112 have detected elevated arterial as well as venous plasma epinephrine
and norepinephrine concentrations in middle-aged
men with long-standing untreated essential hypertension. Arterial plasma epinephrine concentrations
were increased by 73 pg/ml or 80% above those in
age-matched normotensive subjects and were signif-
Hypertension
Vol 19, No 1 January 1992
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icantly greater than venous concentrations in both
groups, indicating uptake of epinephrine by forearm
tissue. The arteriovenous difference for epinephrine
was greater, in absolute terms, in the hypertensive
subjects. Of particular interest, in the context of the
epinephrine hypothesis, was the observation that
venous norepinephrine concentrations were slightly
below arterial levels in the normotensive subjects,
whereas they were 10% above arterial concentrations
in the hypertensive group. Since forearm extraction
of epinephrine and norepinephrine is similar,113
these findings are consistent with both increased
adrenal epinephrine release and augmented norepinephrine release from this specific vascular bed in
these hypertensive subjects, but they do not demonstrate a causal relation between the two observations.
One problem with the epinephrine hypothesis is
that not all studies (only three of 15 reviewed by
Goldstein and Lake to 198298) show distinct increases
in both catecholamines in hypertension. Subjects
were not always subgrouped according to age in these
reports. A second difficulty is that plasma epinephrine concentrations in borderline hypertensive subjects have not been shown to predict the subsequent
development of sustained hypertension.114 Unfortunately, most investigators have studied venous not
arterial epinephrine concentrations, and because venous measurements often differ substantially from
arterial epinephrine concentrations, particularly during stimuli such as mental stress or orthostasis, they
will underestimate adrenomedullary epinephrine release.796112-115 It is therefore difficult to mount a
strong challenge to the epinephrine hypothesis based
on apparently negative observations derived from
venous sampling.96
To obtain an integrated measure of catecholamine
output over time, Brown and his colleagues116 obtained sequential 24-hour urine collections for epinephrine and norepinephrine from 268 placebotreated patients (mean age 51 years) enrolled in the
Medical Research Council Trial for Hypertension
and compared these values with those of similar
collections from age- and sex-matched normotensive
controls. 116 Urine catecholamines were not increased, but since few of the hypertensive subjects
were aged less than 40 years, these data provide little
insight into epinephrine's potential contribution to
the initiation or development of high blood pressure.
y3-blockade.5117-120 Although increased forearm vascular, natriuretic, and platelet responses to low-dose
epinephrine infusion have been documented in one
group of 40-year-old hypertensive men,121 the majority of studies of older subjects and those with established hypertension have demonstrated decreased
postjunctional /3-adrenergic responsiveness to infused agonists.38-86-111-122.123
Since most investigators have documented increased lymphocyte ft-receptor density in hypertension,124"127 reported reductions in postjunctional ftreceptor responsiveness in these subjects could
represent a progressive defect in ft-adrenergic signal
transduction as hypertension becomes established.123
Indeed, Feldman et al128 described similar preceptor
densities in a relatively small number of normotensive and borderline hypertensive subjects, but lymphocyte ^-receptor-stimulated adenylate cyclase activity was reduced, indicating a functional uncoupling
of the lymphocyte ^-adrenergic receptor from the
adenylate cyclase complex in borderline hypertensive
subjects. More recently, Feldman129 has documented
a reduction in isoproterenol-mediated venodilation
in young subjects (less than age 35 years) with
borderline-to-mild hypertension. Both defects could
be reversed by sodium restriction.128-129
A difficulty in interpreting such comparisons of
normotensive and hypertensive subjects is that lymphocyte /3-receptor numbers and /3-adrenergic-stimulated adenylate cyclase activity are, themselves, subject to modification by exogenous or endogenous
epinephrine.130131 A transient doubling of /3-receptor
binding sites in mononuclear cells and a greater heart
rate response to a pulse of isoproterenol can be
induced by a prior 30-60-minute infusion of epinephrine or isoproterenol.130 A single session of exhaustive
exercise has similar effects.132 Thus, as well as facilitating noradrenergk transmission, a transient rise in
epinephrine might also amplify acutely /3-adrenergic
receptor-mediated chronotropic responses through
such a postjunctional mechanism.
Although some of these observations could be
considered consistent with the concept of a period of
increased sensitivity to epinephrine during the developmental stages of hypertension, the assumption that
prejunctional and postjunctional ft-adrenergic receptor number and responsiveness are altered in
parallel in primary hypertension is, as yet, unproven.
ft-Adrenergic Receptors in Primary Hypertension
Whether the facilitative effect on norepinephrine
release of normal or increased circulating epinephrine is potentiated early in the development of primary hypertension should depend on the responsiveness of prejunctional ft-adrenergic receptors to this
agonist at this time. Many young patients with borderline or mild established hypertension have characteristics consistent with increased postjunctional
02-adrenergic receptor responsiveness, such as increased heart rate, cardiac output, or forearm blood
flow. Often these patterns can be "normalized" by
Prejunctional Modulation of Norepinephrine
Release by Epinephrine in Humans
Direct Effects of Epinephrine on
Norepinephrine Release
Musgrave et al133 detected increases in both
arterial and venous norepinephrine concentrations
in response to 10 ng/kg/min epinephrine. A venousarterial norepinephrine gradient was present at rest
in their hypertensive but not their normotensive
subjects, and this gradient increased during the
infusion. Nezu et al100 documented higher venous
Floras
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norepinephrine concentrations during an epinephrine infusion of 1.25-1.50 jig/min (about 20 ng/kg/
min) and prevented this epinephrine-stimulated
increase in plasma norepinephrine concentration by
/3-adrenergic receptor blockade. Despite these
promising observations, on the whole systemic infusions of /3-receptor agonists such as epinephrine,
isoproterenol, and salbutamol have not had consistent effects on plasma norepinephrine concentrations, 3666100133 - 137 and whenever increases in norepinephrine concentrations have been observed,
these have been similar in magnitude in normal and
hypertensive subjects.100135
This lack of consensus reflects two major difficulties
with this experimental approach. First, when epinephrine is infused systemically in doses even as low as 0.05
nmol/kg/min (8.5 ng/kg/min) (i.e., to replicate plasma
concentrations documented during mental stress or
physical exercise138), plasma cyclic AMP concentrations (a marker for stimulation of ft-adrenergic receptor) rise by 50%,6 but heart rate, stroke volume, and
pulse pressure also increase.36 These hemodynamic
perturbations will alter sympathetic outflow reflexiveh/139 and also modify the release and/or clearance of
norepinephrine independently of any prejunctional
influence on noradrenergic transmission.3101 Second,
high plasma or local concentrations of epinephrine
could inhibit norepinephrine release by stimulating
prejunctional a2-a(irenergic receptors.20'39-53-66 Those
studies that have demonstrated increased norepinephrine concentrations have infused epinephrine at doses
of 30 ng/kg/min or less, whereas Brown et al66 did not
detect any increase in plasma norepinephrine concentrations in normal subjects during epinephrine infusions of 50 ng/kg/min unless idazoxan, an a2-blocker,
was administered concurrently.
An alternative experimental strategy has been to
determine whether endogenous or exogenous epinephrine alters the noradrenergic response to stimuli
that increase central sympathetic outflow. De Champlain108 documented augmented noradrenergic responses to standing in hypertensive subjects with high
plasma epinephrine concentrations. In another study
by Vincent and his colleagues,140 increases in plasma
norepinephrine during a cold pressor test and isometric exercise were augmented during systemic infusion of 30 ng/kg/min (or 0.16 pmol/kg/min) epinephrine (Figure 3). This effect of epinephrine
appeared to be mediated via a /3-adrenergic mechanism because it could be blocked if propranolol was
coadministered. On the other hand, Lenders et al141
have recently shown that the pressor and noradrenergic responses to mental arithmetic, head-up tilt,
and the cold pressor test are not attenuated in
adrenalectomized women treated with 9-a-fluorocortisol and glucocorticoids. Since these are more
potent stimuli to neural norepinephrine than to
adrenal epinephrine release, this apparent challenge
to the epinephrine hypothesis may simply reflect the
failure of such stimuli to raise plasma, myocardial, or
vascular epinephrine concentrations in adrenalry in-
Epinephrine and Hypertension
NORAORENALINE
pg/nl
SCO _
txfort
aftir
COLD PRESSOR TEST
bvfora
afttr
ISOMETRIC EXERCISE
FIGURE 3. Line plots show plasma norepinephrine concentrations before and after cold pressor and isometric exercise
test, during systemic infusion of saline (o) or epinephrine (30
ng/kg/min) ( • ) . Blood pressure responses to these two stimuli
(not shown) were also augmented by epinephrine. *p<0.05;
**p<0.01. Reproduced with permission.140
tact normotensive women above a threshold level
needed to demonstrate facilitated norepinephrine
release.
To quantitate its effects on central sympathetic
outflow, plasma norepinephrine concentrations, and
norepinephrine spillover, Persson et al139 recorded
arterial and central venous pressure, arterial and
femoral venous catecholamines, peroneal muscle
sympathetic nerve activity (microneurography), and
norepinephrine spillover (radiotracer technique)
during the stepwise infusion of epinephrine in doses
selected to replicate its physiological plasma concentration in healthy volunteers (0.05-0.6 nmol/kg/min;
i.e., about 10-100 ng/kg/min). Although limited by
its small sample size and lack of a control study day,
this technically demanding investigation is noteworthy in several respects: even at its lowest infusion rate
epinephrine decreased diastolic blood pressure, and
increased sympathetic traffic to muscle, norepinephrine spillover, and venous norepinephrine concentration from pre-epinephrine values was larger than the
fractional increase in total muscle sympathetic nerve
activity (Figure 4). The authors' interpretation of
these observations was that epinephrine, at physiological concentrations, could augment norepinephrine spillover by two distinct mechanisms: increased
central sympathetic nerve outflow and facilitated
norepinephrine release.
8
Hypertension
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20
30
40
50
60
Time (min)
FIGURE 4. Line plot shows ratio between the mean fractional increases in venous plasma norepinephrine concentrations (pNA%) and the mean fractional increase in total
muscle sympathetic nerve activity (MSA%) during and after
stepwise infusion of epinephrine from 0.05 to 0.6 nmol/kg/min.
Reproduced with permission.139
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Sustained Aftereffects of Epinephrine on
Norepinephrine Release
That endogenous epinephrine, transported into
sympathetic varicosities, could subsequently increase
the simultaneous neural discharge of norepinephrine
in humans was demonstrated by Nezu et al,100 who
increased endogenous epinephrine concentrations by
injecting 1.0 mg glucagon. After an initial brisk peak,
epinephrine concentrations subsided to basal levels
within 20 minutes, whereas norepinephrine concentrations remained elevated. This pattern differs from
the parallel time course of glucagon-stimulated norepinephrine and epinephrine release from the isolated adrenal gland.142 Propranolol did not influence
the immediate surge in both catecholamines but
abolished the subsequent sustained elevation of norepinephrine. Noradrenergic responses to glucagon
and epinephrine were similar in normotensive and
hypertensive subjects.100
Persson et al139 documented greater increases in
muscle sympathetic nerve activity and norepinephrine spillover after, not during, the epinephrine infusion described earlier, but the fractional increase in
venous norepinephrine at this particular time was
less than the fractional increase in muscle sympathetic nerve activity (Figure 4). Thus, there was no
evidence for any additional prejunctional influence of
neuronally released epinephrine on norepinephrine
spillover. Rather, changes in norepinephrine spillover, at this time, appeared to be a reflex response to
an abrupt drop in central venous pressure when
epinephrine was stopped. Both Brown et al66 and
Musgrave et al133 have commented on a dissociation
between plasma norepinephrine (increased) and epinephrine concentration (basal) after systemic infusion of epinephrine. Because central hemodynamics
were not measured in these studies, these observations may also be explained simply by a fall in central
venous pressure and do not prove sustained facilitated norepinephrine release by epinephrine.
Functional Consequences of Facilitated
Norepinephrine Release by Epinephrine in Humans
Because of difficulties in interpreting noradrenergic responses to epinephrine infusions, more recent
efforts have focused on the functional cardiovascular
consequences of increases in plasma epinephrine
concentrations. The general purpose of these experiments was to determine whether hemodynamic responses (e.g., changes in blood pressure, heart rate,
and forearm vascular resistance) to stimuli that increase central sympathetic outflow could be augmented during or after an infusion of epinephrine.
Direct Effects of Epinephrine
For example, systemic infusion of epinephrine (30
ng/kg/min) has been reported to amplify increases in
both blood pressure and plasma norepinephrine during a cold pressor test and isometric exercise, suggesting that the augmented pressor responses to
these stimuli are due to facilitated norepinephrine
release (Figure 3). These effects of epinephrine
could be blocked by propranolol.140 On the other
hand, epinephrine did not affect heart rate, possibly
reflecting the contribution of parasympathetic withdrawal, as opposed to sympathetic activation, to the
chronotropic responses to these particular activities.
Our strategy has been to evaluate in humans the
functional significance of the reported facilitated release of norepinephrine by epinephrine as it relates to
neurogenic vasoconstriction.33 In our first study, in
normotensive men, we examined the effect of intraarterial epinephrine and isoproterenol on ipsilateral
forearm vascular responses to vasoconstriction evoked
by applying lower body negative pressure (LBNP), a
reflex stimulus to norepinephrine release. Forearm
blood flow was measured by strain gauge plethysmography, and blood pressure was recorded directly from
the brachial artery. Forearm vasoconstrictor responses
to LBNP at —40 mm Hg were compared with responses
to intra-arterial infusion of the neurotransmitter norepinephrine before, during, and 30 minutes after infusion of epinephrine (50 ng/min) or isoproterenol (10 or
25 ng/min) into the brachial artery. We reasoned that if
stimulation of prejunctional /3-adrenergic receptors by
epinephrine or isoproterenol was functionally important, these agonists should potentiate the vasoconstrictor response, mediated via the neural release of norepinephrine, to LBNP but should not augment the
forearm vascular response to norepinephrine infusion,
which would be mediated via stimulation of postjunctional a-adrenergic receptors. The ratio of vasoconstrictor responses to LBNP/norepinephrine could
therefore be used as an index of the neural release of
the neurotransmitter norepinephrine.
The forearm vasoconstrictor response to LBNP
was preserved during intra-arterial infusions of
epinephrine and isoproterenol, whereas the response to infused norepinephrine was significantly
attenuated (Figure 5). Consequently, the ratio of
vasoconstrictor responses to LBNP/norepinephrine
Floras Epinephrine and Hypertension
EXPERIMENTAL ARM
CONTROL ARM
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LBNP
Baseline
FVR (R.U )
LBNP
n
NE
Period 1
(Pre EPl)
Period 2
(During EPD
Period 3
(Posl EPl)
Period 1 Period 2 Peflod 3
18-1+2.8
12-2+2-1*
23-2 + 3.6 *
23.8 + 3 . 9 22.9 + 3.4 26 ? + 5 7
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FIGURE 5. Bar graphs show baseline forearm vascular resistance (FVR) measured in resistance units (R U.) and forearm
vasoconstrictor responses to —40 mm Hg lower body negative
pressure (LBNP) and to 18 ng/min intra-arterial norepinephrine (NE) before (control Period 1), during (Period 2), and 30
minutes after (Period 3) the intra-arterial infusion of 50
ng/min epinephrine (EPl) into the experimental arm (left
panel). Responses to LBNP only are in the contralateral arm
(right panel). (*p<0.05 compared with Period 1.) In the
experimental arm, the ratio of repsonses to LBNP/NE was
significantly increased in Periods 2 and 3, as compared with
Period 1 (see Figure 8). Responses to LBNP in the contralateral arm did not differ during the three periods and indicate a
reproducible effect of LBNP on the absence of intra-arterial
EPl (from Reference 33).
increased threefold during the infusion of epinephrine and more than 20-fold during isoproterenol33
(Figure 6). These observations provide indirect
evidence that /S-adrenergic receptor agonists can
facilitate the release of norepinephrine from the
adrenergic terminal in humans.
Two distinctive features of this study, relative to
previous investigations in humans, deserve emphasis.
These apply to the interpretation of vasoconstrictor
responses during as well as 30 minutes after these
infusions (see below). First, to localize their influence
to peripheral neuroeffector sites and avoid potential
effects on central and ganglionic sites or sensory
afferents,107-139 we infused these catecholamines into
the brachial artery at doses that restricted theneffects to the experimental arm. Measurement of
central venous pressure, systemic blood pressure,
heart rate, and forearm blood flow in the contralateral arm confirmed these agonists had no detectable
systemic effects.
Second, we measured forearm blood flow simultaneously in the experimental and the contralateral
arm to confirm that LBNP caused a stable reproducible neurogenic vasoconstriction over the course of
these experiments in the absence of local interventions (Figure 5). Differences between responses observed before, during, and after epinephrine or isoproterenol in the experimental arm could thus be
ascribed to the local effects of these intra-arterial
agonists rather than to systemic or "time" effects.
In subsequent experiments, we set out first to
determine if these local effects of epinephrine could
be replicated by systemic infusion to achieve plasma
Pit
EPI
During
m
•
:
n
PT.
m
Outtg
EH
n
»•
rot En
FIGURE 6. Bar graphs show ratio of vasoconstrictor responses to —40 mm Hg of lower body negative pressure
(LBNP)/18 ng/min of intra-arterial norepinephrine (NE) before, during, and 30 minutes after the intra-arterial infusion of
50 ng/min epinephrine (EPl) into the experimental arm of
normotensive (left panel) and borderline hypertensive (right
panel) subjects. Ratio of forearm vasoconstrictor responses to
LBNP/NE in the experimental arm was used as an index of the
neural release of the neurotransmitter norepinephrine. This
ratio increased during epinephrine infusion in both normotensive (+340%; p<0.01 compared with Period 1) and borderline hypertensive (+512%) subjects (NS). Thirty minutes after
epinephrine infusion, this ratio was again increased in both
normotensive (+353%; p<0.05 compared with Period 1) and
borderline hypertensive (+262%; p<0.05 compared with Period 1) subjects compared with Period 1. These observations
indicate facilitated release of norepinephrine in response to
LBNP both during and after epinephrine. However, these
effects of epinephrine are not exaggerated in borderline hypertension (from References 33, 145). FVR, forearm vascular
resistance.
levels achieved during physiological stress and second to determine whether heart rate responses to
LBNP at -40 mm Hg are also augmented during
epinephrine.143 Infusion of 1.5 ^ig/min epinephrine
(about 20 ng/kg/min) led to forearm vasodilation and
a subtle but significant increase in heart rate. Since
the forearm vasoconstrictor response to intra-arterial
norepinephrine is proportional to the initial forearm
vascular resistance,144 we anticipated that by causing
forearm vasodilation, epinephrine would also attenuate the vasoconstrictor response to LBNP unless
countered by increased norepinephrine release during this stimulus. The vasoconstrictor response to
LBNP was not attenuated but rather augmented by
about 50% during the epinephrine infusion. The
heart rate response to LBNP was not altered by
epinephrine. We attributed this observation to the
strong influence of vagal withdrawal on heart rate
responses to this stimulus in healthy young men, but
these contrasting effects of epinephrine on heart rate
and vascular responses to LBNP might also be explained by differences in the ratio of responsiveness
to epinephrine of facilitative ^-inhibitory/ajprejunctional adrenergic receptors in vascular as
opposed to cardiac sympathetic nerves.
Direct Effects of Epinephrine in Primary Hypertension
There is no clear consensus on this point. Kjeldsen
et al,121 who compared responses to epinephrine
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FIGURE 7. Line plot shows mean hourfy values of percent
change in the intra-arterial mean arterial pressure as compared with baseline during and after 6-hour infusion of
epinephrine (15 nglkglmin) or norepinephrine (30 ng/kg/min).
Values corrected for percent change from baseline during and
after 5% dextrose. *p<0.01; tp<0.001. Reproduced with
permission,I47
infusion (from 10 to 40 ng/kg/min) in age-matched
(40 years old) normotensive and hypertensive subjects, documented a fall in blood pressure, forearm
vasodilation, and increased natriuresis and kaliuresis
in the latter group; they therefore postulated a
hyperresponsiveness to low-dose epinephrine infusion in mild essential hypertension. On the other
hand, the effects, in our protocol, of intra-arterial
epinephrine on neurogenic vasoconstriction and by
inference neurotransmitter release appeared to be
similar in age-matched normotensive and young borderline hypertensive subjects145 (Figure 6).
Sustained Aftereffects of Epinephrine
Several groups have observed sustained increases,
often lasting several hours, in blood pressure after
epinephrine infusion into normotensive subjects.100-14*-148 The dose and duration of epinephrine
given in these studies ranged from 20 to 40 ng/kg/
min for 30-60 minutes100146148 to 15 ng/kg/min
sustained for 6 hours.147 In the latter study, 24-hour
intra-arterial ambulatory blood pressure was used to
document, in normal subjects, the effect of 6-hour
infusions of epinephrine, norepinephrine (30 ng/kg/
min), and dextrose administered in a random crossover design. During its infusion, epinephrine caused
a 10-fold increase in its plasma concentration and
lowered mean arterial pressure. Epinephrine concentrations returned to baseline levels less than 5 minutes after the infusion stopped. The subsequent
18-hour recording documented persistent elevation
of mean arterial pressure by as much as 12% above
those levels recorded on the day dextrose was infused
(Figure 7). The pressor effects of prior epinephrine
infusion were particularly evident during episodes of
documented sympathetic activation.
Between 40% and 70% of arterial epinephrine is
removed in one circulation through the forearm
(more than half via uptake-1149),112-113149-151 and
approximately 45% of arterial epinephrine is extracted in a single passage through the heart and
kidney.70105 Therefore, it seems reasonable to assume that both cardiac and vascular mechanisms
could contribute to any sustained pressor response
subsequent to epinephrine.147 Brown et al31-134 documented persistent tachycardia after a 2-hour infusion of epinephrine of 100 ng/kg/min was stopped,
even though its plasma concentration returned to
basal levels within minutes.20-71 Sustained tachycardia was not observed in a small number of subjects
pretreated with desmethylimipramine to reduce neuronal uptake of epinephrine31 or when isoproterenol,
which is not taken up by sympathetic nerves,23134 was
substituted for epinephrine. Brown et al31-134 proposed that the dissociation between the short plasma
half-life of epinephrine and the slow decay of the
tachycardia after its infusion was due to a cyclical
process of reuptake and release of epinephrine from
cardiac nerves. However, there are problems with
this interpretation. Resting tachycardia is not seen
after epinephrine infusions of 50 ng/kg/min or
less.100-147-148-152 Other potential causes of this sustained tachycardia, such as metabolic,153 hemodynamic, reflex, or central effects of infused epinephrine were not excluded, and the potential effect of
prior epinephrine infusion on postjunctional responses to the neurotransmitter norepinephrine was
not examined in these studies.
Earlier, we presented our experimental approach
to the evaluation in humans of the functional significance of the reported facilitated release of norepinephrine by epinephrine.33 In these experiments, we
also explored the possibility that neuronally extracted
epinephrine might have a sustained aftereffect on the
forearm vasoconstrictor response to neurogenic stimulation. Our hypothesis was that if epinephrine were
incorporated into the sympathetic nerve endings of
the forearm during its arterial infusion and later
released as a cotransmitter with norepinephrine, we
might find a selective augmentation of reflex vasoconstriction after an epinephrine infusion. Further,
we hypothesized that such augmentation would not
be detected after an isoproterenol infusion.
Thirty minutes after these infusions, resting forearm vascular resistance was at its initial, preinfusion
level. From similar baselines, the forearm vasoconstrictor response to LBNP increased by about 65% 30
minutes after epinephrine, but this response was not
affected by prior infusion of isoproterenol (Figure 5).
The ratio of forearm vasoconstrictor responses to
LBNP/norepinephrine was not altered by prior infusion of isoproterenol but was more than threefold
higher 30 minutes after epinephrine33 (Figure 6).
These observations provide further support for the
concept that epinephrine augments neurogenic vasoconstriction by a peripheral neuroeffector action.
Since epinephrine has a half-life in plasma of only a
Floras
Epinephrine and Hypertension
11
ISO
IX
140
t
120
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no
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6
130
130
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100
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»
GO
so
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-10
0
10 JO 30 «
SO M
70 «
JO
-10
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10 20 30 40 SO GO 70 10 90
FIGURE 8. Line graphs show blood pressure (BP) (mm Hg) and pulse rate (bpm) responses to the intravenous infusion of
epinephrine (1.25-1.50 figlmin) in normotensive subjects (left panel) and in hypertensive subjects (right panel) before (•) or after
(o) ^-blockade with propranolol. Each circle and vertical line represents mean±SEM. 'Statistically significant when compared
with baseline values. Adapted with permission of the American Heart Association.'00
few minutes,20-71 we attributed the augmented ratio
of responses to LBNP/norepinephrine 30 minutes
after epinephrine (but not isoproterenol) to facilitated release of norepinephrine by epinephrine that
had been taken up into the adrenergic terminal,
converted into a cotransmitter, and coreleased with
norepinephrine during subsequent reflex stimulation.
To test this hypothesis, eight normal men were
studied on 2 separate days at least 1 week apart, 2.5
hours after taking at random either placebo or a dose
of desipramine (125 mg p.o.), shown to block completely neuronal uptake of norepinephrine in the
forearm.154155 On the placebo day, the forearm vasoconstrictor response to LBNP -40 mm Hg was
significantly augmented by about 40% 30 minutes
after an hour of systemic infusion of epinephrine at
1.5 ^tg/min (about 20 ng/kg/min) but tended to be
less after epinephrine and desipramine.148 Resting
mean arterial pressure and the heart rate response to
LBNP after epinephrine administration were also
greater on the placebo day.148 Thus, systemic as well
as local infusion of epinephrine in a dose known to
achieve plasma concentrations documented during
physiological stresses 6 ' 100152136 and to increase
plasma norepinephrine concentrations by a /3-adrenergic mechanism100-140 can have sustained aftereffects
on blood pressure and on specific chronotropic and
vascular responses to reflex sympathetic activation.
Fellows et aJ152 reported similar heart rate and
forearm vascular responses to LBNP (-50 mmHg)
applied 15 minutes after a 30-minute infusion of
epinephrine (50 ng/kg/min). Since resting heart rates
were not increased after epinephrine, doses admin-
istered in these two studies148-152 may not have been
sufficient to maintain synaptic concentrations of epinephrine at levels necessary to facilitate norepinephrine release at rest; yet the doses caused sufficient
loading of the adrenergic terminal to achieve such
concentrations locally during the reflex stimulus to
norepinephrine release.
Sustained Aftereffects of Epinephrine in
Primary Hypertension
Whether the aftereffects of epinephrine infusion
differ in normal and hypertensive subjects has not
been firmly established. Although Nezu et al100 documented similar increases in systolic and diastolic
blood pressure in normotensive and hypertensive
subjects up to 90 minutes after an epinephrine infusion (20 ng/kg/min) (Figure 8), persistent elevation
of blood pressure and heart rate 20 minutes after
epinephrine (39 ng/kg/min) was seen in another
study146 only in a hypertensive group even though
arterial epinephrine concentrations had returned to
basal levels by this time. Epinephrine clearance was
identical in the two groups of subjects.146
Because elevated plasma epinephrine concentrations and characteristics consistent with increased
/3-adrenergjc receptor responsiveness are often seen
in borderline hypertension,5-108-119-120-157 we hypothesized that the local direct and sustained aftereffects
of epinephrine on neurogenic vasoconstriction would
be exaggerated in such subjects. However, when
tested, this was not the case: the effect of prior
intra-arterial epinephrine infusion on the ratio of
forearm vasoconstrictor responses to the LBNP/nor-
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Vol 19, No 1 January 1992
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epinephrine was similar in normotensive and borderline hypertensive subjects33-145 (Figure 6).
We considered several possible explanations for
this observation. Responses to epinephrine might
only be enhanced in a subgroup of borderline hypertensive patients with increased arterial epinephrine
concentrations and/or "hyperadrenergic" characteristics. The latter were not prominent in our subjects.145 Responses to epinephrine might have been
similar because of substantial overlap in prejunctional £-adrenergic receptor density, affinity for agonist, or /3-adrenergic-mediated adenylate cyclase activity in our two groups122-124-126 or because of the
functional uncoupling of the lymphocyte ft-adrenergic receptor from the adenylate cyclase complex
reported to occur in young subjects with borderline
hypertension.128129 Such functional uncoupling may
have minimized any quantitative differences in /3-adrenergic receptor number or affinity for agonist in
our young normotensive and hypertensive subjects.129
Indeed, a specific comparison of the effects of infused isoproterenol on plasma norepinephrine concentrations did not detect any difference in this
response between normotensive and borderline
hypertensive male subjects.135 Last, exaggerated responses in patients with borderline hypertension may
reflect increased central neural (presynaptic)34 or
peripheral ganglionic78107 rather than peripheral
neuroeffector (prejunctional) sensitivity to epinephrine. Evidence in support of this latter possibility was
provided by the comparison, in young normotensive
and borderline hypertensive men, of the effects of
prior administration of epinephrine (1.5 /xg/min for
30 minutes) on muscle sympathetic nerve responses
to LBNP at - 1 0 mm Hg and to a cold pressor test.107
Interventions were applied before and 30 minutes
after epinephrine. The immediate direct effects of
epinephrine on systolic and pulse pressure, heart
rate, and postganglionic muscle sympathetic nerve
activity were similar in the two groups, but the
aftereffects of the infusion were only seen in the
borderline hypertensive subjects: pressor and chronotropic responses to the cold pressor test were
augmented, and the sympathoneural responses to
both interventions more than doubled (Figure 9).
Potential Contribution of Epinephrine to the
Genesis of Hypertension: Summary, Implications,
and Future Directions
Several lines of evidence now suggest a psychophysiological link between stress, adrenomedullary
activation, and the genesis of hypertension in some
humans genetically predisposed to the development
of high blood pressure. These include results of
experiments in a number of animal preparations that
support the facilitative and cotransmitter components of the epinephrine hypothesis, are consistent
with the concept of a period of critical sensitivity to
epinephrine in a genetic model of hypertension (the
SHR), or demonstrate that exogenous epinephrine
can induce sustained hypertension.
LOWER BODY NEGATIVE PRESSURE
MO W H O )
COLD PRESSOR TEST
s
i—p < att—i
I
ao
at
via
—
0
i n
FIGURE 9. Bar graph shows effects of prior infusion of
epinephrine (EPI) (1.5 ug/min) on increases in muscle sympathetic nerve activity (MSNA), expressed as units per minute,
in seven borderline hypertensive subjects. In contrast to normotensive controls, sympathetic outflow was augmented
(p<0.01) after systemic EPI. Adapted from Reference 107.
Evidence in support of the hypothesis that epinephrine participates in the initiation of primary
hypertension by amplifying peripheral neurotransmission may be summarized as:
1) Resting and stimulated arterial and venous
plasma epinephrine concentrations are elevated in
many young subjects with borderline or mild essential
hypertension.7'98-100'108-112'157 Mental stress is one such
provocative stimulus. Increased plasma norepinephrine
concentrations and regional norepinephrine spillover
have also been documented in many young borderline
or mildly hypertensive patients.98"101 Because the results of some investigations differ from these general
conclusions,98-114'158 it should be emphasized that this
hypothesis is not contingent on documentation of increased plasma epinephrine concentrations alone. The
magnitude of neuronal epinephrine uptake as a reflection of the frequency and intensity of adrenomedullary
epinephrine release may be more important than basal
epinephrine concentrations.
2) Increases in endogenous epinephrine cause sustained increases in plasma norepinephrine and blood
pressure in normotensive and hypertensive subjects.
These effects can be abolished by propranolol.100
3) Endogenous epinephrine is taken up into human peripheral sympathetic nerves.70'112-113-149-151 Increased forearm uptake of epinephrine in hypertension may be associated with greater forearm
norepinephrine release.112
4) Exogenous epinephrine, infused at a rate of 30
ng/kg/min or less, has functionally significant
immediate (direct) effects and subsequent (indirect) aftereffects on norepinephrine concentrations6-66-100-133136-139'140 that are similar in magnitude
to its effects on norepinephrine release as documented in experimental preparations.42 Direct effects have been observed at rest and during provocative maneuvers that increase efferent sympathetic
traffic such as isometric exercise or the cold pressor
test. These effects are also blocked by propranolol.140 Increases in norepinephrine concentrations
persist after plasma epinephrine concentrations return to baseline levels.66-100133 These effects are not
Floras Epinephrine and Hypertension
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seen at higher doses of epinephrine unless a2receptors are blocked.66
5) Exogenous epinephrine has functionally significant immediate (direct) effects and subsequent (indirect) aftereffects on neurogenic circulatory regulation that are similar in magnitude to its effect on
neurotransmitter release as documented in experimental preparations.42 Direct effects include greater
blood pressure responses to handgrip and the cold
pressor test140 and a relative augmentation of neurogenic forearm vasoconstriction.33-143 Local infusion of
epinephrine has sustained aftereffects on neurogenic
vasoconstriction in the forearm.33145 Sustained aftereffects of its systemic infusion appear to be dosedependent: at low doses (15-40 ng/kg/min) the
aftereffects include a persistent increase in blood
pressure, augmentation of neurogenic vasoconstriction, and neurogenic tachycardia100143146-148156; at
higher doses (100 ng/kg/min), prior epinephrine
infusion causes persistent tachycardia.31134
6) Aftereffects of epinephrine on sympathetic
outflow are enhanced in borderline hypertensive
subjects.107
These studies have defined two temporally and
functionally distinct roles for epinephrine in the
regulation of vascular resistance. As a circulating
hormone, it causes an immediate and transient vasodilation via its direct action on postjunctional vascular /^-receptors. Its humoral actions are brief, include additional circulatory response analogous to
the defense reaction, and dissipate rapidly. As an
autocrine agent, it causes indirectly a delayed and
sustained vasoconstriction. These aftereffects have
been interpreted as caused by the peripheral conversion of epinephrine from a circulating hormone to a
cotransmitter, which when released neuronally, acts
on prejunctional neuronal /^-receptors. By augmenting the simultaneous discharge of norepinephrine
neurotransmitter release, epinephrine could raise
blood pressure transiently through both cardiac and
vascular mechanisms during periods of increased
sympathetic outflow or at rest after its plasma concentrations subside to basal levels. Through this
mechanism, repetitive surges in endogenous epinephrine could initiate, promote, or permit the development of primary hypertension. In addition, the
trophic effects of intermittently increased neurotransmitter release,159 when continued over months
or years, could initiate early structural changes in
resistance and capacitance vessels that would intensify responses to constrictor signals4160 and allow for
sustained elevations in blood pressure independent
of this neurogenic trigger to hypertension.
This neurogenic mechanism is attractive but as yet
unproven. Evidence challenging the hypothesis that
epinephrine participates in the initiation of primary
hypertension by amplifying peripheral neurotransmission may be summarized as:
1) The conclusion that augmented neurogenic vasoconstriction during and after local epinephrine
infusion is due to increased norepinephrine re-
13
lease33145 is based on indirect evidence. There have
been no published reports of forearm catecholamine
uptake and release in this model, the effect of local
/3-adrenergic receptor blockade on these responses
has not been assessed, and it is not known whether
their kinetics are altered in young hypertensive subjects. Furthermore, indirect actions of epinephrine
that could augment neurogenic vasoconstriction,
such as local induction of endothelin,161 or that could
facilitate norepinephrine release, such as generation
of angiotensin II162"165 or alteration of ionic fluxes
across the adrenergic terminal,134-166-168 have not
been specifically excluded in this preparation.
2) Pressor and noradrenergic response to mental
stress, tilt, and the cold pressor test are not blunted
in adrenalectomized women when compared with
responses in women with intact adrenal function.141
Given the unique opportunity presented by such
patients, it would be of interest to compare the direct
effects and aftereffects of both brief and sustained
epinephrine infusion on responses to these interventions in these two groups.
3) Selective ft-adrenergic receptor blockade has not
proved to be particularly effective in the management
of hypertension.169170 Majewski and Murphy44 have
proposed that this is because the potential antihypertensive effect of such drugs on neurotransmitter release
is offset by concurrent abolition of ft-adrenergic receptor-mediated peripheral vasodilation.
4) Immediate or delayed noradrenergic, pressor,
and neurogenic chronotropic or vascular responses to
epinephrine (and other ^-agonists) are not always
augmented in subjects with borderline or mild essential hypertension.100-135'145
5) There are no prospective evaluations of the
predictive value of increased epinephrine concentrations in childhood or adolescence as a marker for
later hypertension development.
These points highlight a number of present difficulties with the epinephrine hypothesis and suggest a
number of future experiments. Additional questions
would have to be addressed in humans before epinephrine could be considered a causative mechanism
of primary hypertension.
A general series of questions pertains to those
phenomena attributed to the facilitative and cotransmitter effects of exogenous epinephrine themselves.
Can they be replicated by increases in endogenous
epinephrine? How long after surges in epinephrine
does this exaggerated response to neural stimulation
persist? How quickly does it decay?
A second series of questions pertains to other
potential functional consequences of facilitated neurotransmitter release by epinephrine (e.g., effects on
venous tone, renal hemodynamics, and renal tubular
sodium absorption and renin release). Given the
primacy of the kidney in long-term blood pressure
regulation,171 future assessment of the potential contribution of epinephrine to the genesis of primary
hypertension should include a characterization of any
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effects and in particular any sustained aftereffects it
may have on renal hemodynamics and function.
Finally, as suggested by Folkow,2 expression of
hypertension by this mechanism may be restricted to
a specific subset of individuals with a genetic predisposition to high blood pressure, who have more
frequent or exaggerated surges of epinephrine in
response to psychological or physiological stimuli or
greater central or peripheral sensitivity to this catecholamine. Such individuals may manifest sustained
increases in heart rate and cardiac output after
episodic increases in epinephrine and greater neurogenic vasoconstrictor responses to reflex stimuli than
those without this predisposition. A third or more of
primary hypertensive individuals may fall into this
category. However, if a period of "critical prejunctional /^-adrenergic receptor sensitivity" to the facilitative effects of epinephrine on norepinephrine release, similar to that described in SHR,52 precedes
the clinical detection of borderline or mild essential
hypertension or if the prejunctional ft-receptor is
functionally uncoupled from its adenylate cyclase
complex once structural vascular changes have developed,128 the most compelling tests of the epinephrine
hypothesis, whether longitudinal or interventional
(e.g., inhibition of adrenal epinephrine syntheses or
peripheral ft-antagonism), will require identification
of such individuals at the earliest and mildest stage of
their disease, well before the development of clinically established hypertension.
Acknowledgments
I am grateful to Beverley Morris-Senn for her
technical support and to Mary Anne Beddows for
her perseverance through many drafts and revisions
of this review.
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KEYWORDS
hypertension
system
^-adrenergic receptor • epinephrine • essential
norepinephrine • stress • sympathetic nervous
Epinephrine and the genesis of hypertension.
J S Floras
Hypertension. 1992;19:1-18
doi: 10.1161/01.HYP.19.1.1
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