Download Influence of Yohimbine on Blood Pressure, Autonomic Reflexes, and

Influence of Yohimbine on
Blood Pressure, Autonomic Reflexes, and
Plasma Catecholamines in Humans
MICHAEL R. GOLDBERG, M.D.,
P H . D . , ALAN S. HOLLISTER, M.D.,
AND DAVID ROBERTSON,
PH.D.,
M.D.
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SUMMARY We studied the influence of the a2-adrenoreceptor-blocking drug, yohimbine, on blood
pressure, plasma norepinephrine, and other measures of autonomic function in normal male volunteers. These studies were designed to evaluate the role of o2-receptors in the tonic regulation of
sympathetic outflow in humans. In a dose-ranging study, we found that yohimbine HC1 (0.016-0.125
mg/kg) elicited dose-related rises in mean, systolic, and diastolic pressures. At the maximal dose used
(0.125 mg/kg), respective increments in mean, systolic, and diastolic pressures were 14 ± 1 torr; 28 ±
3 torr; and 8 ± 1 torr (p < 0.01) (mean ± SE). NO significant changes in heart rate occurred.
Associated with the rise in blood pressure were enhanced pressor and heart rate responses to the cold
pressor, isometric handgrip, and Valsalva maneuvers. In a double-blind study, yohimbine (0.125 mg/
kg bolus, 0.001 mg/kg/min infusion) induced a two-to-threefold rise in plasma norepinephrine (p <
0.01), without significantly altering plasma epinephrine or plasma renin activity. Ex vivo platelet
aggregation in response to epinephrine was inhibited during yohimbine, showing that non-innervated
a2-adrenoreceptors were inhibited. Central effects of yohimbine were evaluated through use of linear
analog mood rating scales which showed a shift from calm toward excited ends of these scales. If
yohimbine is acting through blockade of a2 receptors, then these receptors tonically suppress sympathetic outflow in humans. (Hypertension 5: 772-778, 1983)
KEY WORDS • a2 adrenoreceptors
• sympathetic outflow
S
* blood pressure regulation
lipolysis.8 The a 2 -receptors located on adrenergic
terminals also inhibit peripheral adrenergic neurotransmission,4"6 although demonstration of this action in
vivo in humans9 and animals 1 0 " has been difficult.
Based on these data, we postulated that a 2 -receptors
tonically inhibit sympathetic outflow in humans and
that the extent of this activity could be estimated
through the study of a 2 -antagonists. Although several
relatively selective a 2 -adrenoreceptor antagonists have
been described,4 6 we chose yohimbine for our studies
because it has been studied in humans, and because its
pharmacology has been extensively investigated.12
Yohimbine (fig. 1) is a plant alkaloid derived from
the bark of the Pausinystalia yohimbe tree and other
sources. It has a long folk history as an aphrodisiac,
and has been given to humans with apparent safety for
over 100 years.12 Yohimbine has high affinity for a2receptors in radioligand-binding studies, and recent
studies in animals have shown yohimbine to be a rela^
tively selective a2-antagonist.12 Thus, yohimbine antagonizes a-adrenergic inhibition of adrenergic transmission and reverses the effects of many centrally
active antihypertensive agents.12 Furthermore, it has
been shown to raise blood pressure and heart rate and
YMPATHETIC outflow can be inhibited in humans and in animals by drugs that stimulate
central alpha adrenergic receptors.1"3 Animal
studies suggest that these actions are mediated by a
subtype of alpha-adrenergic receptors, the a 2 -receptor.4"6 Pharmacologically similar receptors have been
shown to mediate epinephrine-induced platelet aggregation7 and catecholamine-induced inhibition of
From the Division of Clinical Pharmacology, Vanderbilt Medical
School, Nashville, Tennessee.
Supported by Grants 5 MO1-RR00095, GM15431, and HL
14192 from the National Institutes of Health, and a grant from the
Hrafn Sveinbjamarson Foundation. Dr. Robertson was supported
by USPHS Research Career Development Award GMCXM94.
A portion of this work was presented at the annual meeting of the
American Federation for Clinical Research, May 7-10, 1982,
Washington, D.C.
Dr. Goldberg is Clinical Associate Physician, Elliot V. Newman
Clinical Research Center, Nashville, Tennessee.
Dr. Hollister is Burroughs-Wellcome Research Fellow in Clinical Pharmacology.
Address for reprints: David Robertson, M.D., Division of Clinical Pharmacology, Vanderbilt Medical School, Nashville, Tennessee 37232.
Received January 6, 1983; revision accepted March 14, 1983.
772
AUTONOMIC EFFECTS OF YOHIMBINE IN HUMANS/Goldberg el al.
773
Dose-Ranging Study
arithmetic (1 minute), and Valsalva maneuver (40 torr
for 15 seconds). After baseline determinations, cumulatively increasing doses of yohimbine were given intravenously (0.016-0.125 mg/kg yohimbine HC1).
Yohimbine was purchased from Sigma Chemical
Company (F and D Division), St. Louis, Missouri, and
prepared for human use by dissolving in sterile, bacteriostatic saline (0.5 mg/ml) followed by Millipore filter
sterilization (0.22 /A). Yohimbine was prepared freshly
each day. Small doses of yohimbine were given by
rapid intravenous injection, and larger doses were administered over 2 to 5 minutes. Blood pressure was
observed for 10 to 15 minutes after each dose. At that
time, the reflexes were repeated in random order, before administration of the next dose of yohimbine. Ex
vivo platelet aggregation in response to epinephrine
and adenosine diphosphate (ADP) was determined in
three supine volunteers, using a Payton aggregometer
(Payton Associates, Inc., Buffalo, New York) before
yohimbine administration and after two doses of yohimbine.
In single-blinded fashion, three volunteers were given multiple saline injections rather than yohimbine, to
assess the reproducibility of the various reflexes and
platelet aggregation. In these individuals, we noted
that responses to cold pressor, handgrip, and Valsalva
maneuvers were reproducible while the response to
mental arithmetic showed tachyphylaxis and could
not, therefore, be accepted as a reproducible measure
of stimulated sympathetic outflow. Platelet sensitivity
to epinephrine- and ADP-induced aggregation was
stable over time.
In evaluating the cold pressor and isometric handgrip tests, the peak change in mean arterial pressure or
heart rate at the termination of the maneuver was used
as a measure of the reflex response. The Valsalva
maneuver is more complex and not subject to as simplified an interpretation as the other maneuvers. l4 Noting the four phases of the maneuver, we used the
change in mean arterial pressure from baseline to the
peak mean pressure during Phase IV as an index of
reflex sympathetic vasoconstriction. The increase in
heart rate from baseline to peak heart rate during Phase
III was used to measure the reflex tachycardia elicited
by the maneuver.
Volunteers were admitted overnight to the CRC and
kept supine and fasting from midnight through the time
of the study. The morning of the study, an intravenous
line was placed in the forearm for drug administration
and blood sampling. A 20 g 1 Vz inch Teflon catheter
(Quik-Cath) was placed percutaneously in the radial
artery for direct measurement of arterial blood pressure. The electrocardiogram was continuously recorded and used to trigger a rate computer for continuous
readout of heart rate with EKG and blood pressure on a
Hewlett-Packard 4-channel recorder. A 20- to 30-minute accommodation period was allowed before baseline determinations of responses to several pressor reflexes14- " were made, including: cold pressor test
(immersion of hand in icewater for 1 minute), isometric handgrip (30% maximum for 3 minutes), mental
Double-Blind Study
This portion of the study was performed in five
previously dose-ranged volunteers, admitted as outpatients to the CRC on two mornings at least 1 week
apart. On arrival at the CRC, after fasting from the
night before, subjects had an intravenous line placed
for drug administration and a heparin-lock placed in
the opposite arm for blood sampling. Electrocardiogram, heart rate, respirations, and blood pressure
(Dinamap automated sphygmomanometer) were continuously monitored. The subjects were allowed to rest
undisturbed for 60 to 90 minutes. At that time, an
initial blood sample was drawn for measurement of
plasma catecholamines (radioenzymatic method)15-l6
and plasma renin activity. A bolus injection followed
HjCOOC
FIGURE 1. Chemical structure of yohimbine (1la-hydroxyyohimban-16a-carboxylic acid methyl ester).
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induce an anxiety-like state when given to humans in
high doses (0.5 mg/kg i.v.). 12 - l3 We studied the autonomic effects of several doses of yohimbine in humans
and specifically determined its influence on baseline
blood pressure and heart rate and on physiologic and
biochemical indices of sympathetic outflow.
Methods
These studies were performed in 10 normal male
volunteers (aged 21-39 years). All procedures and
consent forms were approved by the Vanderbilt University Committee for the Protection of Human Subjects. Studies were performed in the Elliot V. Newman
Clinical Research Center (CRC). Initially, a doseranging design was employed to determine the doseresponse relationship for yohimbine's effects on both
blood pressure and pressor reflexes. Subsequently, a
double-blind study of yohimbine's effects on plasma
catecholamines, plasma renin, and other autonomic
functions was performed.
HYPERTENSION
774
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by a continuous infusion of test substance was administered (yohimbine: 0.125 mg/kg and 0.001 mg/kg/
min, or equivalent volumes of bacteriostatic saline).
Neither the investigator nor the subject knew the treatment being administered. The subject was maintained
supine for an additional 45 minutes, and blood samples
were drawn for catecholamine and renin determinations 15, 30, and 45 minutes after the bolus injection.
At the end of this 45-minute period, with the infusion
being maintained, the subject stood motionless for an
additional 30 minutes. Blood samples were taken at the
end of 5, 15, and 30 minutes of upright posture. Following the last sample, an estimate was made of each
subject's mood and mental state using linear analog
rating scales.
Statistical analysis of the data was performed using
Student's t test for paired experiments and analysis of
variance with Dunnett's procedure.17 The criterion for
statistical significance wasp < 0.05. Values are means
± SE.
Results
Influence of Yohimbine on Blood Pressure and Heart Rate
Dose-Ranging Study
Cumulative administration of yohimbine (0.0160.125 mg/kg, i.v., total dose = 0.25 mg/kg) to the
normal volunteers resulted in a dose-related increase in
systolic, diastolic, and mean intraarterial blood pressure (fig. 2). The rise in blood pressure following each
dose of yohimbine occurred gradually, beginning
within 5 minutes of drug administration and reaching a
plateau 10 to 15 minutes after each dose. This plateau
of blood pressure persisted through the time of administration of the next yohimbine dose, usually 45 minutes. After termination of the study, blood pressure
returned to baseline within 1 to 2 hours. At the maximal dose used (0.125 mg/kg), the respective increases
in mean, systolic, and diastolic pressures were 14 ± 1
torr, 28 ± 3 torr, and 8 ± 1 torr (p < 0.01). At the
doses studied, yohimbine did not alter heart rate
(fig. 2).
Double-Blind Study
During double-blind administration of yohimbine,
rises in blood pressure were noted, as during the doseranging study. Similarly, heart rate was unaltered by
yohimbine (table 1). The blood pressure and heart rate
VOL 5, No
5, SEPTEMBER-OCTOBER
SBP*
150
130
110
BP
(torr)
90
70
HR
(BPM)
50
0
Ol
Yohimbine (mg/kg iv)
.10
FIGURE 2. Changes in blood pressure (mean ± SE) induced
by yohimbine (0.016 to 0.125 mg/kg i.v.); cumulative dose was
0.25 mg/kg over 3 hours. Statistical analysis was performed on
the changes in pressure and heart rate in each subject following
each dose; the p value indicates a significant change for systolic, diastolic, and mean pressures at each dose (n = 7).
changes in response to 30 minutes of quiet standing
were not significantly altered following administration
of yohimbine (table 1). There was a reduction in respiratory rate from 14.1 ± 0.4 to 12.5 ± 0.6 breaths/min
(p < 0.05), during the first 10 minutes following double-blind administration of yohimbine.
Influence of Yohimbine on Pressor Reflexes
Three different reflexes were studied as reproducible measures of sympathetic responses initiated
through somatic (cold pressor, isometric handgrip),
and baroreceptor (Valsalva's maneuver) input to the
vasomotor centers. As summarized in figure 3, cold
TABLE 1. Hemodynamic Changes During Double-Blind Administration of Yohimbine
Supine
Hemodynamic
15 min
response
45 min
Treatment
0 min
78±4
Mean arterial pressure (torr)
82±5
79±4
Saline
93 ±4*
92 ±5*
83±4
Yohimbine
Standing
5 min
30 min
87±6
84±3
96±5
94±6
60±4
60±5
78±5
83±6
55±5
56±3
69±4
83±6
Treatments were yohimbine (0.125 mg/kg bolus and 0.001 mg/kg/min infusion) or equivalent volume of bacteriostatic
saline.
*p < 0.01, saline vs yohimbine, indicating statistical significance.
Heart rate (bpm)
Saline
Yohimbine
1983
58±5
55±4
775
AUTONOMIC EFFECTS OF YOHIMBINE IN HUMANS/Goldberg et al.
O-O
•-•
40
Control
Yotilmoirx
* Hondgrlp (6)
Voltolva (7)
30
* Cold Pr«s»0f(7)
A
NE
(pg/ml)
(torr)
2000
1800
1600
1400
|200
1000
800
10
600
400
200
• p<0.05
o '
feoi
Supine,
10
aio
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YOHIMBINE DOSE (mg/kgiv)
FIGURE 3. Influence of yohimbine on mean arterial pressure
< ± SE) and mean peak pressor responses to sympathetic reflexes. Reflexes were elicited and interpreted as described in
methods; numbers in parentheses indicate the number of subjects in which the reflex was studied.
pressor, handgrip, and Valsalva maneuver pressor responses were enhanced in a dose-related fashion following yohimbine. The heart rate response to these
reflexes was also increased following yohimbine (fig.
4). Responses to mental arithmetic showed tachyphylaxis after yohimbine, as after placebo.
Influence of Yohimbine on Plasma Catechotamines and
Renin
During the double-blind study, yohimbine (0.125
mg/kg bolus; 0.001 mg/kg/min infusion) elicited a
two- to threefold increase in plasma norepinephrine
(fig. 5, p < 0.01), without significantly altering plasma epinephrine. During upright posture, differences in
plasma catecholamines were not observed when com-
20
30
40
TIME
Upright,
10
(mln)
20
30
FIGURE 5. Influence of yohimbine (0.125 mglkg bolus, 0.001
mglkglmin) and saline infusions on supine and upright plasma
norepinephrine (X ± SE). Yohimbine or saline were administered in double-blind fashion immediately following the 0-time
sample.
paring control to yohimbine, although the expected
postural rise in norepinephrine and epinephrine occurred in each subject.
Changes in mean plasma renin activity in the supine
position were not significant during the double-blind
administration of yohimbine, and the postural rise in
plasma renin activity was not altered (fig. 6). Four of
the five volunteers had baseline plasma renin activities
less than 0.5 ng Al/ml/hr. One volunteer on each occasion had a basal renin of 1.5 ng Al/ml/hr. This indi-
•—•
YohimWiw
O—O
Control
Supinq
10
20
3.0
40
\taholvo (7)
30
2.0
PRA
(ng/ml/hr)
HR
(BPM 20
10
»p< 0.05
0
0.01
YOHIMBINE DOSE
0,10
(mg/kg Iv)
FIGURE 4. Influence of yohimbine on heart rate in response to
sympathetic reflexes; the graph shows the peak heart rate during each maneuver.
30
40
Upright
10
TIME
20
30
FIGURE 6. Influence of yohimbine on plasma renin activity (X
± SE) in supine and standing positions following double-blind
administration of yohimbine.
776
HYPERTENSION
VOL
5,
No
5,
SEPTEMBER-OCTOBER
1983
curve following 0.032 mg/kg is similar to that induced
by 100 nM yohimbine in vitro (data not shown). The
threshold for ADP-induced biphasic aggregation was
not altered following yohimbine.
IOr
SLOPE OF
PHASE I
Influence of Yohimbine on Subjective Rating Scale
At the conclusion of each segment of the doubleblind study, volunteers were asked to complete linear
analog rating scales of their subjective feelings (fig. 8).
These scales showed the subjects to be more alert and
less sedated on the day of yohimbine administration.
I0- 7
10-6
IO-S
EPINEPHRINE (M)
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FIGURE 7. Epinephrine-induced platelet aggregation in one
individual before and following two doses of yohimbine (0.032
and 0.125 mg/kg). Results from the addition of each concentration of epinephrine to platelet-rich-plasma are expressed as the
slope of Phase 1 of aggregation. Shown are data from one
subject which were replicated in two additional subjects.
vidual doubled his renin to 3.4 ng Al/ml/hr during
yohimbine, suggesting that yohimbine might, under
appropriate conditions, cause an elevation in plasma
renin. This individual was otherwise indistinguishable
from the other volunteers in terms of blood pressure,
heart rate, baseline or stimulated plasma catecholamines, or urinary Na + excretion during the period of
the study.
Influence of Yohimbine on Ex Vivo Platelet Aggregation
Epinephrine- and ADP-induced platelet aggregation
was studied in three individuals following yohimbine
infusions of 0.032, and 0.125 mg/kg. In each, as
shown in figure 7, there was a dose-related inhibition
of the platelet response to epinephrine, manifested by a
reduction in the slope of the first phase of epinephrineinduced aggregation. The change in the dose-response
Side Effects
Investigator-observed, or subject-volunteered, effects of yohimbine during dose-ranging and doubleblind phases are listed in table 2. During the doubleblind studies, three of five subjects correctly guessed
the yohimbine day in retrospect. Two were unable to
differentiate yohimbine from saline, even in retrospect. The most prominent observation volunteered by
the subjects was a feeling of restlessness. The more
experienced volunteers stated that they were unable to
relax as they had been able to during previous investigations involving unrelated agents. Three subjects noted an unusual taste or smell immediately following the
yohimbine injections. Prominent autonomic effects
observed directly were a fine rest tremor, which persisted for about 1 hour after the last dose of yohimbine,
and transient piloerection. Three subjects admitted to a
vague feeling of sexual arousal. One of these had an
erection about 10 minutes following the rapid administration of yohimbine at 0.016, 0.032, and 0.125 mg/
kg; it was of modest intensity and resolved spontaneously after 3 to 5 minutes.
Two individuals showed effects of yohimbine beyond the immediate period of drug administration.
One reported the day following yohimbine administration that he felt uneasy and irritable. He also noted easy
fatiguability. These sensations had completely resolved within 36 hours of drug administration. The
other voiced no symptoms following yohimbine, but
his heart rate increased from 86 to 130 and blood
pressure increased from 134/80 to 162/96 on assumpSUBJECTIVE PARAMETERS
FIGURE 8. Results of mood assessment
scales on control (o) and yohimbine (*) days of
double-blind study (X ± SE). Subjects were
asked to mark on the line between each set of
extremes as an estimate of mood. The distance
(mm) from the sedate end of each scale was
measured on each day and compared using
paired analysis.
DEPRESSED
CALM .
TIRED
-4-O-+-4—O
I
-t-0
BORED
I
I
I •
-O-H—•
EASILY-DISTRACTED
SLOW
• «
I • I
MUDDLED
DROWSY
ELATED
-+-OH—I • I
WITHDRAWN
RELAXED
• • YOHIMBINE
O = SALINE
• p<.05
* * p< .01
I
ENERGETIC
«
SOCIABLE
CLEARHEADED
h
ABLE TO CONCENTRATE
K>4—t-4-O-I-
•
H—•—I-O-l
-(—O-
1•
I
TENSE
*
«
RESTLESS
OVERALERT
QUICK-WITTED
-•—I«
INTERESTED
AUTONOMIC EFFECTS OF YOHIMBINE IN HUMANS/Goldberg et al.
TABLE 2.
Subjective Effects of Yohimbine (N = 7)
Effect
Restless
Cold sweaty hands
Urge to void
Fine tremor
Sexual arousal
Erection
Nervous
Piloerection
Stuffy nose
Unusual taste or smell
Number
reporting
7
5
4
3
3
1
2
2
2
3
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tion of upright posture. This unusual postural response
was noted 3 hours following the last dose of yohimbine
and persisted for 8 hours. No hemodynamic abnormalities were noted either at 18 hours after yohimbine
administration or during follow-up visits.
Discussion
In these experiments, the increase in blood pressure
following yohimbine administration in normal humans
is shown to be dose-related and associated with two- to
threefold elevation in plasma norepinephrine, suggesting that the pressor response to yohimbine is mediated
by the sympathetic nervous system. An additional observation is that the rise in blood pressure and heart rate
elicited by a variety of sympathetic reflexes is greater
following yohimbine. If the effects of yohimbine are
due to blockade of a 2 receptors, then the data suggest
that these receptors tonically inhibit sympathetic outflow in man.
The key assumption in interpreting these results is
that a2-receptor blockade is the mechanism of action of
yohimbine. Since platelet responses to epinephrine
were attenuated in dose-related fashion, while the aggregatory response to ADP was unaltered, yohimbine
was present in sufficient levels to block noninnervated
a2-receptors. Substantial evidence for the a2-selectivity of yohimbine is apparent from radioligand-binding
as well as in vitro and in vivo studies in experimental
animals.12 Also, in vitro studies in human subcutaneous fat and platelets show the potency of the alkaloid at
human a2-receptors.7-8
Although most effects of yohimbine observed in the
present study can be attributed to blockade of a r r e ceptors, yohimbine may have other pharmacologic actions, including blockade of a, and dopamine receptors and stimulation or blockade of serotonin
receptors.12 Other non-a 2 effects of yohimbine include
local anesthetic actions, and inhibition of monoamine
oxidase.12 These actions are not consistently demonstrable and are observed at higher doses or concentrations of yohimbine, and therefore do not explain our
observations nearly as well as selective a 2 -blockade. 12
Ill
A key issue that is not resolved by these studies is
whether yohimbine's primary site of action is the peripheral or central nervous system. Pressor effects and
increases in plasma norepinephrine and sympathetic
reflexes could be explained either by a peripheral action to enhance sympathetic transmission10 or by a
central effect on vasomotor relay nuclei to facilitate
sympathetic outflow.18 Several observations are more
suggestive of a central site of action. Earlier studies
with yohimbine in humans and animals suggest that
pressor effects are mediated in the central nervous system.1319"21 These included cross-circulation experiments in dogs," and the finding that ganglionic-blocking drugs and spinal-cord section block pressor effects
of yohimbine in dogs and cats.20-21 Furthermore, our
own psychometric data demonstrate central effects. In
addition, in a recent study in which yohimbine was
given orally to normal men, plasma 3-mefhoxy-4-hydroxyphenylethyleneglycol was increased in dose-related fashion following yohimbine, suggesting that
central catecholamine turnover was increased.22 Observations made in that study22 also suggest that sympathetic outflow was increased, although changes in
blood pressure were not as dramatic as in our present
study in which yohimbine was given intravenously.
Thus, available data are consistent with central actions
of yohimbine, but do not allow for conclusions to be
made about the importance of peripheral prejunctional
a2-receptors in adrenergic neurotransmission.
Regardless of the site of yohimbine's action, the
alkaloid is unique in its capacity to release norepinephrine from adrenergic terminals by a process that is not
dependent either on profound changes in hemodynamics, as is the case with vasodilator drugs, or on uptake
of drug into the adrenergic terminal, as is the case with
indirectly acting sympathomimetic amines like tyramine. This is supported by the observation that yohimbine does not lower, but raises, blood pressure, and by
the findings that pressor effects of yohimbine in humans are enhanced by tricyclic antidepressants that
inhibit the amine uptake pump12 13 and that yohimbine
is of benefit in the treatment of chlorimipramine-induced orthostatic hypotension.23
Although yohimbine appears to raise blood pressure
by enhancing sympathetic outflow, no changes in resting heart rate were noted. This observation contrasts
with the tachycardia observed by Holmberg and Gershon13 using a higher dose of yohimbine. Thus, there
may be different thresholds for yohimbine's effects on
these two autonomic functions. Alternatively, as
shown by others13 and by us, yohimbine alters mood.
At higher doses,13 an intense anxiety reaction could
have elicited a generalized sympathetic discharge
above and beyond that induced by a 2 -blockade. Other
explanations may apply: 1) A peripheral baroreceptor
response to yohimbine's pressor effect could have induced a reflex bradycardia, which summed with the
tachycardia expected to result from enhanced norepinephrine release, resulting in no net change in heart
rate. 2) A rapid resetting of the baroreflex may have
offset any tendency for the heart rate to fall in response
778
HYPERTENSION
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to the pressor effects of yohimbine. 3) Local anesthetic
actions of initially high levels of yohimbine may have
prevented the baroreceptor from responding to
changes in blood pressure.12 4) A more intriguing possibility is that yohimbine acted in the central nervous
system to attenuate vagally mediated bradycardia or
reflex sympathetic withdrawal in response to the rise in
blood pressure. This latter action is complemented by
observations that clonidine, an a 2 -agonist, facilitates
and yohimbine and phentolamine both depress, vagal
bradycardia in the cat and dog.24"26
Yohimbine enhanced the pressor and heart rate responses to the cold pressor and handgrip tests and
Valsalva maneuver. Since these responses were highly
variable, somewhat effort-dependent and involved
multiple neuronal pathways, they must be interpreted
with caution, even though multiple reflexes in placebo-treated control subjects did not change. It is not
known whether the enhanced pressor responses were
due to an increase in the amount of norepinephrine
released by each reflex, or to the superimposition of
normal reflex increments in norepinephrine on increased basal release or increased vascular tone. The
change in heart rate responses could be due to an increase in sympathetic activity or to inhibition of the
vagus.24"26
In summary, we have shown that intravenous administration of yohimbine raises blood pressure, enhances sympathetic reflexes, and increases plasma
norepinephrine. Furthermore, yohimbine antagonizes
ex vivo platelet aggregation in response to epinephrine
and causes changes in mood. We conclude from these
findings that a2-adrenoreceptors are important regulators of sympathetic outflow in humans.
Acknowledgments
The authors acknowledge the assistance of Dawn Wade. R. N.,
in the clinical aspects of these studies, and the technical assistance
of Loretta Speier and Pamela Hoover. Bolton Smith assisted in
improving the grammar and fluency of the manuscript. Dr. Robert
Workman is acknowledged for the determinations of plasma renin
activity.
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M R Goldberg, A S Hollister and D Robertson
Hypertension. 1983;5:772-778
doi: 10.1161/01.HYP.5.5.772
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