(Hypertension. 2000;36:945.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Increased Vascular Adrenergic Vasoconstriction and Decreased Vasodilation in Blacks
Additive Mechanisms Leading to Enhanced Vascular Reactivity
From the Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn.
Correspondence to Dr C. Michael Stein, Division of Clinical Pharmacology, Medical Research Bldg I, Room 560, Vanderbilt University School of Medicine, Nashville, TN 37232-6602.
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Abstract |
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Abstract—Blood pressure reactivity is enhanced in young black subjects through mechanisms that are poorly understood. We compared
-adrenergic–mediated
vasoconstrictor and ß-adrenergic vasodilator sensitivity and their
relation to sympathetic activity in blacks and whites. Ten healthy
black (age, 29.9±2.4 years) and 10 white (age, 28.3±1.9 years) men
were studied. Forearm blood flow was measured with strain-gauge
plethysmography after the intrabrachial artery administration of
phenylephrine (1.25 to 20 µg/min) and isoproterenol (60
and 400 ng/min) after application of lower-body negative pressure and
after a cold pressor test. Forearm and systemic
norepinephrine spillover were measured with a
radioisotope dilution technique. -Adrenergic vasoconstriction was
markedly increased (ANOVA P=0.008) and ß-adrenergic
vasodilation decreased (ANOVA P=0.02) in blacks.
Phenylephrine (10 µg/min) decreased forearm blood flow by
58.0±2.5% in blacks but only by 26.6±6.0% in whites
(P<0.001). Vasoconstrictor response to
endogenous norepinephrine, stimulated by a cold
pressor test, resulted in a higher forearm vascular resistance in
blacks than in whites (107.3±13 versus 64.8±13 mm Hg ·
mL-1 · 100
mL-1, P=0.03). There were no
significant ethnic differences in basal or stimulated forearm or
systemic norepinephrine spillover. Increased
vasoconstrictor and decreased vasodilator responses in blacks were not
correlated. Increased sympathetically mediated vascular tone caused by
enhanced vasoconstriction and attenuated vasodilation, effects that
would be additive, and not increased sympathetic activity could enhance
vascular reactivity and may play a role in the pathogenesis of
hypertension in blacks.
Key Words: blacks • adrenergic agonists • vasoconstriction • vasodilation
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Introduction |
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Hypertension is more prevalent and more severe in black than in white Americans1 2 and is associated with greater morbidity and mortality.2 Several genetic and environmental factors have been proposed as potential explanations for these ethnic differences in the prevalence and severity of hypertension. Higher levels of psychosocial stress, enhanced sympathetic responses to such stress, and increased vascular reactivity to sympathetic stimulation3 4 have been suggested to contribute to interethnic differences in the regulation of vascular response and to the pathogenesis of hypertension in blacks.
Enhanced hemodynamic responses to physiological or psychological stressors, mediated largely through an increase in peripheral vascular resistance, have been reported in normotensive blacks in many studies.3 4 5 6 Thus, it has been suggested that a greater increase in vascular tone in response to stress in blacks, occurring either because of increased sympathetic activity or because of altered vascular sensitivity to sympathetic stimulation, may result in increased peripheral vascular resistance and, coupled with higher levels of environmental stress, result in sustained hypertension. However, definitive studies demonstrating enhanced sympathetic activation or increased vascular adrenergic sensitivity in blacks have not been performed.
The purpose of this study was first to compare direct vascular
vasoconstrictor responses to pharmacological -adrenergic stimulation
in blacks and whites through measurement of forearm blood flow
responses to the intra-arterial infusion of
phenylephrine, an 1-adrenergic
agonist. Second, we compared both vascular and sympathetic responses to
physiological adrenergic stimulation through the
application of lower-body negative pressure (LBNP) and a cold pressor
test, exogenous stimuli that result in adrenergic activation. Third,
because the overall result of altered vasoconstriction and vasodilation
will be additive, we examined vasodilator responsiveness to the
ß-adrenergic agonist isoproterenol and vasoconstrictor sensitivity to
the -adrenergic agonist phenylephrine in the same
individuals.
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Methods |
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Subjects
Twenty healthy, nonsmoking, normotensive male volunteers were studied. All subjects provided written informed consent, and the study protocol was approved by the Vanderbilt Committee for the Protection of Human Subjects. Subjects were compensated for participation. Ten subjects were black (age, 29.9±2.4 years) and 10 subjects were white (age, 28.3±1.9 years). No subject had clinically significant abnormalities on history, physical examination, or routine laboratory tests including complete blood count, prothrombin and partial thromboplastin times, renal and liver function tests, and ECG. Six black subjects and 5 white subjects reported a family history of hypertension in a first-degree relative. Subjects were maintained on a diet that was free of alcohol and caffeine and contained 150 mmol of sodium and 70 mmol of potassium per day for 5 days before the study day. The diet was prepared under supervision of a dietitian by the metabolic kitchen of the Vanderbilt University Clinical Research Center. Subjects did not take any medications for at least 2 weeks before each study day.
Experimental Protocol
All experiments were performed in the morning, in the same
temperature-controlled room, with the subjects resting supine in bed.
An intravenous cannula was placed in an antecubital vein of
both arms. After subdermal administration of 1% lidocaine, a 20-gauge
polyurethane catheter (Cook Inc) was inserted into the brachial artery
of the nondominant arm, allowing direct intra-arterial
administration of drugs. Arterial catheter patency was
maintained with an infusion of 5% dextrose in water infused at a rate
of 40 mL/h. By altering the concentration of the drug infusion, the
total flow rate through the cannula was maintained constant at 40 mL/h
during the intra-arterial administration of drugs.
Arterial blood pressure was measured by means of a pressure
transducer (HP 1295C, Hewlett Packard) and heart rate was recorded
from a continuous ECG monitor.
After the arterial line and intravenous catheters had been placed, subjects rested quietly for a 30-minute equilibration period.[3H]Norepinephrine (norepinephrine levo-[ring-2,5,6-3H] 56.9 Ci/mmol, New England Nuclear) was then infused intravenously into the arm opposite to the arterial line for measurement of systemic and forearm norepinephrine spillover, as we have previously described.7 8
Resting forearm blood flow, hemodynamic, and catecholamine measurements were obtained after 30 and 40 minutes of the tritiated norepinephrine infusion. These values were similar and were averaged. Forearm blood flow was measured by venous occlusion plethysmography with a mercury-in-silastic strain-gauge plethysmograph, as we have previously described.8 Immediately after the measurement of forearm blood flow, arterial and venous blood samples were drawn simultaneously for the determination of norepinephrine kinetics.
After resting measurements had been obtained, subjects were positioned in a chamber that enclosed the lower body below the waist. The LBNP chamber was sealed at the level of the iliac crests and connected to a vacuum source controlled by a rheostat. LBNP at -15 mm Hg was applied for 10 minutes and then increased to -30 mm Hg for a further 10 minutes. Heart rate, blood pressure, and forearm blood flow were measured and arterial and venous blood was drawn during the last 2 minutes of each 10-minute LBNP period. Then, after a 15-minute recovery period during which measurements returned to their resting values, a cold pressor test was performed by immersing each subject’s left foot to the level of the malleoli in a slurry composed of equal parts water and crushed ice for 2 minutes. Subjects were instructed to breathe normally and to avoid straining or performing a Valsalva maneuver. Forearm blood flow, heart rate, and blood pressure measurement and drawing of blood for catecholamines were performed during the second minute of the cold pressor test.
After a 30-minute recovery period during which responses returned to
baseline, phenylephrine was infused into the brachial
artery in increasing doses (1.25 to 20 µg/min). Each dose was infused
for 7 minutes by a Harvard infusion pump, with forearm blood flow
recorded during the last 2 minutes of each dose. To minimize the
risk of arterial thrombosis, if, during 2 consecutive doses
of phenylephrine forearm blood flow decreased to <1
mL · min-1 ·
dL-1, then higher doses of
phenylephrine were not administered. After completion of
the phenylephrine dose response, a 45-minute washout period
was allowed to elapse. Then, to determine the relation between the
attenuation of vasodilation in response to intra-arterial
isoproterenol that we had previously observed in blacks8
and -adrenergic vasoconstriction, we administered 2 doses (60 and
400 ng/min) of isoproterenol (Isuprel, Winthrop Pharmaceuticals). Each
dose was administered for 7 minutes, and forearm blood flow was
recorded during the last 2 minutes of the infusion. The dose ranges
of isoproterenol and phenylephrine were selected to have a
substantial effect on local forearm blood flow but to have no systemic
hemodynamic effects.
Blood Collection and Analysis
Blood was drawn into cooled tubes with EGTA and reduced
glutathione (Amersham), placed on ice, and centrifuged at
4°C. Samples of the
[3H]norepinephrine infusion
solution were collected, stored, and later assayed, as described below
for the blood samples, to allow determination of the actual rate of
[3H]norepinephrine infusion.
Norepinephrine and epinephrine concentrations were
measured by high-performance liquid
chromatography with electrochemical detection, as we
have described previously.9
Measurement of Forearm and Systemic Norepinephrine
Spillover
Measurement of sympathetic activity in vivo is complex because
norepinephrine does not function as a circulating hormone
but acts locally at the nerve terminal with a small amount "spilling
over" into the circulation. Circulating plasma
norepinephrine concentrations reflect not only the
spillover from the nerve terminal but also the clearance of
norepinephrine from plasma. Radioisotope dilution
techniques, which determine the clearance of
norepinephrine, allow more accurate determination of
norepinephrine release (spillover).7 10
Systemic norepinephrine spillover provides a measure of
global sympathetic activity, whereas forearm norepinephrine
spillover measures norepinephrine release across the
forearm. Norepinephrine and epinephrine samples
were analyzed in duplicate, and the average value was used for
the calculations. Calculations for the determination of
norepinephrine kinetics by the isotope dilution method were
performed as we and others have previously
described.7 10
Statistical Analysis
For technical reasons, 1 black subject performed only the LBNP
part of the protocol, another performed only the
intra-arterial drug administration part of the protocol,
and in 1 white subject, the radiolabeled norepinephrine
infusion was not completed. Two white subjects, one of whom became
syncopal and another who became dizzy during the -15 mm Hg LBNP,
did not go on to the higher -30 mm Hg LBNP part of the protocol,
and their data have not been included in the analysis of those
data.
Forearm blood flow tracings were analyzed by a single investigator who was not aware of the race of the subjects. The average of 8 to 10 flow curves was obtained for the measurement of forearm blood flow at any time point. For safety reasons, only 2 blacks as compared with 9 whites received doses of phenylephrine >10 µg/min. The repeated-measures ANOVA was performed on the phenylephrine dose response up to 10 µg/min. As a measure of sensitivity to phenylephrine, linear regression analysis was used to analyze individual phenylephrine dose-response curves with the line of best fit plotted through the linear portion of the log-linear dose-response curve. The dose required to decrease forearm blood flow 25% (P25) was calculated for each subject and then expressed as geometric means with 95% CIs for the 2 groups. The P25 was not calculated in 1 white subject because he was so insensitive to phenylephrine that his forearm blood flow decreased by only 12% after the highest dose of phenylephrine administered, without a clear linear dose-response relation. Statistical analyses were performed with the repeated-measures ANOVA, examining the effects of each intervention, and each intervention was analyzed by race (interventionxrace), the unpaired t test, and Fisher’s exact test, as appropriate, with SPSS for Windows Release 6. All results are expressed as mean±SEM. A 2-tailed P value of <0.05 was the criterion for statistical significance.
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Results |
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Resting Hemodynamic and Catecholamine Measurements
The 2 study groups were well matched in terms of demographic characteristics (Table 1) and resting hemodynamic and catecholamine measurements (Table 2). The 2 groups did not differ significantly with regard to age, weight, height, body mass index, 24-hour urinary sodium excretion or resting heart rate, mean arterial pressure, forearm blood flow, norepinephrine spillover, and epinephrine concentrations.
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Forearm Blood Flow Responses to Phenylephrine
Forearm blood flow decreased in response to increasing doses of
phenylephrine, an 1-adrenergic
agonist, in both blacks and whites. Responses to
phenylephrine were significantly enhanced in black subjects
(Figure 1). After
phenylephrine (1.25 to 10 µg/min), forearm blood flow
decreased from 1.9±0.2 to 0.83±0.01 mL ·
dL-1 ·
min-1 in blacks and from
2.1±0.4 to 1.5±0.3 mL · dL ·
-1 ·
min-1 in whites (ANOVA
P=0.008). Phenylephrine (10 µg/min) decreased
forearm blood flow by 58.0±2.5% in blacks and 26.6±6.0% in whites
(P<0.001). Response to phenylephrine was not
affected by the presence or absence of a family history of hypertension
and was not correlated with resting blood pressure in blacks, whites,
or all subjects (data not shown). Because of the increased vascular
sensitivity to phenylephrine in blacks, only 2 black
subjects as opposed to 9 white subjects received doses of
phenylephrine >10 µg/min. The dose of
phenylephrine required to decrease forearm blood flow by
25% (P25) was significantly lower in blacks than
in whites (2.7 µg/min, 95% CI 2.1 to 3.4 µg/min compared with 6.0
µg/min, 95% CI 3.8 to 9.4 µg/min, P=0.003), indicating
increased sensitivity to phenylephrine in blacks.
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Forearm Blood Flow Responses to Isoproterenol
Isoproterenol (60 and 400 ng/min) resulted in a forearm blood flow
of 3.4±0.7 and 9.1±1.8 mL · 100
mL-1 ·
min-1, respectively, in
blacks and 6.4±1.7 and 19.6±4.1 mL · 100
mL-1 ·
min-1 in whites
(P=0.02). There was no correlation between vasodilator
response, measured as the forearm blood flow response to 400 ng/min
isoproterenol, and vasoconstrictor response, measured as the response
to 10 µg/min phenylephrine in whites
(r2=0.09, P=0.8), blacks
(r2=0.06, P=0.5), or all
subjects (r2=0.07,
P=0.28).
Hemodynamic and Catecholamine Responses
to Physiological Adrenergic Stimulation
The physiological relevance of increased
-adrenergic and decreased ß-adrenergic vascular sensitivity was
examined by measuring the hemodynamic and
catecholamine responses to LBNP and cold pressor testing.
There was no evidence that sympathetic responses were greater in blacks
than in whites. The application of LBNP increased epinephrine,
norepinephrine, and norepinephrine
spillover, measures of sympathetic activity, modestly and to a
similar degree in both blacks and whites, and
hemodynamic changes in the two ethnic groups were
similar (Table 2).
The application of a cold pressor test resulted in a higher forearm vascular resistance in blacks (107±13 mm Hg · mL-1 · min-1 · dL-1) than in whites (65±13 mm Hg · mL-1 · min-1 · dL-1) (P=0.03) (Figure 2). Norepinephrine concentrations and norepinephrine spillover after cold pressor testing increased significantly from resting values in both ethnic groups (P=0.03),; however, they did so to a similar extent in blacks (637±300 ng/min) and whites (643±115 ng/min) (P=0.86) (Table 3), indicating that the higher vascular resistance in blacks in response to the cold pressor test was not due to increased sympathetic activity. Heart rate, mean arterial pressure, forearm blood flow, and epinephrine responses to cold pressor testing were similar in blacks and whites (Table 3).
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Discussion |
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The major findings of this study are first, that vascular
-adrenergic vasoconstrictor sensitivity is increased in normotensive
black men; second, that an exogenous sympathetic stimulus, the cold
pressor test, despite a similar increase in norepinephrine
spillover in blacks and whites, resulted in a greater increase in
peripheral vascular resistance in blacks; and third, that
attenuated ß-adrenoceptor–mediated vasodilation and enhanced
-adrenergic vasoconstrictor sensitivity in blacks were independent
of each other and hence will produce additive effects.
Vascular responses to stress include vasodilation mediated by
epinephrine, the endogenous ß-adrenergic agonist,
vasodilation mediated through nitric oxide,11 and
vasoconstriction mediated through norepinephrine, which is
predominantly an -adrenergic agonist. This study suggests that
increased sensitivity to -adrenergic vasoconstriction would act to
amplify the increase in vascular tone that would result from attenuated
ß-adrenergic and nitric oxide–mediated vasodilation in blacks under
conditions of stress. Thus, our findings of increased -adrenergic
sensitivity coupled with an attenuated response to vasodilators
explains the increased hemodynamic responses and
peripheral vascular resistance in response to stress noted
in blacks in many previous studies.3 4 5 6
Adrenergic vasoconstrictor sensitivity in blacks, previously studied
through measurement of blood pressure responses to systemic infusion of
an -adrenergic drug, has been poorly characterized. Dimsdale et
al12 reported no ethnic difference in the pressor
sensitivity to intravenous infusion of
norepinephrine in normotensive subjects, whereas Sherwood
et al13 reported that -adrenergic sensitivity was
increased, independent of blood pressure, in borderline hypertensive
and normotensive blacks. However, extrapolation of the effects of
systemic infusion of vasoactive drug on blood pressure to a measure of
vascular sensitivity is complicated by the confounding effects of
systemic reflex responses, including reflex sympathetic responses, that
occur after the systemic infusion of vasoactive drugs.
A more rigorous technique for examining vascular sensitivity is to
measure the vascular response to low doses of drug that do not have
systemic effects infused directly into the blood vessel or vascular bed
of interest. One such study has examined the dorsal hand vein responses
to the local infusion of the -adrenergic agonist
phenylephrine and found decreased rather than increased
sensitivity in blacks.14 However, that study also found
that responses to isoproterenol in the hand vein were similar in blacks
and whites,14 in contrast to the findings in the forearm
vasculature.8 The hand vein model, although attractively
simple, may not reflect arterial or resistance vessel
responses.15 In the present study, we infused
phenylephrine, an -adrenergic agonist, directly into the
brachial artery in healthy normotensive white and black subjects and
showed that vasoconstriction in the forearm was markedly increased in
blacks. Thus, these findings show that vascular sensitivity to an
infused -adrenergic vasoconstrictor is increased in normotensive
blacks.
Forearm vasodilation in response to isoproterenol,8 whose
actions are mediated both through ß-adrenergic receptors and the
release of nitric oxide,16 and in response to sodium
nitroprusside, methacholine, and acetylcholine,11 17 whose
actions are mediated through nitric oxide, is attenuated in blacks.
These findings must now be considered in the light of concomitant
enhanced -adrenergic–mediated vasoconstriction. Vascular tone is
the result of vasoconstricting and vasodilating forces. Thus, under
conditions of stress and adrenergic activation, increased adrenergic
vasoconstrictor sensitivity would serve to independently augment the
vascular and hemodynamic effects of attenuated
vasodilator responses.
In addition to altered vascular adrenergic sensitivity, it is important to consider increased endogenous adrenergic activation in blacks as a potential mechanism for enhanced cardiovascular response in blacks. Resting and stimulated plasma norepinephrine concentrations have generally been found to be similar in normotensive and hypertensive blacks and whites.18 However, measurement of plasma norepinephrine concentrations is not an ideal index of sympathetic activity because norepinephrine does not primarily function as a circulating hormone but acts locally at the postsynaptic receptor. Using a radioisotope dilution technique that measures norepinephrine clearance and thus provides a more accurate measurement of norepinephrine release, we have previously reported that resting systemic norepinephrine spillover was similar in blacks and whites.19 However, stress-stimulated sympathetic responses, the critical measure in defining the relation between stress-induced sympathetic activation and hemodynamic effects, have not previously been defined in blacks and whites through the use of this technique.
Two physiological stimuli, cold pressor testing and LBNP, were used to stimulate endogenous adrenergic activity in this study. By simultaneously measuring norepinephrine spillover and hemodynamic responses, we were able to determine the relation between sympathetic activation and hemodynamic responsiveness.
The effector limb of the sympathetic response can be tested by
measuring neurohormonal and vascular responses to a cold
stimulus.20 The cold pressor test resulted in a similar
degree of sympathetic activation in blacks and whites; however,
vascular responsiveness was increased in blacks. Thus,
consistent with our findings of increased vascular
-adrenergic sensitivity as determined by increased sensitivity to
phenylephrine, a significantly greater forearm vascular
resistance in response to the cold pressor test in blacks occurred.
There was no significant ethnic difference in the blood response to the
cold pressor test. The probable reason is that the cold pressor
response, in addition to the changes resulting from sympathetic
activation, is also affected by the baroreflex response and the degree
of discomfort perceived by the subjects.
We found that the increases in sympathetic activity in response to
LBNP, as measured by increases in systemic norepinephrine
spillover and in plasma epinephrine concentrations, were
similar in blacks and whites. Similarly, hemodynamic
responses were not significantly different in the two groups. One would
expect from our findings of increased vascular sensitivity to
phenylephrine and increased forearm vascular responses to
cold pressor testing in blacks that LBNP, which resulted in a similar
degree of sympathetic stimulation in blacks and whites, would result in
enhanced vascular responses in blacks. Forearm vascular resistance in
response to LBNP in blacks (94±15 U) and whites (68±10 U) was not
significantly different (P=0.23). Cold pressor testing is a
powerful sympathetic stimulus inducing vasoconstriction in
peripheral muscle beds that is thought to be largely
mediated through peripheral -adrenergic
receptors,6 whereas subhypotensive LBNP, a relatively
weak sympathetic stimulus, decreases the firing rate of low-pressure
baroreceptors, thus increasing peripheral vascular
resistance.21 LBNP increased systemic spillover by
40% and, as found by others, did not increase forearm
norepinephrine spillover.22 In contrast,
cold pressor testing increased systemic norepinephrine
spillover by >100%. It is possible that another stimulus that
resulted in greater sympathetic activation than did subhypotensive LBNP
may also have detected ethnic differences in vascular reactivity.
Several possible mechanisms for the attenuated response to multiple
vasodilators and enhanced -adrenergic–mediated vasoconstriction in
blacks can be considered. The possibility that increased
vasoconstrictor sensitivity to phenylephrine may have
occurred because of an increased baseline vascular tone caused by
attenuated vasodilation in response to the basal nitric oxide released
by the endothelium was considered. This appears to be
unlikely for several reasons. First, resting forearm blood flow was
similar in blacks and whites; second, there was no correlation between
the vasoconstrictor response to phenylephrine and the
vasodilator response to isoproterenol in either ethnic group; and
third, vascular responsiveness to phenylephrine in the
human forearm is not altered by the basal production of nitric
oxide.23
The forearm blood flow technique has been used extensively to study local regulation of vascular response,24 primarily because it allows the measurement of vascular sensitivity free of the confounding effects of systemic reflex responses. This technique allows the delivery of an exact dose of drug directly into the forearm vascular bed, whose response is being measured and therefore also has the advantage that the responses are unlikely to be confounded by interindividual or interethnic differences in drug disposition.
Recently, polymorphisms of the
ß2-adrenoceptor have been described and found
to be associated with race, salt sensitivity, hypertension, and forearm
blood flow response to isoproterenol.25 26 27
Polymorphisms of the 1-adrenoceptor
subtypes also exist,28 and there are ethnic differences in
their distribution.28 The relation between
polymorphisms of -adrenergic and
ß2-adrenergic receptors and of nitric oxide
synthase genes and the interethnic differences in vascular
responsiveness in blacks and whites has not been determined but might
contribute to our findings.
The effector system of the G-protein–coupled
1-adrenoceptor includes phospholipase C and
phosphatidylinositol29 and differs from the
adenylate cyclase–coupled ß-adrenoceptor and the
guanylate cyclase–coupled effector system mediating
vasodilation to nitric oxide agonists. This argues for ethnic
differences either at several different sites or at a single site
further downstream in the vascular smooth muscle.
Ethnicity can be considered to represent a clustering of genetic and environmental factors.30 In this study, we controlled for factors such as gender, diet, and sodium, caffeine, and alcohol intake, which might affect vascular responses. In addition, subjects were of similar educational backgrounds, and the two ethnic groups had a similar frequency of a family history of hypertension. Nevertheless, it is possible that other environmental factors, perhaps interacting with genetic factors, could account for our observation of increased adrenergic-mediated vasoconstriction. However, the confirmation of attenuated ß-adrenergic–mediated and nitric oxide–mediated vasodilation in blacks by other investigators31 elsewhere in the United States, in a study population that included both men and women, supports the general significance of our findings.
Several limitations must be noted. First, although there is
considerable information linking blood pressure reactivity to the
future risk of hypertension,6 there are no data regarding
the importance of -adrenergic vascular sensitivity because it is not
feasible to measure this in a large number of individuals. However, it
is of interest that several studies that failed to find a difference
between blacks and whites in blood pressure reactivity to stressors did
find increased peripheral vascular resistance to these
stressors in blacks.6 Second, for safety reasons, we could
not determine the maximum responses to phenylephrine and
thus could not obtain exact measures of maximum response or the dose
required to produce 50% of the maximum response
(ED50). However, in many biological experiments
it is not feasible to produce maximum responses, and analysis
of the linear portion of the dose-response curve allows comparisons of
sensitivity between groups or individuals to be made. Third, we studied
healthy normotensive men, and the more general significance of our
findings will need to be tested in a wider range of subjects, including
those with hypertension.
In summary, the decrease in forearm blood flow in response to phenylephrine is markedly increased in normotensive black men. Enhanced adrenergic-mediated vasoconstriction in blacks will further accentuate the increase in vascular tone that results from attenuated vasodilation to nitric oxide and to epinephrine, the endogenous ß2-adrenoceptor agonist. Our findings indicate that increased vasoconstriction, in addition to attenuated vasodilation, contributes to enhanced vascular reactivity to stress and may play a role in the pathogenesis of hypertension in blacks.
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Acknowledgments |
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This study was supported by a Grant-in-Aid from the American Heart Association (Tennessee Affiliate) and USPHS grants HL-56251, HL-04012, and GM-5-M01-RR00095. C. Michael Stein was the recipient of a Pharmaceutical Research and Manufacturers Association Foundation Career Development Award. Chim C. Lang was supported by a Merck Sharp and Dohme International Fellowship in Clinical Pharmacology.
Received March 31, 2000; first decision April 19, 2000; accepted June 5, 2000.
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