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(Hypertension. 1998;31:1235-1239.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Racial Differences in Nitric Oxide–Mediated Vasodilator Response to Mental Stress in the Forearm Circulation

Carmine Cardillo; Crescence M. Kilcoyne; Richard O. Cannon, III; ; Julio A. Panza

From the Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.

Correspondence to Dr Julio A. Panza, Cardiology Branch, NHLBI, NIH, Bldg 10, Room 7B-15, 10 Center Dr, Bethesda MD 20892-1650. E-mail panzaj{at}gwgate.nhlbi.nih.gov

	Abstract

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Abstract—An abnormal hemodynamic response to stressful stimuli has been proposed as a mechanism involved in the higher prevalence of hypertension in blacks. Given the important role of nitric oxide (NO) in the regulation of cardiovascular homeostasis, we investigated the possibility of racial differences in vascular NO activity during mental stress. To test this hypothesis, we compared the forearm blood flow (FBF) response to mental stress in 14 white and 12 black healthy subjects during intra-arterial infusion of either saline or NO synthesis inhibitor N^G-monomethyl-L-arginine (L-NMMA; 4 µmol/min). We also examined vascular responses of the two groups to intra-arterial infusion of sodium nitroprusside (0.8 to 3.2 µg/min), an exogenous NO donor. During saline infusion, the increase in FBF from baseline induced by mental stress was significantly higher in whites than in blacks (109±20% versus 58±8%; P=0.03). L-NMMA significantly reduced stress-induced increase in FBF in whites (from 109±20% to 54±11%; P=0.004) but not in blacks (from 58±8% to 42±10%; P=0.24); thus, the vasodilator effect of stress testing during L-NMMA was similar in whites and blacks (54±11% versus 42±10%; P=0.44). The vasodilator response to sodium nitroprusside was also lower in blacks than in whites (maximum flow, 6.9±2 versus 11.6±3.5 mL · min^-1 · dL^-1; P=0.001) and was not significantly modified by L-NMMA in either group. Our findings indicate that blacks have a reduced NO-dependent vasodilator activity during mental stress. This difference seems related to reduced sensitivity of smooth muscle to the vasodilator effect of NO and may play some role in the increased prevalence of hypertension and its complications in blacks.

Key Words: race • nitric oxide • stress • vasodilation

	Introduction

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The prevalence of essential hypertension is considerably higher and the severity of its cardiovascular complications greater in blacks than in whites.^{1 2} This greater susceptibility to end-organ involvement leads in turn to higher rates of morbidity and mortality from those diseases that are directly related to hypertension, such as cerebrovascular accidents and renal failure.³

Various genetic and environmental factors have been postulated to explain these racial differences in the clinical presentation of hypertension.^{4 5 6} One hypothesis is that the development and subsequent course of hypertension in blacks are related to an abnormal pattern of hemodynamic reactivity, characterized by increase in peripheral vascular resistance after exposure to environmental stimuli such as cold or mental stress.^{7 8 9 10 11 12} The mechanism responsible for this hemodynamic abnormality, however, has not been clearly defined.

Among the vasoactive substances that physiologically participate in the regulation of vascular adaptation to mental stress, endothelium-derived NO plays an important role, as demonstrated by recent studies showing that NO synthesis inhibition in normal subjects results in marked blunting of forearm vasodilator response to mental tasks.^{13 14} Importantly, a reduction in NO activity has been widely demonstrated in hypertensive patients^{15 16 17 18 19 20} and, more recently, even in normotensive offspring of hypertensive parents²¹; these findings support the concept that decreased action of NO might play a pathophysiological role in the development of hypertension. It is therefore reasonable to hypothesize that a decreased vascular activity of NO also could be involved in the abnormal hemodynamic reactivity pattern to stress and the increased susceptibility to developing high blood pressure over repeated exposures to stressful situations that are observed in African Americans. Thus, the present study was designed to investigate the possibility of racial differences in NO-dependent vasodilator response to mental stress in the forearm circulation of healthy subjects.

	Methods

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Study Population
A population of 26 normal volunteers (14 whites and 12 blacks) with no evidence of present or past hypertension or hypercholesterolemia (plasma cholesterol 200 mg/dL) was selected for this study. The clinical characteristics of the 2 groups are reported in Table 1. The distribution of premenopausal and postmenopausal women was similar between the white (2 and 5, respectively) and black (3 and 3, respectively) populations (P=0.53).

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of Study Population

Before admission, subjects of each group were screened by clinical history, physical examination, routine chemical analyses, electrocardiography, and chest radiography. Exclusion criteria were history or evidence of present or past diabetes mellitus, cardiac disease, peripheral vascular disease, coagulopathy, or any other disease predisposing them to vasculitis or Raynaud's phenomenon.

The study protocol was approved by the National Heart, Lung, and Blood Institute Investigational Review Board, and all participants gave written informed consent for all procedures.

Protocol
All studies were performed in the morning in a quiet room with a temperature of approximately 22°C. Participants were asked to refrain from drinking alcohol or beverages containing caffeine and from smoking for at least 24 hours before studies.

Each study consisted of the measurement of the response of the forearm vasculature by means of strain-gauge venous occlusion plethysmography under different experimental conditions. All drugs used in this study were approved for human use by the Food and Drug Administration in the form of Investigational New Drug (IND) and were prepared by the Pharmaceutical Development Service of the National Institutes of Health following specific procedures to ensure accurate bioavailability and sterility of the solutions.

While the participants were supine, a 20-gauge polytetrafluoroethylene (Teflon) catheter (Arrow Inc) was inserted into the brachial artery of the left arm. This arm was slightly elevated above the level of the right atrium and a mercury-filled silicone elastomer (Silastic) strain gauge was placed in the widest part of the forearm.²² The strain gauge was connected to a plethysmograph (model EC-4, DE Hokanson), calibrated to measure the percent change in volume and connected in turn to a chart recorder to record the flow measurements. For each measurement, a cuff placed around the upper arm was inflated to 40 mm Hg with a rapid cuff inflator (model E-10, DE Hokanson) to occlude venous outflow from the extremity. A wrist cuff was inflated to suprasystolic pressures 1 minute before each measurement to exclude the hand circulation.²³ Flow measurements were recorded for approximately 7 seconds every 15 seconds; 7 readings were obtained for each mean value.

Basal measurements were obtained after a 3-minute infusion of saline solution at 1 mL/min. FBF was then measured during mental stress and during the infusion of SNP. These measurements were separated by a 30-minute resting period. The mental stress testing required each subject to subtract continuously the number 7 from a 3-digit number as quickly and as accurately as possible for 3 minutes. During the test, the participants were intentionally frustrated by being asked to perform faster and by being immediately corrected in case of wrong answers. The test procedure was explained to the subjects at their arrival in the laboratory room, and they were asked to practice to become familiar with the task.

A 30-minute rest period was allowed, and another basal measurement was obtained between mental stress and the infusion of SNP. SNP was used as an endothelium-independent vasodilator because its vasodilator effect is largely due to its direct action on smooth muscle cells.²⁴ SNP was infused at 0.8, 1.6, and 3.2 µg/min (the infusion rates were 0.25, 0.5, and 1 mL/min). Each dose was infused for 5 minutes, and forearm flow was measured during the last 2 minutes.

After another 30-minute rest period, flow measurements were obtained to corroborate the return to basal values. Then, L-NMMA (Calbiochem) was infused at 4 µmol · L^-1 · min^-1 (infusion rate 1 mL/min) for 15 minutes, and baseline flow measurements were obtained during the last 2 minutes of infusion. L-NMMA is an arginine analogue that competitively antagonizes the synthesis of NO from L-arginine and thus provides a tool for investigating the rate of vascular NO production.²⁵

Subsequently, the mental arithmetic task and the cumulative dose-response curve for SNP were repeated using the same procedure, doses, infusion rates, and resting interval reported above. The infusion of L-NMMA was discontinued during the resting period but reinstated 15 minutes before the second of these procedures. The sequence of mental stress and SNP infusion, both before and after the infusion of L-NMMA, was randomized to avoid any bias related to the order of these procedures.

To test the possibility of nonspecific racial differences in vasodilator function, reactive hyperemic blood flow responsiveness to forearm ischemia was also measured on a separate day. Ischemia was induced by inflation of a sphygmomanometric cuff on the upper arm to suprasystolic pressure (200 mm Hg) for 5 minutes. These experiments were aimed at producing a vasodilator response of a magnitude at least similar to that observed in response to the highest dose of SNP. Peak reactive hyperemic flow was measured 5 seconds after release of the cuff.

During the study, all blood pressures were recorded directly from the intra-arterial catheter immediately after each flow measurement, and heart rate was recorded from an electrocardiographic lead.

Statistical Analysis
Group differences were analyzed by unpaired Student's t test and ² test as appropriate. The effects of L-NMMA on vascular responses to mental stress were analyzed by paired Student's t test. Differences in the response to SNP were analyzed by ANOVA for repeated measures. All calculated P values are two-tailed, and a value of P<0.05 was considered to indicate statistical significance. All group data are reported as mean±SEM.

	Results

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Baseline Measurements
The clinical characteristics of the subjects in the two study groups are shown in Table 1. There was no significant difference between the two groups in gender, age, weight, body mass index, smoking habit, baseline FBF, mean arterial pressure, family history of hypertension, plasma glucose, and plasma lipids.

Hemodynamic Responses to Mental Stress in Whites and Blacks
During infusion of saline, mental stress testing induced a significant increase in FBF from baseline in both groups, but its vasodilator effect was significantly reduced in blacks compared with whites (Figure 1).

View larger version (13K): [in this window] [in a new window]   Figure 1. FBF responses to mental stress in white () and black () subjects. Values represent mean±SEM.

Mental stress testing resulted in a significant increase in mean arterial pressure from baseline in both whites and blacks (both P<0.001) (Table 2), without any significant difference between the two groups (P=0.69). Similarly, the performance of mental arithmetic determined a significant increase in heart rate over baseline in both groups (both P<0.001) (Table 2), without any significant difference between them (P=0.66).

View this table: [in this window] [in a new window]   Table 2. Systemic Hemodynamic Variables at Baseline and During Mental Stress Before and After NO Synthesis Inhibition in Whites and Blacks

Effects of L-NMMA on Vascular Responses to Mental Stress
During L-NMMA administration, the performance of mental stress testing resulted in a significant increase in FBF from baseline in both whites (from 2.5 to 3.5 mL · min^-1 · dL^-1; P<0.001) and blacks (from 2.1 to 2.9 mL · min^-1 · dL^-1; P=0.003). In whites, however, the percent increase in FBF from baseline during the performance of mental arithmetic testing was significantly lower during NO synthase inhibition than during saline infusion (Figure 2), whereas in blacks it was not significantly different during saline and L-NMMA infusions (Figure 2). The vasodilator effect of mental stress testing was significantly higher in whites than in blacks during saline infusion but was not significantly different between the 2 groups during NO synthesis inhibition by L-NMMA (Figure 2).

View larger version (16K): [in this window] [in a new window]   Figure 2. Percent changes in FBF in response to mental stress in whites and blacks during infusion of saline or L-NMMA (4 µmol/min). Values represent mean±SEM.

During L-NMMA administration, mean arterial pressure and heart rate values during mental stress testing (Table 2) were not significantly different in blacks and whites (P=0.70 and P=0.95 for mean arterial pressure and heart rate, respectively), and in both groups they were similar to those observed during saline infusion (all P>0.05).

FBF Responses to SNP and Effects of L-NMMA
During saline infusion, infusion of increasing doses of SNP resulted in a progressive increase in FBF from baseline in both groups; the vasodilator response to SNP, however, was significantly greater in whites than in blacks (Figure 3). L-NMMA administration did not significantly modify the FBF response to the three doses of SNP either in whites (6.3±0.7, 8.4±0.9, 10.9±1 mL · min^-1 · dL^-1; P=0.43 versus saline) or in blacks (4.1±0.3, 5.4±0.4, and 7.1±0.6 mL · min^-1 · dL^-1; P=0.84 versus saline).

View larger version (18K): [in this window] [in a new window]   Figure 3. FBF responses to increasing doses of SNP in whites () and blacks (). Values represent mean±SEM.

Vascular Response to Reactive Hyperemia
After 5 minutes of forearm ischemia, a marked increase in FBF from baseline was observed in both whites (from 3±0.4 to 20.6±2.5 mL · min^-1 · dL^-1) and blacks (from 3.3±0.2 to 22.4±2.3 mL · min^-1 · dL^-1), without any significant difference between the two groups in the peak reactive hyperemic response (P=0.30).

	Discussion

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The results of the present study demonstrate that compared with white subjects, normotensive blacks have a blunted vasodilator response to mental stress. NO synthase inhibition by L-NMMA significantly reduced the mental stress–induced vasodilation in whites but did not result in any significant change in blacks. As a result, during NO synthesis inhibition, the vasomotor response to mental stress was similar in both groups. These findings indicate that the defect in vasodilator responsiveness to mental stress testing observed in blacks was likely related to decreased NO-mediated vasorelaxation.

NO is known to produce its vasorelaxing effect through activation of the soluble guanylyl cyclase within vascular smooth muscle, leading to increased intracellular content of cGMP and subsequent vasodilation.²⁶ A decreased NO-dependent vasodilator capacity could be potentially related to either reduced availability of NO at the level of smooth muscle cell (as a consequence of decreased NO production and/or increased NO breakdown) or to reduced smooth muscle sensitivity to the dilatory effect of NO.

To investigate the potential mechanism underlying the decreased NO-dependent dilatory response to mental stress observed in healthy blacks compared with whites, we assessed the vasodilator effect of an exogenous NO donor, SNP. We observed that the vasodilator effect of SNP was lower in blacks than in whites, suggesting a decreased smooth muscle responsiveness to nitrovasodilators as a mechanism to explain the decreased NO-dependent vasodilation during mental stress testing observed in African Americans. This mechanism seems different from that underlying the decreased vasodilator response to mental stress in patients with essential hypertension recently observed in our laboratory.²⁷ Thus, in hypertensive patients, a decreased vascular relaxation to mental stress is associated with preserved responsiveness to SNP. This suggests that the vasodilation defect in these patients is related to decreased availability of NO at the smooth muscle level rather than to blunted responsiveness to NO. The precise intracellular mechanism involved in the decreased vascular smooth muscle responsiveness to endogenous and exogenous NO in African Americans cannot be determined from our data. It is known that cGMP-mediated smooth muscle relaxation is dependent on stimulation of cGMP-dependent protein kinase and phosphorylation of cellular substrates that modulate cytosolic Ca²⁺ concentration and/or Ca²⁺ sensitivity of the contractile apparatus.^{27 28} Thus, it is reasonable to speculate that racial differences in one or more sites along this intracellular pathway might be involved in the decreased vascular smooth muscle responsiveness to NO observed in African Americans. Among the molecules involved in this pathway are phospholamban (which modulates sarcoplasmic reticulum Ca²⁺ uptake), sarcolemmal Ca²⁺ pumps, myosin light chain kinase, and myosin phosphatase.^{28 29} Moreover, because both cGMP-dependent protein kinase and NO directly can activate K⁺ channels, it is also possible that racial differences in intracellular regulation of this ion might affect Ca²⁺ handling. This mechanism could in turn lead to decreased NO-dependent smooth muscle vasodilation in African Americans, as suggested by a recent study showing that changes in dietary potassium may modulate the vasodilator responsiveness to mental stress.³⁰

To rule out the possibility that the decreased vascular smooth muscle dilator capacity in response to both endogenous and exogenous NO observed in African Americans could be related to a generalized defect in vasodilator function, we compared the vasodilator response to forearm ischemia in blacks and whites. Ischemia is a stimulus that induces vasodilation through involvement of different biochemical mediators, as well as structural mechanisms.³¹ The peak reactive hyperemic response to ischemia in the forearm microcirculation, however, seems independent of NO availability, as demonstrated in a previous study showing that the peak flow response to ischemia is not different before and after NO synthesis inhibition with L-NMMA.³² We observed that blacks and whites have a similar peak reactive hyperemic response to ischemia, thereby suggesting that the reduction in NO-mediated vasodilation of African Americans is not related to a generalized defect in vasodilator function. In our study, we cannot exclude the presence of early vascular structure abnormalities in healthy blacks as previously reported by other investigators,^{33 34} because the existence of vascular hypertrophy can be detected only when ischemia is applied for 10 minutes or more in conjunction with hand exercise.^{35 36} It is important to consider, however, that 5 minutes of forearm ischemia in our study population resulted in a reactive vasodilator response of a magnitude greater than those observed during mental stress and SNP infusion. Thus, this observation supports the view that the racial differences in the vasodilator responsiveness to endogenous and exogenous NO observed in our study could not be accounted for by structural changes of the vessel wall.

Interestingly, in our study, despite the presence of reduced NO-dependent vasodilator responsiveness to mental stress in healthy blacks, the increase in systemic arterial pressure during the psychological challenge was not different between the two groups. Because blood pressure response to mental stress may be achieved through variable combinations of changes in cardiac output and peripheral resistance,³⁷ our findings are likely explained by a different pattern of hemodynamic reactivity in the two groups, with higher peripheral resistance and lower cardiac output responses in blacks, in keeping with previous observations by other investigators.^{38 39}

In conclusion, our study indicates that healthy blacks have reduced NO-dependent vasodilator responsiveness to mental stress compared with whites. This difference appears to be related to an attenuation of vascular smooth muscle responsiveness to NO, a mechanism that might play a role in the increased prevalence of hypertension and its complications in blacks.

	Selected Abbreviations and Acronyms

 

FBF = forearm blood flow L-NMMA = NG-monomethyl-L-arginine NO = nitric oxide SNP = sodium nitroprusside

Received November 4, 1997; first decision December 12, 1997; accepted February 2, 1998.

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