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(Hypertension. 1997;30:157-162.)
© 1997 American Heart Association, Inc.

Articles

Blunted Blood Pressure Response to Central Sympathoinhibition in Normotensive Blacks

Increased Importance of Nonsympathetic Factors in Blood Pressure Maintenance in Blacks

Chim C. Lang; C. Michael Stein; Huai B. He; Frank J. Belas; Ian A. Blair; Margaret Wood; ; Alastair J. J. Wood

From the Departments of Pharmacology and Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.

	Abstract

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Abstract Enhanced sympathetic reactivity may predispose blacks to the development of hypertension and may occur because of increased sympathetic stimulation and/or attenuated sympathoinhibition. A potential site for such attenuated sympathetic inhibition may be at the level of central ₂-adrenergic receptors, which play an important role in the feedback inhibition of norepinephrine release. We used cumulative doses (1, 2, and 3 µg/kg IV) of the centrally acting ₂-adrenergic agonist clonidine to measure the sensitivity of ₂-adrenoceptor–mediated sympathoinhibition and the resultant hypotensive response in 8 normotensive blacks and 10 normotensive whites. Sympathetic activity was determined by radioisotope dilution methodology. Basal norepinephrine spillover was similar in blacks (0.80±0.14 µg/min) and whites (0.73±0.19 µg/min, P=NS) and after clonidine decreased significantly in both blacks (0.21±0.07 µg/min, P<.0001) and whites (0.24±0.06 µg/min, P<.0001), with no difference between the groups (P=NS). Despite this similar degree of sympathoinhibition, the hypotensive response to clonidine was markedly blunted in blacks, such that mean arterial pressure decreased by only 10% in blacks but by 21% in whites (P<.0001). The smaller blood pressure decrement after clonidine in normotensive blacks, in the face of an equal degree of sympathoinhibition, suggests that even when sympathetic tone is decreased to the same level in blacks and whites, normotensive blacks have less reduction in blood pressure than whites, implying that nonadrenergic mechanisms contribute more to blood pressure maintenance in blacks than whites. Whether a similar interethnic difference in response to sympathoinhibition occurs in hypertensive patients is as yet unknown.

Key Words: receptors, adrenergic, alpha • blacks • clonidine • norepinephrine

	Introduction

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The incidence and severity of essential hypertension vary by race and geography. In the United States, the prevalence of essential hypertension is greater at all ages after young adulthood in blacks^{1 2} and is associated with greater morbidity and mortality.³ A variety of genetic and environmental factors have been proposed to account for the racial differences in the prevalence and severity of hypertension.^{4 5 6} Adolescent and young adult American blacks have been shown to have greater blood pressure responses to certain laboratory stressors than age-matched American whites.^{7 8 9 10 11} This heightened blood pressure response generally occurs in conjunction with an increase in total peripheral vascular resistance that is unaccompanied by a change in cardiac output.^{10 11} Enhanced vascular reactivity in blacks, perhaps coupled with higher levels of environmental stress, may result in sustained increases in peripheral vascular resistance and consequently elevation of blood pressure.^{12 13} The mechanism of this enhanced vascular reactivity in blacks has not been defined.

Recording muscle sympathetic nerve activity, Calhoun et al¹⁴ have shown that the sympathetic nerve activity and blood pressure response to the cold pressor test increased more in normotensive blacks than whites and suggested that the greater blood pressure response to stress is mediated through an exaggerated sympathetic response. The underlying mechanism responsible for this response in blacks remains unknown.

Within the central nervous system, a role in the regulation of cardiovascular function and sympathetic outflow has been ascribed to a number of noradrenergic cell groups located in the subcortical areas of the brain and include the A6 (locus ceruleus), A5, and A2 nuclei.^{15 16} These nuclei, which are reported to function abnormally in animal models of hypertension,¹⁷ are regulated by a stream of afferent neural signals¹⁸ and also by local feedback mechanisms.¹⁷ With respect to the latter, ₂-adrenoceptors are found in abundance in the central nervous system^{19 20} and also on the peripheral presynaptic nerve terminal^{20 21} where they play an important role in local feedback inhibition of norepinephrine release. Exaggerated sympathetic activation seen in blacks may reflect altered regulation by this control system with attenuation of central ₂-adrenergic feedback inhibition.

Most previous studies examining adrenergic mechanisms in different ethnic groups have focused on ß-adrenergic receptors, in which increased heart rate responses to ß₁-adrenergic stimulation have been reported in normotensive blacks²² although a blunted ß₂-adrenergic vasodilation has been described in normotensive blacks.^{23 24} In addition to differences in ß-adrenergic sensitivity, ethnic differences in ß-adrenergic receptor density have been reported, with similar,²⁵ lower,²⁶ and higher²⁷ ß-adrenergic receptor density being reported in normotensive blacks compared with whites. Ethnic differences in -adrenergic receptors have been studied less. Increased blood pressure responses to the systemic infusion of both norepinephrine²⁸ and phenylephrine²⁹ have been described in blacks, although the response in the superficial dorsal hand vein to local infusion of phenylephrine is blunted in normotensive blacks.³⁰ Despite the importance of central ₂-adrenergic receptors in regulating sympathetic tone, their responsiveness in blacks has not been studied.

Blood pressure response and sympathetic activity are interrelated. Thus, a decreased central ₂-adrenergic sympathoinhibition, or an attenuated blood pressure decrement to sympathetic withdrawal, may contribute to the enhanced vascular reactivity in blacks. Conversely, by suppressing sympathetic tone to the same extent in blacks and whites and comparing the reduction in blood pressure, it is possible to define the relative contribution of the sympathetic and nonsympathetic mechanisms to the maintenance of blood pressure in the two racial groups. We have therefore compared the sensitivity of the central ₂-adrenergic sympathoinhibitory response and the hypotensive response with the resultant decrease in sympathetic activity in normotensive black and white subjects.

	Methods

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Study Population
Eighteen healthy, nonsmoking, normotensive male volunteers provided written informed consent to participate in the study, which was approved by the Vanderbilt University Committee for the Protection of Human Subjects. The procedures followed in this study were in accordance with the guidelines of the Vanderbilt University Committee for the Protection of Human Subjects. No subject had clinically significant abnormalities on history, physical examination, or hematologic and biochemical laboratory testing. Ten subjects were American whites (mean age, 29.8±3.3 [SEM] years) and 8 were American blacks (26.1±2.0 years). Five of the white subjects also served as control subjects in a study that has been previously reported in abstract form³¹ and has been submitted for publication. Race was determined by self-report. Three of the black and 5 of the white subjects were university/college students, and all remaining subjects were employed full time. One black and no white subject reported a family history of hypertension in a first-degree relative. Subjects did not take any medications for at least 2 weeks before the study.

Experimental Protocol
All studies were performed in the morning after subjects had fasted and rested supine overnight in the Vanderbilt University Clinical Research Center. Throughout the study, subjects remained resting in the supine position. An intravenous cannula was placed in the antecubital fossa in each arm for subsequent blood sampling and intravenous infusion ([³H]norepinephrine) and drugs. Sixty minutes after placement of these cannulas, an intravenous infusion of 70.1 Ci/mmol [³H]norepinephrine (norepinephrine levo-[ring-2,5,6-³H], New England Nuclear) in normal saline was administered into the nondominant arm. An initial loading dose of 25 µCi [³H]norepinephrine was administered over 2 minutes, followed by a constant infusion of 0.9 µCi/min [³H]norepinephrine, an infusion regimen that we have shown to achieve constant plasma concentrations of [³H]norepinephrine within 30 minutes.³² The [³H]norepinephrine was prepared for human administration by the Vanderbilt Hospital Radiopharmacy, and appropriate sterility and pyrogen testing was performed. It was reconstituted in normal saline containing 1 mg/mL ascorbic acid immediately before use.

Venous blood samples were drawn for determination of plasma norepinephrine and [³H]norepinephrine after 50 and 60 minutes of the [³H]norepinephrine infusion. Blood pressure and heart rate were measured at the same time by a semiautomatic sphygmomanometer (Dinamap 1846, Critikon, Inc). Sixty, 90, and 120 minutes later, subjects received three 10-minute infusions of the vehicle (normal saline, Volume (mL)=Body Weight (kg)÷3), followed at 150, 180, and 210 minutes by cumulative doses of 1, 2, and 3 µg/kg clonidine (Catapres, Boehringer Ingelheim Pharmaceuticals) administered by slow intravenous infusion over 10 minutes. The infusions were administered in a single-blind fashion. Venous blood was drawn, and hemodynamic recordings were made 30 minutes after each infusion.

Blood Collection and Analysis
Blood was collected into cooled tubes with EGTA and reduced glutathione (Amersham Corp), which were placed on ice and centrifuged at 3000 rpm at 4°C. The plasma was stored at -20°C until assayed in duplicate. Samples of the [³H]norepinephrine infusate were also collected, stored, and later assayed in quadruplicate, as described for the blood samples, to allow determination of the actual rate of [³H]norepinephrine infusion. During the clonidine infusion period, plasma was also collected for determination of clonidine concentrations.

Norepinephrine concentrations were measured by high-performance liquid chromatography (HPLC) using electrochemical detection with dihydroxybenzylamine as the internal standard as we have previously described.³² All plasma samples for each subject were assayed in the same assay performed in duplicate. The HPLC effluent coinciding with the norepinephrine peak was collected and counted in a liquid scintillation counter. This allowed determination of plasma [³H]norepinephrine concentration without interference from tritiated metabolites. The intraday and interday coefficients of variation were 7.8% and 7.6%, respectively.

Plasma clonidine concentrations were determined by a modification of a previously described gas chromatography–electron capture negative chemical ionization–mass spectrophotometric method (GC-ECNCI/MS).³³ The assay was linear over a range of 173 to 3457 pg/mL. Standard curve correlation coefficients of .99 or better were obtained throughout the validation. The intra-assay and interassay precisions were within 8.5% relative to the SD for quality control samples in the lower, middle, and upper control portions of the standard curve.

Determination of Norepinephrine Kinetics
Norepinephrine kinetics were determined as described by Esler et al.³⁴ Norepinephrine plasma clearance was determined as follows: Norepinephrine Clearance=[³H]Norepinephrine Infusion Rate÷V*, where V* is the venous concentration of [³H]norepinephrine. The rate at which norepinephrine entered plasma (norepinephrine spillover) was determined as follows: Norepinephrine Spillover=Norepinephrine ClearancexV, where V is the venous concentration of endogenous norepinephrine.

Data Analysis
The mean of all hemodynamic and norepinephrine kinetic values obtained after 50 and 60 minutes of the [³H]norepinephrine infusion was used as the mean baseline value, and the mean of values obtained after 90, 120, and 150 minutes of vehicle infusion was taken as the preclonidine value. Statistical analyses were performed using repeated measures ANOVA, unpaired t test, and Fisher's exact test (SPSS for Windows Release 6, SPSS Inc). All data are expressed as mean±SEM. A two-tailed value of P<.05 was the criterion for statistical significance.

	Results

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Table 1 summarizes the demographic and baseline hemodynamic data and norepinephrine kinetics of the two groups. There were no significant baseline differences between the two groups.

View this table: [in this window] [in a new window]   Table 1. Demographic Characteristics, Baseline Hemodynamic Parameters, and Norepinephrine Kinetics of Study Subjects

[³H]Norepinephrine Kinetics and Clonidine in Blacks and Whites
Increasing doses of clonidine resulted in a dose-dependent decrease in norepinephrine spillover in both blacks and whites, with no difference between the two groups (Table 2, Figure). The decrease in venous plasma norepinephrine concentration was also similar in blacks and whites (Table 2). Clonidine decreased norepinephrine clearance in both blacks and whites, with no significant difference between the two groups (Table 2).

View this table: [in this window] [in a new window]   Table 2. Plasma Concentrations of Clonidine, Hemodynamic Measurements, and Norepinephrine Kinetics During Cumulative Doses of Intravenous Clonidine In Blacks and Whites

View larger version (12K): [in this window] [in a new window]   Figure 1. Norepinephrine (NE) spillover (left) and mean blood pressure (MAP, right) responses to clonidine in normotensive blacks and whites. Results are mean±SEM. Horizontal arrows indicate timing of either saline (dashed arrows) or clonidine infusion of 1 µg/kg (solid arrows).

Hemodynamic Responses to Clonidine in Blacks and Whites
The blood pressure fall in response to clonidine was markedly blunted in blacks. Mean arterial pressure decreased by 21% in whites but by only 10% in blacks (Table 1, Figure; P<.0001, blacks versus whites). Clonidine did not alter heart rate in either group.

Plasma Clonidine Concentrations
Plasma clonidine concentrations achieved after the clonidine infusions were similar in blacks and whites (Table 2).

	Discussion

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Normotensive blacks manifest greater stress-induced increases in blood pressure^{7 8 9 10 11} and muscle sympathetic activity¹⁴ than normotensive whites, suggesting that enhanced sympathetic reactivity may predispose blacks to the development of hypertension. Such enhanced sympathetic activation in blacks may occur because of increased sympathetic stimulation, attenuated sympathoinhibition, or both. A potential site for such attenuated sympathetic inhibition may be at the level of ₂-adrenergic receptors, which are found in abundance in the central nervous system,^{19 20} where they play an important role in feedback inhibition of norepinephrine release. The purpose of the present study was first to determine whether there was an interethnic difference in sensitivity to ₂-adrenergic receptor–mediated sympathoinhibition and second to determine whether the hypotensive response resulting from such sympathoinhibition differed in blacks and whites. Since clonidine has actions on peripheral presynaptic ₂-adrenergic receptors,^{20 21} it has previously been suggested that clonidine influences sympathetic outflow by a combination of central and peripheral effects.³⁵ However, Kooner and colleagues³⁶ have shown that clonidine when administered to tetraplegic patients did not alter blood pressure or sympathetic activity, indicating that clonidine exerts its major effects centrally. Thus, the sympatholytic and hypotensive effects of clonidine are almost exclusively mediated through central mechanisms, therefore providing a useful pharmacological tool for examination of central ₂-adrenergic sensitivity in humans.^{31 36} Second, because clonidine reduced sympathetic tone to a similar extent in the two groups, the contribution of sympathetic and nonsympathetic factors to the maintenance of blood pressure in the two ethnic groups could also be demonstrated.

Both groups had a similar sympathoinhibitory response, with a reduction in norepinephrine spillover to a similar level. However, despite this similar degree of sympathoinhibition, the hypotensive response to this degree of sympathoinhibition was markedly blunted in blacks. To exclude the possibility that higher plasma clonidine concentrations in whites accounted for the greater hypotensive response in that group, plasma clonidine concentrations were measured by mass spectrometry. No ethnic difference was seen. Thus, our data demonstrate that blood pressure in normotensive blacks is less responsive to sympathoinhibition than that in whites.

There are several possible explanations for this. Blacks, because of increased vascular sympathetic reactivity, may require a greater reduction in norepinephrine release to produce the same reduction in blood pressure. An alternative explanation is that sympathetic tone contributes less to blood pressure maintenance in blacks than whites.

Normotensive blacks have previously been shown to have an exaggerated sympathetic reactivity to stressors that may be manifested by an increase in both sympathetic nerve activity and vascular response. Muscle sympathetic nerve activity¹⁴ does not differ between blacks and whites in the resting state, in agreement with the findings of the present study, which demonstrated no difference between blacks and whites in resting norepinephrine spillover and norepinephrine clearance. It should be noted that Ziegler et al³⁷ previously demonstrated decreased norepinephrine clearance in resting blacks. Of greater interest is the increased sympathetic activity in response to stress in blacks. During the cold pressor test, muscle sympathetic activity was much higher in normotensive blacks,¹⁴ suggesting that the increased sympathetic vascular reactivity may be due to this increased muscle sympathetic nerve activity in response to stress. Besides this possibility, an increased sympathetic vascular reactivity may also be mediated by an increase in vascular -adrenergic sensitivity, for which there is some supportive data. An increased pressor sensitivity to both systemically infused norepinephrine²⁸ (a mixed ₁- and ₂-agonist) and phenylephrine²⁹ has been reported in blacks compared with whites, although the ethnic difference in response to norepinephrine was observed only after salt loading.²⁸ The role of such differences in contributing to our findings is unclear.

A more likely explanation for our observation is that removal or reduction of sympathetic activity unmasks the increased role of other nonadrenergic factors responsible for maintaining blood pressure in blacks so that when sympathetic tone is reduced substantially, and to the same extent, in blacks and whites, the greater role of nonadrenergic mechanisms in blood pressure maintenance in blacks becomes apparent. This greater role of nonadrenergic mechanisms in maintaining blood pressure in blacks has previously been suggested from interethnic differences in response to antihypertensive drugs.^{6 38} The majority of controlled trials show that blacks respond less well to monotherapy with ß-blockers, whereas blacks and whites respond equally to calcium channel blockers and diuretics.^{39 40 41} In the Veterans Affairs Cooperative Study,⁴¹ the blood pressure reduction with the ß-blocker atenolol and the ₁-adrenergic antagonist prazosin was less in blacks than whites. In contrast, black and white hypertensive subjects have generally been thought to respond equally well to centrally acting sympatholytic drugs such as clonidine.³⁹ However, in patients older than 60 years, close examination of comparative data with clonidine shows a response rate of 45% in blacks compared with 58% in whites. In patients younger than 60 years, the difference in response rate was smaller, with 45% of blacks and 50% of whites responding. However, the mean reduction in blood pressure to clonidine was 23% less in the younger black group than in the younger whites.⁴¹ These findings, together with our findings, would suggest that blood pressure is maintained less by the sympathetic nervous system in blacks and therefore drugs that target the sympathetic nervous system may be less effective in blacks.

Other possible explanations for our findings include possible ethnic differences in vascular structure so that blacks may have impaired vasodilator capacity to all vasodilator stimuli, including sympathetic withdrawal. In this regard, normotensive blacks have been shown to have reduced maximal forearm vasodilation to ischemic exercise,⁴² which is determined in part by the structural characteristic of the precapillary resistance vessels but also by the complex mechanisms producing reactive hyperemia, including mediators such as prostaglandins and adenosine.⁴³ The specific effects on vascular responsiveness to these and other mediators in blacks will need to be examined in further studies. A second consideration might involve ethnic differences in baroreceptor reflex sensitivity to the reduction in blood pressure, although this would have been accompanied by an altered sympathoinhibitory response in blacks that we did not see. Moreover, a recent study found no evidence of altered baroreceptor function in blacks.⁴⁴ Third, it is possible that greater stress-induced increases in smooth muscle cell hypertrophy in normotensive blacks may lead to greater increases in peripheral resistance and consequently greater sustained increases in blood pressure in blacks. A final consideration is that intravenous administration of clonidine will have direct effects on vascular postsynaptic ₂-adrenergic receptors that mediate vasoconstriction.⁴⁵ Thus, an increased sensitivity of postsynaptic vascular ₂-adrenergic receptors to clonidine in blacks will lead to a smaller fall in blood pressure after clonidine infusion. However, since central ₂-adrenergic–mediated sympathoinhibition was similar in blacks and whites, it raises the unlikely possibility that ethnic differences in ₂-adrenoceptor sensitivity differ depending on the site of these receptors.

A limitation of this study is that the use of the [³H]norepinephrine dilution methodology, although a reliable and widely used technique that is sensitive to changes in sympathetic activity in disease states and during physiological or pharmacological manipulation,^{24 32 34} allows only an indirect measure of neuronal norepinephrine release.

In conclusion, we have shown that the blood pressure decrement after clonidine is markedly blunted in normotensive blacks compared with whites. The smaller blood pressure decrement after clonidine in normotensive blacks, in the face of an equal degree of sympathoinhibition, suggests that even when sympathetic tone is decreased to the same level in blacks and whites, normotensive blacks still have less reduction in blood pressure than whites. Further studies will be required to extend the present findings in normotensive blacks to hypertensive subjects.

	Acknowledgments

 
This work was supported in part by grants from the American Heart Association and US Public Health Service grants HL 56251 and GM 5MO1-RR00095. C.C. Lang was a recipient of a Merck International Fellowship in Clinical Pharmacology Award. C.M. Stein was a recipient of a Faculty Development Award in Clinical Pharmacology from the Pharmaceutical Manufacturers' of America Foundation.

	Footnotes

 
Reprint requests to Dr Alastair J.J. Wood, Division of Clinical Pharmacology, Room 552, Medical Research Building I, Vanderbilt University School of Medicine, Nashville, TN 37232-6602.

Received August 28, 1996; first decision September 19, 1996; accepted January 21, 1997.

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