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(Hypertension. 2001;37:46.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Interactive Effect of Ethnicity and ACE Insertion/Deletion Polymorphism on Vascular Reactivity

James V. Gainer; C. Michael Stein; Tami Neal; Douglas E. Vaughan; Nancy J. Brown

From the Divisions of Clinical Pharmacology and Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tenn.

Correspondence to James V. Gainer, M.D., 422 Medical Research Building-II, Vanderbilt University Medical Center, Nashville, TN 37232-6602. E-mail jay.gainer{at}mcmail.vanderbilt.edu

	Abstract

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Abstract—Bradykinin is a potent endothelium-dependent vasodilator that contributes to the blood pressure lowering effect of angiotensin-converting enzyme inhibition. Angiotensin-converting enzyme inhibitors are widely prescribed for the treatment of hypertension, although the efficacy of this therapy has been reported to vary among different ethnic groups. To determine whether vascular sensitivity to bradykinin is decreased in blacks compared with whites, we measured forearm blood flow with venous plethysmography in response to intraarterially-administered bradykinin (100, 200, and 400 ng/min) under salt-controlled conditions in 28 (14 black, 14 white) normotensive subjects genotyped for the ACE insertion/deletion (I/D) polymorphism. Acetylcholine (ACh) (15, 30, and 60 µg/min) and sodium nitroprusside (SNP) (0.8, 1.6, and 3.2 µg/min) were infused as endothelium-dependent and endothelium-independent controls. Compared with whites, blacks exhibited a blunted vasodilator response to bradykinin (maximal blood flow: 20.4±2.5 versus 10.9±1.4 mL · 100 mL^-1 · min^-1, P=0.004) and SNP (14.1±1.6 versus 9.9±1.7 mL · 100 mL^-1 · min^-1, P=0.05) but not to ACh (10.5±2.8 versus 6.6±1.0 mL · 100 mL^-1 · min^-1, P=0.21). White subjects who carried at least 1 ACE D allele demonstrated significantly greater vasodilator responses to bradykinin compared with those homozygous for the I allele (DD or ID versus II, F=5.6, P<0.04). In contrast, only blacks homozygous for the ACE D allele had a significantly greater vasodilator response to bradykinin than those who carried the I allele (DD versus ID or II, F=8.3, P=0.01). The ethnic difference was most pronounced in subjects heterozygous at the ACE I/D locus in which blacks had a markedly attenuated response to bradykinin compared with whites (F=41.0, P<0.001). There was no effect of ACE I/D genotype on the vasodilator responses to SNP or ACh in either ethnic group. These data confirm that vascular reactivity to bradykinin and the endothelium-independent vasodilator SNP is decreased in normotensive blacks compared with whites, consistent with attenuated vascular smooth muscle reactivity. The data suggest that genetic variation at the ACE gene locus interacts with ethnicity to impact the vascular response to bradykinin.

Key Words: bradykinin • ethnicity • genetics • peptidyl-dipeptidase A • vasodilation

	Introduction

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The prevalence of essential hypertension, congestive heart failure, and diabetic nephropathy is greater in black Americans than in white Americans.^{1 2 3} Ethnic differences in the kallikrein-kinin system may contribute to the increased prevalence of hypertension in blacks compared with whites. Bradykinin is a potent endogenous endothelium-dependent vasodilator that exhibits cardioprotective properties⁴ and contributes to the effect of angiotensin-converting enzyme (ACE) inhibition in humans⁵ and animals.^{6 7 8} Decreased production of bradykinin, or decreased vasodilation in response to bradykinin, could play a role not only in the pathogenesis of hypertension,⁴ but also in the decreased antihypertensive response to ACE inhibition in blacks.¹

Several lines of evidence suggest that endogenous bradykinin levels are decreased in hypertension, especially in blacks.^{9 10} Compared with whites, hypertensive blacks have lower excretion of urinary kallikrein,⁹ an index of activity of the kallikrein-kinin system.⁴ Decreased levels of endogenous bradykinin would be expected to result in upregulation of its major receptor^{11 12 13} and increased sensitivity to exogenous bradykinin. Compatible with this hypothesis, blacks exhibit a greater wheal response to intradermally-administered bradykinin than do whites.¹⁰ However, blacks have been shown to be less sensitive to the effects of a variety of endothelium-dependent and independent vasodilators.^{14 15 16} Whereas decreased endogenous bradykinin might be expected to cause increased sensitivity to exogenous bradykinin, a generalized decrease in vascular smooth muscle relaxation in blacks would be expected to result in an attenuated vasodilator response to bradykinin as occurs with other vasodilators. The effect of ethnicity on the vasodilator response to bradykinin is not known.

One possible factor which could modulate the effect of ethnicity on the response to bradykinin is genetic variation in ACE, the predominant enzyme for bradykinin metabolism in humans.⁴ ACE levels in plasma and in tissue reflect a variety of environmental and genetic factors, including the presence of an insertion/deletion (I/D) polymorphism in the ACE gene.¹⁷ The ACE D allele has been associated with increased conversion of angiotensin I to angiotensin II¹⁸ and increased degradation of bradykinin¹⁹ in predominantly white populations. However, studies suggest that ethnicity affects both ACE I/D allele frequency²⁰ and the relationship between ACE I/D genotype and serum ACE concentration.^{21 22} Therefore, the present study was designed to determine vascular sensitivity to bradykinin in the forearm circulation in normotensive blacks compared with whites under salt-controlled conditions while controlling for variation at the ACE gene locus.

	Methods

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Subjects
Thirty normotensive subjects, ages 20 to 53 years, participated in this study and underwent a complete history, physical, and laboratory examination. Subjects were defined as normotensive if they had a seated systolic blood pressure less than 140 mm Hg, diastolic blood pressure less than 90 mm Hg on at least 3 occasions before the period of study, and no history of prior treatment for hypertension. Subjects with any disease or who weighed >25% of ideal body weight were excluded, as were pregnant women. None of the subjects was taking medications or dietary supplements at the time of study. The protocol was approved by the Vanderbilt Institutional Review Board, and the study was conducted according to the Declaration of Helsinki.

Experimental Protocol
Each subject was studied under salt-replete (185 mmol sodium/d) conditions. Sodium-controlled, xanthine-free diets containing 70 mmol potassium and 2500 mL water per day were provided by the Vanderbilt General Clinical Research Center (GCRC) for 6 days. On the fifth day of each diet period, subjects collected a 24-hour urine sample for measurement of sodium and creatinine to document dietary compliance. On the sixth diet day, they reported to the GCRC early in the morning after an overnight fast. Blood for plasma renin activity (PRA) and plasma aldosterone was drawn through an indwelling venous catheter after 30 minutes of ambulation. To determine the intra-individual effect of dietary salt intake on vascular sensitivity, a subset of 12 subjects was studied under both salt-deplete (10 mmol sodium/d) and salt-replete conditions with a randomized, crossover design.

Measurement of Forearm Blood Flow
Forearm blood flow (FBF) was measured with the use of methods previously described.²³ FBF measurements were made without knowledge of a subject’s ACE I/D genotype.

Study Drugs
Bradykinin (Calbiochem: 100, 200, and 400 ng/min), acetylcholine (Ach) (Miochol-E,: 15, 30, and 60 µg/min), and sodium nitroprusside (SNP) (Gensia Sicor Pharmaceuticals: 0.8, 1.6, and 3.2 µg/min) were infused in single-blind, randomized order after a 30-minute rest period and measurement of basal blood flow. SNP and ACh were used as endothelium-independent and endothelium-dependent controls, respectively. Drug concentrations in the infusate were adjusted to maintain infusion volumes at 1 mL/min. Doses of the vasodilators were chosen with the intent of achieving comparable levels of vasodilation based on previously published studies of whites and blacks.^{14 24} Each dose was infused for 5 minutes, and FBF was measured during the last 2 minutes of the infusion.

Laboratory Analysis
Blood samples were collected on ice and centrifuged immediately. Plasma was stored at -70°C until the time of assay. PRA was measured by radioimmunoassay for angiotensin I at 37°C and pH 7.4, and aldosterone was measured by radioimmunoassay (Coatacount, Products Corp). Urine sodium and creatinine were measured by flame photometry. ACE genotype was determined according to published methods by Rigat et al.¹⁷ Because of the preferential amplification of the ACE D allele with the use of this protocol, DNA samples typed homozygous for the D allele were confirmed by an insertion-allele-specific procedure.²⁵

Statistical Analysis
Data are presented as mean values ± standard error of the mean. Comparisons between ethnic and ACE genotype groups were made by ANOVA with repeated measures in which within-subject variables were vasodilator, dose increment, and salt condition (either salt-deplete or salt-replete) and between-subject variables were ethnicity and ACE genotype. Factors such as age, gender, body mass index, cholesterol, and serum potassium having the potential to affect FBF were assessed in a multivariate analysis. All probability values are 2-sided with a criterion of P0.05 for statistical significance.

	Results

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Baseline Characteristics
In a pilot study, 12 subjects (6 blacks, 6 whites) were studied under both salt-deplete and salt-replete conditions. Forearm vasodilation was not significantly different between salt-deplete and salt-replete states within subjects for each vasodilator (SNP: F=0.02, P=N.S.; ACh: F=0.8, P=N.S.; bradykinin: F= 0.1, P=N.S.; df =1,11 for each). Nor was there an effect of dietary salt when the analysis was repeated within an ethnic group (data not shown). Of the 30 subjects who were studied under salt-replete conditions, 2 subjects were excluded because of dietary noncompliance.

Clinical characteristics of the subjects (14 blacks, 14 whites) are shown in the Table. There were no significant differences in age, body mass index, gender, plasma glucose, or creatinine between ethnic groups or among ACE genotype groups. Serum potassium and cholesterol were significantly greater in the white subjects than in the black subjects. Baseline FBF, heart rate, mean arterial pressure, and 24-hour urinary sodium, potassium excretion, and plasma aldosterone were similar between blacks and whites. Forearm vascular resistance tended to be increased in blacks, but this difference did not reach significance. PRA was greater in whites compared with blacks (P=0.004).

View this table: [in this window] [in a new window]   Table 1. Baseline Subject Characteristics

Vascular Response to SNP, ACh, and Bradykinin
Figure 1 illustrates the FBF response to SNP, ACh, and bradykinin. None of the vasodilators had an effect on systemic blood pressure or heart rate. All 3 vasodilators produced dose-dependent increases in FBF (SNP: F=60.6, P<0.001; ACh: F=13.2, P<0.001; bradykinin: F=44.7, P<0.001; df=3,81 for each). Comparing the FBF response to each vasodilator within an ethnic group, the response to bradykinin was significantly greater than that to SNP (F=13.5, P=0.003; df=3,39) and ACh (F=13.8, P=0.003; df=3,39) in whites, whereas FBF responses between SNP and ACh were similar (F=2.9, P=0.1; df=3,39). In blacks, the FBF response to bradykinin was comparable to that of SNP (F=1.2, P=0.3; df=3,39) but greater than that to ACh (F=12.5, P=0.004; df=3,39), and the FBF response to SNP was also greater than that to ACh (F=7.4, P<0.02; df=3,39).

View larger version (17K): [in this window] [in a new window]   Figure 1. Vasodilator responses to SNP, ACh, and bradykinin in blacks and whites.

Ethnicity and Vascular Reactivity
The vasodilator responses to SNP (F=4.1, P=0.05; df=1,26) and bradykinin (F=10.2, P=0.004; df=1,26) but not ACh (F=1.6, P=0.21; df=1,26) were significantly attenuated in blacks compared with whites. There was no effect of age, body mass index, gender, cholesterol, or serum potassium on FBF. There was no correlation between PRA and baseline FBF or vascular response to the 3 vasodilators.

ACE I/D Polymorphism and Vascular Reactivity
Figure 2 summarizes the effect of the ACE genotype on FBF in response to bradykinin for each ethnic group. The distribution of ACE I/D genotypes was similar in each group (white: II (n=2), ID (n=8), DD (n=3); black: II (n=4), ID (n=7), DD (n=3); X²=0.7, P=N.S.). Genomic DNA was unavailable for 1 white male. The ACE genotype had no effect on baseline FBF. In contrast, ACE genotype interacted with ethnicity to affect the FBF response to bradykinin (F=4.1, P=0.03; df=2,21). The forearm vasodilator response to bradykinin was significantly greater in white subjects who carried the ACE D allele compared with those homozygous for the ACE I allele (DD or ID versus II: F=5.6, P<0.04; df=1,11). There was a relationship between ACE genotype and the FBF response to bradykinin in blacks, such that those who were homozygous for the ACE D allele had greater bradykinin-induced blood flow than those who carried the I allele (DD versus ID or II: F=8.3, P=0.01; df=1,12). The ethnic difference in the vasodilator response to bradykinin was most pronounced in subjects heterozygous at the ACE I/D locus (F=41.0, P<0.001; df=1,13). There was no effect of ACE I/D genotype on the FBF responses to SNP or ACh in either ethnic group (data not shown).

View larger version (21K): [in this window] [in a new window]   Figure 2. Effect of the ACE I/D polymorphism on the vasodilator response to bradykinin in blacks and whites.

Because of the limited number of subjects in each ethnic-ACE genotype group in this prospective study, we retrospectively examined the interactive effect of ethnicity and ACE genotype in all subjects who had previously undergone intra-arterial bradykinin infusion under the same conditions. Data from 21 whites (5 II, 11 ID, 5 DD) and 15 blacks (4 II, 7 ID, 4 DD) were analyzed. There were no differences in the baseline characteristics for these subjects compared with those reported by ethnic group for the prospective study in the Table (data not shown). The FBF responses to bradykinin according to ACE genotype for all subjects who completed the bradykinin blood flow protocol were similar to those shown in Figure 2. As in the prospectively studied subjects, there was an interactive effect between ACE genotype and ethnicity (F=4.4, P=0.02; df=2,30) on the vasodilator response to bradykinin. Again the forearm blood flow response to bradykinin was greater in whites who carried a D allele compared with those who were homozygous for the I allele (DD or ID versus II: F=6.3, P=0.02; df=1,19). Blacks who were homozygous for the ACE D allele had greater bradykinin-induced blood flow than those who carried the I allele (DD versus ID or II: F=11.9, P=0.004; df=1,13).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Bradykinin is an endothelium-dependent vasodilator that contributes to the antihypertensive effects of ACE inhibitors⁵ and plays a role in the regulation of blood pressure.^{4 5 6 7 8} Previous studies have suggested that endogenous bradykinin is decreased in blacks⁹ and that, consequently, the response to exogenous bradykinin may be increased in certain tissues.¹⁰ The present study examines the effect of ethnicity on the vascular sensitivity to bradykinin. The results indicate that vascular responsiveness to bradykinin is decreased in normotensive blacks compared with whites. To the extent that the vasodilator response to SNP is also diminished, these findings reflect a generalized attenuation in nitric oxide-mediated smooth muscle relaxation in blacks compared with whites, rather than a specific effect of ethnicity on the response to bradykinin.

The findings of the present study are consistent with other studies that have reported an attenuated vasodilator response to agonists that produce vascular smooth muscle relaxation through either cGMP- or cAMP-dependent pathways in normotensive blacks compared with whites.^{14 15 16} In separate studies, Stein et al,¹⁴ Lang et al,¹⁵ and Cardillo et al¹⁶ have reported attenuated vasodilation in normotensive blacks compared with whites in response to a variety of vasodilators, including isoproterenol, SNP, methacholine, and ACh.^{14 15 16} The results of these studies and the present study may help to explain the increased prevalence of hypertension and its complications in blacks. In particular, decreased sensitivity to bradykinin may contribute to the development of salt-sensitivity in blacks.²⁶ Decreased sensitivity to bradykinin may also contribute to the decreased efficacy of ACE inhibitors in blacks. On the other hand, the present data were obtained in healthy normotensive volunteers and should not be generalized to hypertensive populations. Studies of forearm vasodilator responses in hypertensive blacks have not been reported, whereas hypertensive whites exhibit endothelial dysfunction. Further studies are needed to assess endothelium-dependent and independent function in hypertensive blacks.

In the current study, the ethnic difference in the vasodilator response to ACh, in contrast to previously reported data,¹⁶ did not reach statistical significance. The reason for this may have related to the fact that the magnitude of the ACh-induced increase in FBF in whites in the present study was attenuated compared with that reported previously by Panza et al²⁴ and compared with the vasodilator response to either bradykinin or SNP. A possible explanation for the differential effect of ethnicity on the vasodilator responses to the 2 endothelium-dependent vasodilators ACh and bradykinin, and for the diminished response to ACh per se in the white subjects, relates to the relatively higher serum cholesterol concentration in these subjects.^{27 28 29} Previous studies in humans suggest that in early dyslipidemia, the vasodilator response to agonists acting through a G_i protein-dependent pathway (such as ACh) is blunted, whereas the response to other endothelium-dependent agonists (including bradykinin) is preserved.²⁸ Thus, the higher, albeit normal, serum cholesterol in the white subjects compared with the black subjects studied may have obscured an ethnic difference in the vasodilator response to ACh.²⁹

A novel finding in the current study involves the effect of the ACE genotype on FBF in response to bradykinin. ACE is the predominant enzyme for bradykinin metabolism in humans.⁴ The ACE D allele has been associated with higher serum ACE levels¹⁷ and increased conversion of angiotensin I to angiotensin II¹⁸ in white populations. In addition, the ACE D allele has been associated with increased degradation of bradykinin.¹⁹ Individuals who carry the ACE D allele might be expected to have a decreased response to exogenous bradykinin because of accelerated degradation. Conversely, diminished endogenous bradykinin concentrations in these individuals might result in receptor upregulation and enhanced responsiveness to exogenous bradykinin. Consistent with the hypothesis that increased sensitivity to exogenous bradykinin occurs in the setting of reduced endogenous concentrations, we found that white subjects who carried the ACE D allele had significantly greater forearm vasodilator responses to exogenous bradykinin compared with those homozygous for the ACE I allele.

Previous studies suggest that ethnicity modulates the relationship between the ACE I/D genotype and serum ACE activity.^{21 30 31} For example, Bloem et al²¹ confirmed the relationship between the number of ACE D alleles and increasing serum ACE activity in whites but found no correlation between the ACE I/D genotype and serum ACE in blacks. In contrast, Forrester et al reported a relationship between the ACE I/D polymorphism and serum ACE in individuals of African descent,²² similar to that previously reported in whites.¹⁷ Segregation-linkage studies done in both white³⁰ and African Caribbean³¹ populations suggest that 2 genetic loci control ACE levels and that the interaction between these loci differs in the 2 ethnic groups. In the present study, bradykinin-induced forearm vasodilation was greater in black subjects homozygous for the ACE D allele compared with those who carried the ACE I allele. However, a striking effect of ethnicity was observed when comparing subjects heterozygous at the ACE locus such that the FBF response to bradykinin was markedly decreased in black subjects compared with white subjects. These data support the hypothesis that the relationship between the ACE I/D polymorphism and the response to bradykinin differs in blacks and whites.

Other studies are inconsistent as to an effect of the ACE polymorphism in the FBF response to other vasodilators.^{32 33} In a recent study that examined the interactive effects of cigarette smoking and ACE genotype, Butler et al³² reported an association of the ACE D allele with decreased vasodilator responses to both ACh and SNP in a normotensive, predominantly white population. In never-treated hypertensive white subjects, Perticone et al³³ reported a decreased forearm vasodilator response to ACh but not to SNP in subjects homozygous for the ACE D allele compared with subjects who carried the ACE I allele, but found no effect of ACE genotype in normotensive subjects.³³ Similarly, in the current study we detected no significant difference in the vasodilator response to ACh or SNP according to ACE genotype in our normotensive subjects.

In conclusion, this study demonstrates decreased forearm vasodilation and a differential effect of the ACE genotype to modulate bradykinin-induced FBF in normotensive blacks compared with whites. These findings may have important implications in understanding the observed ethnic variation in the antihypertensive efficacy of ACE inhibition. The blunted vasodilator response to bradykinin may have other ramifications given recent reports from this laboratory³⁴ and others³⁵ describing a role for bradykinin in regulating endothelial t-PA release. We speculate that the combined effects of ethnicity and genotype may interact to alter the risk of arterial thrombosis through bradykinin-dependent mechanisms.

	Acknowledgments

 
This work was supported by NIH grants HL 51387, HL 60906, HL 56251, HL 56963, and M01-RR00095-S33, and by a Pharmaceutical Research and Manufacturers Association Foundation Career Development Award (C.M.S.).

Received April 19, 2000; first decision May 18, 2000; accepted July 19, 2000.

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