Interactive Effect of Ethnicity and ACE Insertion/Deletion Polymorphism on Vascular Reactivity.
-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 I:D versus I:I, 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.
Gainer
James V.
JV
Divisions of Clinical Pharmacology and Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tenn.
Stein
C. Michael
CM
Neal
Tami
T
Vaughan
Douglas E.
DE
Brown
Nancy J.
NJ