(Circulation. 1995;91:2933-2942.)
© 1995 American Heart Association, Inc.
Articles |
Angiotensin-Converting Enzyme Gene Polymorphism Has No Influence on the Circulating Renin-Angiotensin-Aldosterone System or Blood Pressure in Normotensive Subjects
From Broussais Hospital Clinical Investigation Center (M.-L.L., M.A., T.-T.G., J.M.), Assistance Publique des Hôpitaux de Paris, and INSERM U 367 (F.A.-G., J.M.), Paris, France.
Correspondence to Dr Michel Azizi, Clinical Investigation Center, Broussais Hospital, 96 rue Didot, 75674 Paris Cedex 14, France.
Background Angiotensin-converting enzyme (ACE) is involved in the metabolism of two major vasoactive peptides, converting angiotensin (Ang) I into Ang II and inactivating bradykinin. An insertion/deletion (I/D) polymorphism is present in the 16th intron of the ACE gene and is strongly associated with plasma and cellular ACE levels. Contrasting with the lack of relation between ACE gene polymorphism and blood pressure level, a large case-control study has shown that the deletion marker allele of the ACE gene was associated with an increased risk of myocardial infarction. The pathophysiological link between ACE gene polymorphism and cardiovascular events remains hypothetical. One hypothesis is that this polymorphism influences Ang II and bradykinin concentrations in the peripheral and/or local circulations through its effects on ACE levels in plasma and endothelial cells. The aim of this study was to investigate the effect of the ACE gene I/D polymorphism on blood pressure, plasma active renin, and aldosterone regulation in normal subjects.
Methods and Results Twenty-four normotensive male volunteers homozygous for the ACE I/D polymorphism (12 DD and 12 II) received a renin inhibitor infusion (remikiren 0.1 mg · kg-1 · h-1 for 130 minutes) to suppress endogenous Ang I and Ang II production. Forty minutes after initiating the remikiren infusion, an exogenous Ang I infusion was begun and increased gradually every 15 minutes from 1 to 10 ng · kg-1 · min-1. Median (range) plasma ACE levels (mU/mL) were 39 (32 to 57) and 24 (12 to 30) in the DD and II groups, respectively. Remikiren suppressed plasma Ang I and Ang II, increased plasma active renin (from 23±12 to 154±161 pg/mL), decreased plasma aldosterone (from 106±42 to 82±33 pg/mL), and slightly decreased diastolic blood pressure (from -2.4±2.7 mm Hg). The blood pressure and hormonal responses to Ang I infusion after renin inhibition and the slope of the rise in plasma Ang II with increasing Ang I dose were identical in both groups, as was the plasma Ang I/Ang II ratio before (DD, 2.09±1.04; II, 2.59±0.76) and after (DD, 0.15±0.13; II, 0.09±0.03) combined renin inhibitor and Ang I infusion.
Conclusions Despite its association with a major difference in plasma ACE levels, the ACE I/D polymorphism did not influence the Ang II and plasma aldosterone production, plasma active renin decrease, or diastolic blood pressure increase induced by exogenous Ang I infusion, suggesting that ACE has no limiting influence on systemic Ang II generation and effects under these experimental conditions.
Key Words: blood pressure • angiotensin • genes • peptides • peptidyl-dipeptidase A
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