ACE (I/D) genotype as a predictor of the magnitude and duration of the response to an ACE inhibitor drug (Enalaprilat) in humans

• Published in: Circulation (New York, N.Y.) Vol. 98; no. 20; pp. 2148 - 2153
• Main Authors: UEDA, S, MEREDITH, P. A, MORTON, J. J, CONNELL, J. M. C, ELLIOTT, H. L
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 17.11.1998
• Subjects: Adult; Angiotensin II - blood; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Biological and medical sciences; Blood Pressure - drug effects; Cardiovascular system; Enalaprilat - blood; Enalaprilat - pharmacology; Genotype; Humans; Male; Medical sciences; Peptidyl-Dipeptidase A - genetics; Peptidyl-Dipeptidase A - metabolism; Pharmacology. Drug treatments; Renin-Angiotensin System - physiology; Time Factors; Vasodilator agents. Cerebral vasodilators; Human; Vasodilator agent; Intravenous administration; Enzyme; Enzyme inhibitor; Genotype; Genetic determinism; Biological activity; Dose activity relation; Peptidases; Peptidyl-dipeptidase A; Enalaprilat; Hydrolases; Peptidyl-dipeptidases; Hemodynamics
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.cir.98.20.2148

We have investigated the possible effects of contrasting ACE (I/D) genotypes on the responses to the ACE inhibitor enalaprilat in normotensive men. Subjects with DD (n=12) and II (n=11) ACE genotypes received an intravenous infusion of enalaprilat or placebo. Pressor responses to stepwise, incremental doses of angiotensin I were measured at 1 and 10 hours after dosing. The dose required to raise mean blood pressure by 20 mm Hg (PD20) was calculated individually, and the ratio of PD20 during enalaprilat to that during placebo (dose ratio, DR) was used for assessment of the extent of ACE inhibition. The pressor response was significantly attenuated at 1 hour after enalaprilat in both groups, but significant attenuation was evident at 10 hours after dose only in the II subjects. The DRs at both 1 hour (median, 5.43 versus 2.82, P=0.0035) and 10 hours (2.06 versus 0.84, P=0.0008) after enalaprilat were significantly higher in II subjects than in DD subjects. The effect of enalaprilat was significantly greater and lasted longer in normotensive men homozygous for the II ACE genotype. By multivariate analysis, ACE (I/D) genotype and plasma angiotensin II levels were predictive of >50% of the variation in response to ACE inhibition.