Eur J Clin Pharmacol. 2007 Jan;63(1):17-26. Epub 2006 Dec 5.

Angiotensin II type 1 receptor 1166A/C polymorphism in association with blood pressure response to exogenousangiotensin II.

Lim HS, Cho JY, Oh DS, Chung JY, Hong KS, Bae KS, Yu KS, Lee KH, Jang IJ, Shin SG.

Abstract

BACKGROUND:

The angiotensin II type 1 receptor (AT1R) 1166A/C polymorphism is reported to be implicated in cardiovascular diseases. Theassociation between the 1166A/C polymorphism and diastolic blood pressure (DBP) changes in response to exogenous angiotensin II and valsartan was evaluated by pharmacokinetic and pharmacodynamic modeling.

METHODS: Thirteen normotensive, healthy adults (six with the 1166A/A polymorphism and seven with 1166A/C) were enrolled in this clinical study.Angiotensin II was infused continuously over a 2-min period at four different rates (from 5 ng/kg/min and increased by 5 ng/kg/min) at 0 (before valsartan dosing), 2, 4, 8, 12, and 24 h after a single oral dose of valsartan (40 mg). BP was measured serially before and at the end of each rate ofangiotensin II infusion. Plasma concentration-time profiles of valsartan were established over a 24-h period. We analyzed data using NONMEM and studied the relationship between the AT1R 1166A/C genotypes and BP responses.

RESULTS:

Plasma valsartan concentrations and DBP data best fitted into a two-compartment linear model and E(max) model (E(max) with baseline for angiotensin II and inhibitory E(max) for valsartan), respectively. The ED50 for angiotensin II in the subjects with 1166A/C [95% confidence interval (CI): 4.30 approximately 14.02 ng/kg/min] was significantly lower than in those with 1166A/A (95% CI: 14.23 approximately 28.77 ng/kg/min), while the E(max) for angiotensin II and EC50 for valsartan was similar in both genotype groups.

CONCLUSIONS: These results suggest that exogenous human angiotensin II increases the BP more potently in subjects with 1166A/C than in those with 1166A/A.