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

Background The angiotensin II type 1 receptor (AT1R) 1166A/C polymorphism is reported to be implicated in cardiovascular diseases. The association 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 of angiotensin 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∼14.02 ng/kg/min] was significantly lower than in those with 1166A/A (95% CI: 14.23∼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.