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 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.
Lim
Hyeong-Seok
HS
Department of Pharmacology, College of Medicine, Seoul National University, 28 Yongon-dong, Chongro-gu, Seoul 110-744, South Korea.
Cho
Joo-Youn
JY
Oh
Dal-Seok
DS
Chung
Jae-Yong
JY
Hong
Kyoung-Sup
KS
Bae
Kyun-Seop
KS
Yu
Kyung-Sang
KS
Lee
Kyung-Hoon
KH
Jang
In-Jin
IJ
Shin
Sang-Goo
SG
D000328:Adult; D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D001794:Blood Pressure; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan
D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000804:Angiotensin II; D000068756:Valsartan; D014633:Valine