Pharmacodynamic studies on the angiotensin II type 1 antagonists irbesartan and candesartan based on angiotensin II dose response in humans

The in vivo effects of two unsurmountable angiotensin II type 1 (AT(1)) antagonists, irbesartan (150 mg) and candesartan (8 mg), were studied in a double-blind, randomized, crossover study in 18 healthy men. The drugs' direct vascular effects were assessed as the rightward shift (dose ratio - 1) of angiotensin dose-effect curves on diastolic blood pressure (DBP). Renal and adrenal effects were assessed by plasma renin activity (PRA), aldosterone concentrations, and antagonistic concentration equivalents (n x K-i) in a radioligand rat lung receptor assay. Both drugs exerted similar substantial (> 30-fold) and long-lasting (> 2-fold 47 h after dosing) rightward shifts of the angiotensin II dose effect declining with half-lives of 15 h irbesartan and 12 h candesartan, respectively. Dose ratio - 1 versus n x K-i showed a linear relationship in Schild regression plots; both drugs increased PRA, decreased DBP, and suppressed aldosterone. The slopes of linear relationship between angiotensin antagonism (dose ratio - 1) and PRA increase were almost threefold steeper (p = 0.005) following irbesartan as compared with candesartan. The findings suggest that for the same degree of angiotensin II antagonism, irbesartan produces a greater increase in PRA than candesartan. These pharmacodynamic differences warrant further investigation and clarification.