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 (AT1) 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 Ki) 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 Ki 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.
Belz
Gustav G
GG
Center for Cardiovascular Pharmacology, ZeKaPha GmbH, Alwinenstrasse 16, D-65189 Wiesbaden, Germany.
Butzer
Raunhild
R
Kober
Susan
S
Mutschler
Ernst
E
D000328:Adult; D000450:Aldosterone / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006207:Half-Life; D006801:Humans; D000077405:Irbesartan; D008297:Male; D011869:Radioligand Assay; D044140:Receptor, Angiotensin, Type 1; D012083:Renin / Q000378:metabolism; D013777:Tetrazoles / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000804:Angiotensin II; D000450:Aldosterone; D012083:Renin; D000077405:Irbesartan; C081643:candesartan