Characterization of angiotensin II antagonism displayed by Ib, a novel nonpeptide angiotensin AT(1) receptor antagonist.
The pharmacologic profile of Ib, 5-n-butyl-4-{4-[2-(1H-tetrazole-5-yl)-1H-pyrrol-1-yl]phenylmethyl}-2,4-dihydro-2-(2,6-dichloridephenyl)-3H-1,2,4-triazol-3-one, a novel nonpeptide angiotensin AT(1) receptor antagonist, was investigated by receptor-binding studies, functional in vitro assays with rabbit and rat aorta, and in vivo experiments in rats. Ib inhibited [(125)I] angiotensin II binding to AT(1) receptors in rat liver membranes (K(i)=2.5+/-0.5 nM) and did not interact with AT(2) receptors in bovine cerebellar membranes. In functional studies with rat and rabbit aorta, Ib inhibited the contractile response to angiotensin II (pD(2)' value: 7.43 and 7.29, respectively) with a significant reduction in the maximum. In pithed rats, Ib inhibited the angiotensin II induced pressor response in a dose-related manner. After intravenous administration, Ib produced a dose-dependent antihypertensive effects in spontaneously hypertensive rats and renal hypertensive rats. These results suggest that Ib is a potent angiotensin AT(1) selective receptor antagonist with a mode of insurmountable antagonism.
Department of Physiology, China Pharmaceutical University, Nanjing, China.
Jinhui
J
Wu
Qiujuan
Q
Wang
Jiyuan
J
Guo
Zheyi
Z
Hu
Zhiyong
Z
Yin
Jinyi
J
Xu
Xiaoming
X
Wu
D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002417:Cattle; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D008297:Male; D011485:Protein Binding; D011758:Pyrroles / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D014230:Triazoles / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
C532103:5-n-butyl-4-(4-(2-(1H-tetrazole-5-yl)-1H-pyrrol-1-yl)phenylmethyl)-2,4-dihydro-2-(2,6-dichloridephenyl)-3H-1,2,4-triazol-3-one; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D011758:Pyrroles; D044140:Receptor, Angiotensin, Type 1; D014230:Triazoles; D000804:Angiotensin II; D019808:Losartan