| Autor: |
R M, Edwards, N, Aiyar, E H, Ohlstein, E F, Weidley, E, Griffin, M, Ezekiel, R M, Keenan, R R, Ruffolo, J, Weinstock |
| Rok vydání: |
1992 |
| Předmět: |
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| Zdroj: |
The Journal of pharmacology and experimental therapeutics. 260(1) |
| ISSN: |
0022-3565 |
| Popis: |
The angiotensin II (AII) antagonist activity of (E)-alpha-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5- yl]methylene]-2-thiophenepropanoic acid (SKF 108566), was examined in a number of in vitro and in vivo assays. In rat and human adrenal cortical membranes, SKF 108566 displaced specifically bound [125I]AII with IC50 of 9.2 and 3.9 nM, respectively. SKF 108566 also inhibited [125I]AII binding to human liver membranes (IC50 = 1.7 nM) and to rat mesenteric artery membranes (IC50 = 1.5 nM). In rabbit aortic smooth muscle cells, SKF 108566 caused a concentration-dependent inhibition of AII-induced increases in intracellular Ca++ levels. In rabbit aortic rings, SKF 108566 produced parallel rightward shifts in the AII concentration-response curve without affecting the maximal contractile response. Schild analysis of the data yielded a KB value of 0.26 nM and a slope not different from 1, indicative of competition antagonism. SKF 108566 had no effect on the contractile responses to KCl, norepinephrine or endothelin in rabbit aorta. In conscious normotensive rats, i.v. administration of SKF 108566 (0.01-0.3 mg/kg) produced dose-dependent parallel shifts in the AII pressor dose-response curve. Administration of SKF 108566 (3-10 mg/kg) intraduodenally or intragastrically to conscious normotensive rats resulted in a dose-dependent inhibition of the pressor response to AII (250 ng/kg, i.v.). At 10 mg/kg, i.d., significant inhibition of the pressor response to AII was observed for 3 hr. In this same rat model, SKF 108566 had no effect on base-line pressure or on the pressor response to norepinephrine or vasopressin. The data demonstrate that SKF 108566 is a potent, highly selective, competitive nonpeptide AII antagonist.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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