Pharmacological properties of KW-3433, a new angiotensin II receptor antagonist

• Published in: Japanese Journal of Pharmacology Vol. 64; no. suppl.2; p. 337
• Main Authors: Ishikawa, Tomoko, Sano, Tomoyuki, Furuta, Shiho, Aikawa, Nobuo, Yamada, Koji
• Format: Journal Article
• Language: English; Japanese
• Published: The Japanese Pharmacological Society 1994
• ISSN: 0021-5198
• DOI: 10.1016/s0021-5198(19)50983-0

Angiotensin II (Ang II) antagonistic activities of KW-3433 (KW) were examined in various in vitro and in vivo studies. KW inhibited selectively 「125-I」 Ang II binding to the AT_1 receptor with an IC_50 value of 11nM in bovine adrenal cortical membranes. In isolated rabbit aorta. KW inhibited Ang II-induced contractions with pA_2 value of 9.2 and shifted Ang II curves to the right, in a parallel fashion. KW had no effect on the contractile responses to KCl, norepinephrine, U46619 and endothelin-1 in rabbit aorta. In in vitro functional assay utilizing Ang II-induced aldosterone release in bovine adrenal glomerulosa cells, KW exhibited a dose-dependent inhibition. In conscious normotensive rats, oral administration of KW antagonized the Ang II pressor response at 1 and 3mg/kg. The effect still remained at 7 hours after the administration. Furthermore, in the same rat model, the aldosterone release induced by Ang II at 100ng/kg/min i.v. were abolished by KW at 1mg/kg p.o. In addition, intravenous injection of KW attenuated Ang II pressor response in anesthetized dogs. Intraduodenal administration of KW also showed potent and long-lasting Ang II antagonism. These findings indicate that KW is an orally active, potent and selective Ang II receptor antagonist with properties of long action.