Jpn. J. Pharmacol. 76 (2), 185-192 (1998)

A Novel Angiotensin II-Receptor Antagonist, 606A, Induces Regression of Cardiac Hypertrophy, Augments Endothelium-Dependent Relaxation and Improves Renal Function in Stroke-Prone Spontaneously Hypertensive Rats

Yoshihiro Hashimoto (1), Yukie Kurosawa (1), Koichi Minami (1), Keiko Fushimi (2) and Hiroshi Narita (1)

(1) Pharmaceutical Development Research Laboratory, (2) Lead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., 2-2-50, Kawagishi, Toda, Saitama 335, Japan

Abstract: It is well-known that cardiac hypertrophy and arterial and renal dysfunction are serious complications of hypertension. Therefore, we investigated the chronic effects of 606A (2-propyl-3-[2'(1H-tetrazole-5-yl)biphenyl-4-yl]methyl-5-acetyl-4,5,6,7-tetrahydro imidazo[4,5-c]pyridine-4-carboxylic acid disodium salt), a novel AT1-receptor antagonist, on these complications of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP) using Wistar Kyoto rats (WKY) as the control. After 8 weeks treatment from 16 weeks of age with 606A by a subcutaneously implanted osmotic pump, cardiac function, cardiac weight, acetylcholine-induced endothelium-dependent relaxation in the isolated aorta and renal function were estimated. Furthermore, wall thickness of the left ventricle was studied morphologically. We found that 606A (0.3 mg, 1 mg and 3 mg/head/day) dose-dependently lowered blood pressure without any effects on heart rate in SHRSP. Long-term treatments with 606A significantly reduced cardiac weight, left ventricular wall thickness and left ventricular end diastolic pressure, whereas it did not affect cardiac contractility. Endothelium-dependent relaxation of the aorta was recovered, and total protein excretion as well as total protein excretion/creatinine excretion ratio was reduced to the level of WKY by the treatment. These results suggest that 606A not only has a hypotensive effect but also protects cardiac, renal and vascular tissues from complications of hypertension. Thus, 606A could be an useful drug for treatment of hypertension.

Keywords: 606A, Angiotensin II-receptor antagonist, Cardiac hypertrophy, Vascular endothelium, Renal function

Copyrightę The Japanese Pharmacological Society 1998

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