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