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.
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.
Hashimoto
Y
Y
Pharmaceutical Development Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda, Saitama, Japan.
Kurosawa
Y
Y
Minami
K
K
Fushimi
K
K
Narita
H
H
D000109:Acetylcholine / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D006332:Cardiomegaly / Q000188:drug therapy* / Q000503:physiopathology; D002561:Cerebrovascular Disorders / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D007668:Kidney / Q000503:physiopathology*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009929:Organ Size; D051381:Rats; D011918:Rats, Inbred SHR; D013777:Tetrazoles / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*
C106452:606A compound; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D013777:Tetrazoles; D000109:Acetylcholine