Hideto Amano (1), Kazuko Fujimoto (1), Takeshi Suzuki (1), Takeshi Fujii (1), Seiichiro Mochizuki (2), Akira Tomiyama (2) and Koichiro Kawashima (1,*)
(1) Departments of Pharmacology, Kyoritsu College of Pharmacy, Minato-ku, Tokyo 105, Japan
(2) Research Laboratories, Kotobuki Seiyaku Co., Ltd., Sakaki-machi, Nagano 389-06, Japan
Abstract: KT3-671 (2-propyl-8-oxo-1- [(2'-(1H-tetrazole-5-yl) biphenyl-4-yl)methyl]- 4,5,6,7-tetrahydro-cycloheptimidazole), a structurally new nonpeptide angiotensin AT1-receptor antagonist, was administered orally and repeatedly to 15-week-old stroke-prone spontaneously hypertensive rats for 7 weeks; and its effects on blood pressure, heart rate, renal function, plasma renin concentration (PRC), plasma aldosterone concentration (PAC) and hypertension-related tissue damage in the brain, heart, kidney and mesenteric artery were investigated. KT3-671 at a dose of 3 or 10 mg/kg, p.o. per day prevented development of hypertension and produced a significant and consistent reduction of blood pressure in a dose-dependent manner. Enalapril at a dose of 10 mg/kg per day produced cardiovascular effects similar to those of KT3-671 at 10 mg/kg. Despite marked reduction in blood pressure, neither KT3-671 nor enalapril affected the heart rate. KT3-671 at 10 mg/kg produced a transient and significant reduction of urinary sodium excretion in the second week, but did not affect renal function at any other time during the experimental period. Both KT3-671 at 10 mg/kg and enalapril at 10 mg/kg produced a significant increase in PRC and showed a tendency to decrease PAC. Repeated administration of KT3-671 reduced the severity of the pathological changes in the kidney. These results suggest that KT3-671 is a potentially useful antihypertensive drug.
Keywords: KT3-671, ATI-receptor antagonist, Stroke-prone spontaneously hypertensive rat, Antihypertensive effect, Renal lesion