ANTIHYPERTENSIVE EFFECT OF CHRONIC KT3-671, A STRUCTURALLY NEW NONPEPTIDE ANGIOTENSIN AT(1)-RECEPTOR ANTAGONIST, IN STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

KT3-671 4-yl)methyl]-4,5,6,7-tetrahydrocycloheptimidazole) , a structu rally new nonpeptide angiotensin AT(1)-receptor antagonist, was admini stered orally and repeatedly to 15-week-old stroke-prone spontaneously hypertensive rats for 7 weeks; and its effects on blood pressure, hea rt rate, renal function, plasma renin concentration (PRC), plasma aldo sterone 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 bl ood 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 produce d 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 tende ncy to decrease PAC. Repeated administration of KT3-671 reduced the se verity of the pathological changes in the kidney. These results sugges t that KT3-671 is a potentially useful antihypertensive drug.