Antihypertensive effect of repeatedly administered YM358, an angiotensin AT(1)-receptor antagonist, in stroke-prone spontaneously hypertensive rats

YM358 (2,7-diethyl-5-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]-triazole potassium salt), a novel nonpeptide angiotensin AT(1)-receptor antagonist, was administered daily for 4 weeks to 24-week-old stroke-prone spontaneously hypertensive rats (SHRSP). Its effects on systolic, mean and diastolic arterial pressure (SAP, MAP and DAP), heart rate and locomotor activity were investigated by using radiotelemetry. A clear diurnal Variation in blood pressure, heart rate and locomotor activity was observed in synchrony with the light cycle. YM358 at a daily oral dose of 10 or 30 mg/kg produced a reduction of blood pressure in a dose-dependent manner. Although a mild attenuation of the antihypertensive effect of YM358 was observed during the early stage of therapy, YM358 at 30 mg/kg per day produced a significant and consistent decrease in 24-hr MAP and DAP, and it prevented the further development of hypertension. YM358 did not affect either heart rate or locomotor activity or their diurnal variations. After the discontinuation of therapy with YM358, the blood pressure recovered promptly to the control level while there was no sign of a rebound increase in blood pressure. These results suggest that YM358 may be potentially useful for the treatment of hypertension.