ANTIHYPERTENSIVE ACTIVITY AND PHARMACOKINETICS OF KD3-671, A NONPEPTIDE AT(1)-RECEPTOR ANTAGONIST, IN RENAL HYPERTENSIVE DOGS

The antihypertensive activity and pharmacokinetics of KD3-671 (previou sly named KT3-671), a nonpeptide AT(1)-receptor antagonist, were inves tigated in renal hypertensive dogs with normal or high plasma renin ac tivity (PRA). A single administration of KD3-671 at 3 and 10 mg/kg, p. o., to the hypertensive dogs with high PRA dose-dependently reduced me an blood pressure (MBP), which was not correlated with plasma KD3-671 concentration. Significant increases in PRA and plasma angiotensin (An g) II occurred 2 h after KD3-671 dosing. Enalapril at 3 mg/kg, p.o., a lso reduced MBP. Neither KD3-671 nor enalapril affected heart rate. Wh en given orally once a day for 29 days to the hypertensive dogs with n ormal PRA, KD3-671 at 3 and 10 mg/kg/day dose-dependently reduced MBP, which was smaller than that in the dogs with high PRA. This was the c ase for enalapril. The hypotension induced by the first dose of KD3-67 1 or enalapril was consistently observed after doses 8, 15, 22, and 29 . After cessation of repeated dosing, no rebound phenomenon in MBP was observed. Pharmacokinetic parameters of KD3-671 were not influenced b y repeated dosing. KD3-671 markedly increased both PRA and plasma Ang II concentration at 2 h after dosing. These results suggest that KD3-6 71 may be useful for the treatment of hypertension.