The
antihypertensive activity and pharmacokinetics of
KD3-671 (previously named
KT3-671), a nonpeptide AT1-receptor antagonist, were investigated in renal hypertensive dogs with normal or high plasma
renin activity (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 mean blood pressure (MBP), which was not correlated with plasma
KD3-671 concentration. Significant increases in PRA and plasma
angiotensin (Ang) II occurred 2 h after
KD3-671 dosing.
Enalapril at 3 mg/kg, p.o., also reduced MBP. Neither
KD3-671 nor
enalapril affected heart rate. When given orally once a day for 29 days to the hypertensive dogs with normal 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 case for
enalapril. The
hypotension induced by the first dose of
KD3-671 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 by repeated dosing.
KD3-671 markedly increased both PRA and plasma Ang II concentration at 2 h after dosing. These results suggest that
KD3-671 may be useful for the treatment of
hypertension.