Abstract
The possibility of using KRI-1314, a new cyclohexylnorstatine derivative, as an antihypertensive drug was examined using common marmosets. KRI-1314 strongly inhibited plasma renin activity (PRA) in both humans and marmosets, with a 50% inhibitory concentration of 4.7×10-9 and 6.9×10-9 M, respectively. In anesthetized marmosets, the increase in both blood pressure and PRA induced by bolus intravenous injection of RH-renin (0.15 μg/kg) was suppressed by constant intravenous infusion of KRI-1314 (0.01 and 0.1 mg/kg/min) in a dose-dependent manner. In the sustained hypertension induced by continuous intravenous infusion of RH-renin (0.1 μg/kg/min), a dose-dependent hypotensive response was produced by bolus intravenous injection of KRI-1314 (0.03-3 mg/kg). In the sodium-depleted model, whose PRA was increased by a two-week low-sodium diet coupled with furosemide loading, both intravenous injection (0.1-3 mg/kg) and oral administration (10 and 30 mg/kg) of KRI-1314 to anesthetized and conscious animals, respectively, lowered blood pressure dose-dependently with PRA suppression. The hypotensive activity of orally administered KRI-1314 (30 mg/kg) was almost equal to that of orally administered captopril (1 mg/kg). KRI-1314 did not affect heart rate in any of the experiments. These results indicate that the potent human renin inhibitor KRI-1314 may become an orally effective drug for treating renin-dependent hypertension.
