| Abstrakt: |
Cl-992, a novel potent inhibitor of primate renin, was tested for blood pressure-lowering efficacy in sodium-restricted, furosemide-treated conscious normotensive cynomolgus monkeys and conscious renal hypertensive monkeys. The hypertensive monkey model provided an opportunity to determine the response to a renin inhibitor in a pathological nonhuman primate model of hypertension without concurrent diuretic treatment or dietary sodium restriction and on repeated oral administration. Cl-992 has IC50 values of 0.58 +/- 0.06 (n = 4) and 0.36 +/- 0.03 nM (n = 8) against human and monkey renin, respectively. In normotensive monkeys, oral Cl-992 at doses of 3, 10 and 30 mg/kg reduced mean arterial blood pressure (MABP) by 8 +/- 2, 15 +/- 7 and 29 +/- 7 mm Hg (n = 5 animals per dose level, P < .05), respectively (base line, 103 +/- 3 mm Hg). Intravenous Cl-992 (0.0001 to 0.1 mg/kg) also caused dose-dependent decreases in MABP and a maximum reduction of 23 +/- 4 mm Hg. The decrease in MABP after Cl-992 was paralleled by an inhibition of plasma renin activity (PRA) and a reduction in immunoreactive angiotensin II. In renal hypertensive monkeys, oral Cl-992 at doses of 3, 10 and 30 mg/kg reduced MABP by 6 +/- 2, 18 +/- 6 and 37 +/- 8 mm Hg (n = 3 or 4, P < .05), respectively (base line, 134 +/- 4 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS) |
