Effects of the renin inhibitor A-64662 in monkeys and rats with varying baseline plasma renin activity

H D Kleinert, D Martin, M A Chekal, J Kadam, J R Luly, J J Plattner, T J Perun, R R Luther
1988 Hypertension  
The efficacy of the potent, primate selective renin inhibitor A-64662 was studied in monkeys and rats with varying baseline plasma renin activity (PRA) to elucidate the relationship between PRA and the hypotensive response induced by this compound. The effect of a single bolus of vehicle or A-64662 at 0.001, 0.01,0.1,1.0, and 10.0 mg/kg i.v. was compared in 30 normal and 30 saltdepleted, anesthetized monkeys (n = 5/dose). Baseline mean arterial pressure (MAP) was similar among all groups, but
more » ... seline PRA was elevated in salt-depleted monkeys. A-64662 induced a comparable dose-related fall in MAP, affecting the magnitude and duration of action, accompanied by inhibition of PRA, the duration of which was dose-related in both the normal and salt-depleted groups. However, the minimum effective doses required to reduce MAP by approximately 10% were 0.01 mg/kg for the salt-depleted monkeys and 0.1 mg/kg for the normal monkeys. In a second study, three consecutive boluses of vehicle or A-64662 at 0.1, 1.0, and 10.0 mg/kg were administered to anephric monkeys, human renin-infused anephric monkeys, and normal monkeys (n = 4/group). A dose of 0.1 mg/kg was ineffective, but the 1.0 mg/kg dose lowered MAP by 11 ± 3% (mean ± SE)inthe anephric monkeys. The infusion of renin into anephric monkeys restored the efficacy of A-64662 at the 0.1 and 1.0 mg/kg doses to responses comparable to those of the normal monkeys. A-64662 at 10.0 mg/kg caused a similar fall in MAP of 50 to 60% in anephric, renin-infused anephric, and normal monkeys in the absence of detectable PRA. A-64662, which is inactive against rat renin in vitro, was given as a 1.0 mg/kg i.v. bolus followed by a 0.1 mg/kg/min infusion and was without effect on MAP and PRA in sham-operated and two-kidney, one clip conscious rats (n = 6/group). We conclude that 1) PRA is involved, at least in part, in mediating the observed hypotension and 2) A-64662 may exert actions secondary to its effect on PRA. (Hypertension 11: 613-619, 1988) KEY WORDS monkeys renin inhibitors • hypotension • plasma renin activity • cynomolgus R ENIN is the enzyme that catalyzes the first and rate-limiting step in the formation of angioten-.. sin II. Unlike angiotensin converting enzyme, which has multiple substrates, renin is selective for a single naturally occurring substrate, angiotensinogen. 1 Although angiotensin converting enzyme inhibitors provide an effective blockade of the renin-angiotensinaldosterone system and are successful therapeutic agents in the treatment of hypertension and congestive
doi:10.1161/01.hyp.11.6.613 fatcat:oep75pbhnvcmrd5zxvj4j5y6ai