Effects of the renin inhibitor A-64662 in monkeys and rats with varying baseline plasma renin activity.
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 salt-depleted, anesthetized monkeys (n = 5/dose). Baseline mean arterial pressure (MAP) was similar among all groups, but baseline 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) in the 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Kleinert
H D
HD
Abbott Laboratories, Cardiovascular Research Division, Abbott Park, IL 60064.
Martin
D
D
Chekal
M A
MA
Kadam
J
J
Luly
J R
JR
Plattner
J J
JJ
Perun
T J
TJ
Luther
R R
RR
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology*; D005665:Furosemide / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D009392:Nephrectomy; D051381:Rats; D011919:Rats, Inbred Strains; D012083:Renin / Q000097:blood; D012965:Sodium Chloride / Q000172:deficiency; D012982:Sodium, Dietary / Q000008:administration & dosage; D000092502:Renin Inhibitors
D004151:Dipeptides; D005665:Furosemide; D012083:Renin; D012965:Sodium Chloride; D012982:Sodium, Dietary; D000092502:Renin Inhibitors; C056622:enalkiren