Cardiovascular actions of the primate-selective renin inhibitor, A- 62198

HD Kleinert, D Martin, M Chekal, G Young, S Rosenberg, JJ Plattner and TJ Perun

Abbott Laboratories, Cardiovascular Research Division, Abbott Park, Illinois.

A-62198 [dimethylacetyl-Phe-His-NHCH(cyclohexylmethyl)CH-(OH)C H(OH)CH2N3] is a potent, selective inhibitor of primate renin. This compound induced a dose-dependent fall in mean arterial blood pressure (MAP) when administered as an i.v. bolus to anesthetized, salt-depleted monkeys. Both the magnitude and the duration of the hypotensive effect were dose related. Its actions were also studied during acute infusions in anesthetized anephric, normal and salt-depleted monkeys. MAP, heart rate and plasma renin activity (PRA) were determined during baseline and 30-min infusions of vehicle alone, followed by A-62198 as boluses of 0.01, 0.1 and 1.0 mg/kg, each maintained by infusing one-tenth of the bolus dose per minute. Vehicle did not alter base-line values. In the normal monkeys, A-62198 induced a dose-related fall in MAP which achieved statistical significance only at the highest dose, while maximally suppressing PRA at all doses (P less than .05, compared to vehicle). The salt-depleted monkeys responded with a dose-related fall in MAP and inhibition of PRA at all doses (P less than .05, compared to vehicle). A-62198 was relatively ineffective in the anephric monkeys which, as expected, had exceedingly low levels of PRA. Heart rate was unaltered regardless of dose or treatment group. Finally, infusion of 1.0 mg/kg bolus + 0.1 mg/kg/min of A-62198 had no effect on MAP or PRA in 2 kidney-1 clip rats, although MAP was reduced subsequent to a superimposed bolus of 0.1 mg/kg of captopril. We conclude that the renin inhibitor, A-62198, is an effective, primate selective hypotensive agent.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 246, Issue 3, pp. 975-979, 09/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics