Effects of renin inhibitor A-72517 on hemodynamics and cardiac function in sodium-depleted dogs.
A-72517 is a potent inhibitor of human renin (IC50 = 1.0 nmol/L, pH 7.4 in plasma) and, aside from displaying modest activity against canine plasma renin (IC50 = 110 nmol/L), has been shown to be orally active in the dog and other animals. Renin inhibitors, in general, are presumed to exert their hypotensive effect through a reduction in total peripheral resistance. To elucidate the hemodynamic mechanism of action of this new dipeptidic renin inhibitor, the cardiac and systemic hemodynamic effects of A-72517 were studied in sodium-depleted, pentobarbital-anesthetized dogs. Each dog received either vehicle (n = 8) or a single dose (n = 8/dose) of A-72517 administered intravenously as a priming bolus followed by a 30 min constant infusion; infusion doses were 0.01, 0.05, and 0.1 mg/kg/min. A-72517 elicited significant (P < .05) dose-related reductions in mean arterial pressure (MAP) and systemic vascular resistance (SVR) compared to baseline values and the vehicle-treated group, and the recoveries of MAP and SVR were also dose-related. Plasma renin activity, measured by radioimmunoassay, was nearly completely suppressed during drug infusion at all doses. The hypotensive responses did not alter cardiac output nor did they induce reflex tachycardia at any dose. Left ventricular dP/dtmax did not change during infusion of A-72517, but, when corrected for changes in afterload, showed dose-related increases with drug treatment. Moreover, left ventricular end-diastolic pressure and pulmonary arterial wedge pressure were significantly reduced at the high dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Wessale
J L
JL
Cardiovascular Research Division, Abbott Laboratories, Abbott Park, IL 60064.
Kleinert
H D
HD
Calzadilla
S V
SV
Kovar
P J
PJ
Rosenberg
S H
SH
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004039:Diet, Sodium-Restricted; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006439:Hemodynamics / Q000187:drug effects*; D007275:Injections, Intravenous; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011863:Radioimmunoassay; D012083:Renin / Q000097:blood*; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D000092502:Renin Inhibitors
D010879:Piperazines; D011480:Protease Inhibitors; D012083:Renin; D013844:Thiazoles; D000092502:Renin Inhibitors; C076903:zankiren hydrochloride