Cardiovascular effects and hemodynamic mechanism of action of the novel, nonpeptidic renin inhibitor A-74273 in dogs.
A-74273 is a nonpeptidic, potent inhibitor of human and canine renin (IC50 = 3.1 and 43 nM, respectively, in plasma at pH 7.4) and has been shown to be orally active in dogs. To determine the hemodynamic mechanism underlying this renin inhibitor's hypotensive activity, the cardiac and hemodynamic effects of A-74273 were studied in sodium-depleted and sodium-replete pentobarbital-anesthetized dogs. Vehicle [5% dextrose in water (V, D5W), n = 8] or a single dose of A-74273 was administered intravenously (i.v.) as a bolus followed by a 30-min infusion (one tenth the bolus dose per minute). Baseline mean arterial pressure (MAP) was similar among all treatment groups, but baseline plasma renin activity (PRA) was increased in the sodium-depleted dogs as compared with the sodium-replete dogs. In sodium-depleted dogs (n = 7-8/dose), MAP decreased maximally as compared with baseline by 4 +/- 1, 19 +/- 3, and 23 +/- 3% during infusion of A-74273 at doses of 0.001, 0.01, and 0.1 mg/kg/min, respectively (p < 0.05 vs. baseline or V). The two highest infusion doses also produced significant reductions (p < 0.05 vs. baseline and V) in systemic vascular resistance (SVR, 21 +/- 2 and 25 +/- 2%) and left ventricular end-diastolic pressure (LVEDP, 40 +/- 8 and 47 +/- 12%). In sodium-replete dogs (n = 4/dose), an infusion dose of 0.01 mg/kg/min elicited no hemodynamic response, whereas 0.1 mg/kg/min reduced MAP by 13 +/- 2% (p < 0.05 vs. baseline) and SVR by 7 +/- 6%.(ABSTRACT TRUNCATED AT 250 WORDS)
Wessale
J L
JL
Cardiovascular Research Division, Abbott Laboratories, Abbott Park, IL 60034.
Calzadilla
S V
SV
Boyd
S A
SA
Baker
W R
WR
Stein
H H
HH
Kovar
P J
PJ
Barlow
J
J
Klinghofer
V
V
Mantei
R
R
Kleinert
H D
HD
D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002302:Cardiac Output / Q000187:drug effects; D004039:Diet, Sodium-Restricted; D004285:Dogs; D006439:Hemodynamics / Q000187:drug effects*; D007275:Injections, Intravenous; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D000092502:Renin Inhibitors
D000577:Amides; D009025:Morpholines; D000092502:Renin Inhibitors; C078248:A 74273