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 mechan ism underlying this renin inhibitor's hypotensive activity, the cardia c and hemodynamic effects of A-74273 were studied in sodium-depleted a nd sodium-replete pentobarbital-anesthetized dogs. Vehicle [5% dextros e in water (V, D5W), n = 8] or a single dose of A-74273 was administer ed 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 ac tivity (PRA) was increased in the sodium-depleted dogs as compared wit h the sodium-replete dogs. In sodium-depleted dogs (n = 7-8/dose), MAP decreased maximally as compared with baseline by 4 +/- 1, 19 +/- 3, a nd 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 highe st infusion doses also produced significant reductions (p < 0.05 vs. b aseline and V) in systemic vascular resistance (SVR, 21 +/- 2 and 25 /- 2%) and left ventricular end-diastolic pressure (LVEDP, 40 +/- 8 an d 47 +/- 12%). In sodium-replete dogs (n = 4/dose), an infusion dose o f 0.01 mg/kg/min elicited no hemodynamic response, whereas 0.1 mg/kg/m in reduced MAP by 13 +/- 2% (p < 0.05 vs. baseline) and SVR by 7 +/- 6 %. A-74273 had no significant effect on cardiac output (CO), stroke vo lume (SV), and LV contractility. Heart rate (HR) either remained uncha nged or decreased slightly. PRA was significantly decreased (p < 0.05 vs. baseline and V) during infusion of A-74273 at all doses except 0.0 1 mg/kg/min in sodium-replete dogs. Furthermore, PRA, MAP, SVR, and LV EDP exhibited dose-related recoveries, and the parallel recoveries of SVR and MAP reflected PRA. A-74273 behaves as a vasodilator through bl ockade of the renin-angiotensin system (RAS), and does so without indu cing reflex tachycardia and without compromising cardiac function. Mor eover, the results in sodium-depleted dogs suggest that increasing the dose of A-74273 preferentially prolongs duration of action without in ducing profound hypotension.