| Abstrakt: |
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. A-74273 had no significant effect on cardiac output (CO), stroke volume (SV), and LV contractility. Heart rate (HR) either remained unchanged or decreased slightly. PRA was significantly decreased (p < 0.05 vs. baseline and V) during infusion of A-74273 at all doses except 0.01 mg/kg/min in sodium-replete dogs. Furthermore, PRA, MAP, SVR, and LVEDP exhibited dose-related recoveries, and the parallel recoveries of SVR and MAP reflected PRA. A-74273 behaves as a vasodilator through blockade of the renin-angiotensin system (RAS), and does so without inducing reflex tachycardia and without compromising cardiac function. Moreover, the results in sodium-depleted dogs suggest that increasing the dose of A-74273 preferentially prolongs duration of action without inducing profound hypotension. |
