COMPARATIVE HEMODYNAMIC-EFFECTS OF MK-422, A CONVERTING ENZYME-INHIBITOR, AND A RENIN INHIBITOR IN DOGS WITH ACUTE LEFT-VENTRICULAR FAILURE

  • 1 January 1984
    • journal article
    • research article
    • Vol. 6  (6) , 1067-1075
Abstract
The angiotensin-converting enzyme (ACE) inhibitor MK-422 (enalaprilat) was compared with the potent renin inhibitor SCRIP for its ability to improve left ventricular function in closed-chest dogs. Acute left ventricular failure (ALVF) was induced by repeated embolization (EMB) of the left coronary arterial vasculature with 50-.mu.m plastic microspheres. Baseline stability data were obtained in 30 dogs in which the evolution of ALVF was monitored over time. Guided by a progressive rise in left ventricular end-diastolic pressure (LVEDP), a stepwise perturbation of the coronary circulation with microspheres over 30 min caused reductions in left ventricular dP/dt [change in pressure with time] and cardiac output, averaging 47 and 40%, respectively. EMB reduced heart rate (20 beats/min) and mean arterial pressure by .apprx. 20mm Hg which, along with other hemodynamic variables, remained stable after induction of heart failure. MK-422 (100 .mu.g/kg i.v.) given 45 min after ALVF was induced, decreased mean arterial pressure by 20 mm Hg (P < 0.05) and reduced total peripheral resistance (TPR) from 5453 to 4150 dyne .cntdot. s .cntdot. cm-5 (P < 0.05). The decline in LVEDP (from 14 .+-. 1 to 11 .+-. 1 mm Hg) and TPR suggests that MK-422 dilates resistance and, conceivably, capacitance vessels. In dogs with sham EMB (vehicle injections into coronary circulation), MK-422 reduced arterial pressure but had no important effects on the other hemodynamic indices. The renin inhibitor SCRIP (100 .mu.g/kg i.v. plus 10 .mu.g/kg per min i.v.) produced effects on systemic hemodynamics and left ventricular function qualitatively and quantitatively similar to those of enalaprilat, suggesting that the latter reduces TPR owing primarily to inhibition of angiotensin II formation rather than bradykinin-induced vasodilation. Renal function and electrolyte excretion studies revealed that EMB paradoxically increased Na+ excretion and glomerular filtration rate, but there was no further increase in these parameters after ACE inhibition. Inhibition of angiotensin II formation with ACE or renin inhibitors improves global ventricular performance by reducing both LVEDP and afterload.