Negative Inotropic Properties of Isradipine, Nifedipine, Diltiazem, and Verapamil in Diseased Human Myocardial Tissue

Abstract

We investigated the inotropic responses to Ca2+ antagonists using electrically driven human papillary muscle strips and human auricular trabeculae. Specimens were obtained during cardiac surgery for mitral valve replacement [New York Heart Association (NYHA) Class II-III] or heart transplantation (NYHA IV) and during aortocoronary bypass operations. The inotropic effects were studied with cumulative concentration-response curves. All Ca2+ antagonists tested significantly (p < 0.05) depressed force of contraction at concentrations above 0.01 μmol/L, but their potencies were different. A 50% reduction of the initial force of contraction occurred at the following concentrations (NYHA II–III): nifedipine (mean IC50) 0.09 μmol/L isradipine 0.12 μmol/L, diltiazem 0.69 μmol/L, and verapamil 0.79 μmol/L. There were no significant differences in the negative inotropic effects of any tested Ca2+ antagonist between NYHA II–III and NYHA IV. When the initial force of contraction was reduced by 90%, addition of Ca2+ increased force of contraction significantly less after diltiazem (2.76 ± 0.4 mN), isradipine (1.82 ± 0.23 mN), and nifedipine (1.68 ± 0.25 mN) compared to control (4.63 ± 0.56 mN) (NYHA II–III). The negative isotropic potencies of nifedipine and verapamil were significantly greater in human auricular trabeculae compared to papillary muscle strips (p < 0.05). However, on the relation between therapeutic vasoactive plasma concentrations and IC25 values, an entirely different rank order of potential negative inotropism could be observed: verapamil > nifedipine > diltiazem > isradipine.