Different negative inotropic activity of Ca2+-antagonists in human myocardial tissue

Abstract

To evaluate the negative inotropic effect of various Ca2(+)-antagonists in human myocardium without additional influences of preload, afterload, or frequency, we examined their effects on isometric force of contraction in isolated human papillary muscle strips and in auricular trabeculae. The 1,4-dihydropyridines isradipine, nitrendipine, and nifedipine, the phenylalkylamine verapamil, and the benzothiazepine diltiazem exerted concentration-dependent negative inotropic effects. The potency of the investigated Ca2(+)-antagonists was identical in papillary muscle strips of patients with only moderate clinical signs of heart failure undergoing mitral valve replacement-operation (NYHA II-III) and in terminally failing (heart transplantation, NYHA IV) human hearts. The IC50 values were lower in auricular trabeculae than in papillary muscle strips. The difference was significant for nifedipine, nitrendipine, and verapamil. The restorative effects of external Ca2+ after pretreatment with Ca2(+)-antagonists were significantly less strong after pretreatment with 1,4-dihydropyridine than with non-dihydropyridines in papillary muscle strips. It is concluded that 1,4-dihydropyridines and verapamil and diltiazem did differently influence Ca2(+)-mediated increase in force of contraction. Moreover, a relation between the therapeutically active free plasma concentration in vivo and the negative inotropic potency in vitro can be found. This relation follows a rank order of potency for negative inotropism (isradipine less than or equal to nitrendipine less than diltiazem less than nifedipine less than verapamil) and might have clinical relevance in the treatment of patients with compromised cardiac function.