The use of calcium antagonists in the treatment of cardiac failure is limited by the negative inotropic effects they exert. The comparative inotropic activity of four calcium antagonists was therefore investigated, using electrically driven human papillary muscle strips and human atrial trabeculae. These inotropic effects were studied with cumulative concentration-response curves. The four calcium antagonists included in this study were all found to significantly (P less than or equal to .05) diminish the force of contraction above 0.01 mumol/L, but with different potencies. On the basis of the relationship between therapeutic vasoactive plasma concentrations and the negative inotropic effective concentrations in our system in vitro, the ranking order of potential negative inotropism in the treatment of cardiac failure with calcium antagonists was verapamil greater than nifedipine greater than diltiazem greater than isradipine. Thus, to minimize cardiodepressant risk, the use of calcium antagonists with weak negative inotropic effects at relevant concentrations should be preferred, especially in the case of patients with compromised cardiac function.