The calcium channel blocking agents verapamil and nifedipine have been reported to lessen abnormalities of left ventricular relaxation in patients with severe left ventricular hypertrophy or coronary artery disease. Whether these effects in human beings are related in part to a direct effect on myocardial calcium metabolism is difficult to determine because of complicating drug influences on ventricular loading via systemic arterial vasodilation, on myocardial blood supply via coronary artery vasodilation and on reflex changes in sympathetic tone. For this reason, the effects of verapamil were investigated in a cellular model of impaired relaxation using spontaneously contracting tissue cultured monolayers of chick embryo ventricular cells exposed to high external calcium ([Ca] 0). Under control conditions ([Ca] 0, 0.9 m M), verapamil (2 × 10 −8 M) induced a 57 ± 8% decrease in amplitude of cell contraction monitored with a phase contrast microscope video motion detector system. Elevation of [Ca] 0 from 0.9 to 8.0 m M resulted in a decrease in amplitude and velocity of contraction and a decrease in velocity of relaxation associated with an upward shift in diastolic cell wall position, suggesting a failure of normal myofilament dissociation. These abnormalities were completely reversible on reperfusion with [Ca] 0, 0.9 m M. On re-exposure of the cells to [Ca] 0, 8.0 m M, in the presence of verapamil, there was an increase in amplitude of contraction (0.56 ± 0.11 to 1.03 ± 0.09 µm, p < 0.01) and velocity of relaxation (4.97 ± 0.89 to 9.94 ± 0.87 (µm/s, p < 0.01) compared with exposure to [Ca] 0, 8.0 m M, alone, and an attenuation of the upward shift in diastolic cell wall position. Furthermore, partial contracture induced by calcium overload could also be directly reversed by exposure to verapamil during continued perfusion with high [Ca] 0. These data show that verapamil can improve relaxation and increase amplitude of contraction of a calcium-overloaded ventricular cell. Thus, the effects of calcium channel blockers on myocardial performance may depend in part on the degree of myocardial calcium levels.