In studies of the calcium paradox, we have used an isolated rat heart preparation to investigate the relationship between myocardial creatine kinase leakage and the concentration of slow-calcium-channel blockers (nifedipine or verapamil) in the perfusion fluid during a cycle of calcium reduction and repletion. The results indicated that enzyme leakage could be further reduced to a degree greater than that seen under conditions of a full calcium paradox (complete calcium depletion). Detailed dose-response studies with verapamil and nifedipine at a calcium concentration of 1.0 mM during a 20-min period of calcium repletion following a 10-min period of calcium reduction (12 microM calcium) revealed complex dose-response characteristics for each drug. In the dose range studied (0-20 microM), nifedipine was able to reduce enzyme leakage maximally by 57 +/- 8% and verapamil by 37 +/- 4%. Optimal concentrations for verapamil and nifedipine were 4.0 and 2.0 microM, respectively. Both drugs exhibited bell-shaped dose-response curves without a loss of efficacy at higher concentrations. There was no resumption in contractile activity in the drug-treated groups. Simultaneous use of verapamil and nifedipine at their optimal concentrations failed to improve the reduction in enzyme leakage to a reduction greater than that observed with one drug alone.