The effect of SEA0400, a novel Na+-Ca2+ exchanger inhibitor, on mechanical and electrophysiological parameters of coronary-perfused guinea-pig right ventricular tissue preparation was examined during no-flow ischemia and reperfusion. Contractile force and action potential duration were decreased during no-flow ischemia, while the resting tension was increased. Upon reperfusion, transient arrhythmias were observed and contractile force returned to less than 50% of preischemic values. SEA0400 (1 microM) had no effect on the decline in contractile force during the no-flow ischemia, but abolished the rise in resting tension. SEA0400 significantly improved the recovery of contractile force after reperfusion to about 80% of the preischemic value. SEA0400 had no effect on the action potential under normal conditions and during ischemia, but significantly improved the recovery of action potential duration after reperfusion. Enhancement of the recovery of contractile force during reperfusion by SEA0400 was also observed when the drug was applied only before and during the ischemic period and when the drug was applied only during reperfusion. The present results indicate that inhibition of Na+-Ca2+ exchanger either during ischemia or during reperfusion exerts cardioprotective effects and enhances the recovery of myocardial contractile function.