During reperfusion with pH 7.2 media after 55 min of ischemia, the recovery of developed tension (DT) and the maximal resting tension (RT) of the isolated right ventricular wall of rats were 58.8 +/- 6.5 and 201 +/- 20%, respectively, of the preischemic values. DT and RT in the ventricular wall perfused with pH 7.9 media for 6 min during reperfusion were 40 +/- 5.9 and 285 +/- 13%, respectively, of the preischemic values (P less than .05 vs. pH 7.2 group). The Na(+)-H+ exchange inhibitor, 5-(N,N-dimethyl)amiloride (DMA), effectively antagonized the detrimental effect of pH 7.9 media. A pH 6.5 media inhibited DT recovery and the rise in RT in the first 6 min of reperfusion. Subsequent reperfusion with pH 7.2 media resulted in cardiac dysfunction similar to that observed when reperfused at pH 7.2 only. Cellular Na+ and Ca++ were significantly elevated after 6 min of reperfusion at pH 7.2. Na+ and Ca++ levels were increased further if reperfusion was carried out at pH 7.9. Inclusion of 20 microM DMA during reperfusion at 7.9 significantly reduced cellular Na+ and Ca++. Creatine phosphokinase activity in the coronary effluent rose significantly during reperfusion at pH 7.2 and this was exacerbated if the reperfusion pH was 7.9. DMA treatment during reperfusion could significantly inhibit this elevation. The data lend further support for an important role of Na(+)-H+ exchange in the development of ischemia-reperfusion injury.