Reverse-mode activation of the Na+-Ca2+ exchanger (NCX) at the time of reperfusion following ischemia contributes to Ca2+ overload and cardiomyocyte injury. The aim of the present study was to determine whether increased NCX in the myocardium that survived after infarction enhances its vulnerability to ischemia/reperfusion injury. Rabbits were divided into post-MI and sham groups and underwent ligation of the left circumflex coronary artery and sham operation, respectively. Two weeks later, hearts were isolated and perfused with crystalloid in the Langendorff mode with monitoring of left ventricular (LV) pressure. NCX level in the myocardium was determined by Western blotting. Myocardial stunning was induced by 5 episodes of 5-min global ischemia/5-min reperfusion. Using separate groups of hearts, myocardial infarction was induced by 30-min global ischemia/2-h reperfusion with or without treatment with 0.3 microM KB-R7943, a reverse-mode selective blocker of NCX. Heart weight-to-body weight ratio was 20% larger and NCX protein level was 60% higher in the post-MI group than in the sham group. However, there were no significant differences between severities of myocardial stunning after the repetitive ischemia/ reperfusion (18 +/- 7 vs. 25 +/- 2% reduction in LV developed pressure) and between infarct sizes after 30-min ischemia (59.1 +/- 4.1 vs. 63.0 +/- 4.5% of risk area) in the post-MI and sham groups. KB-R7943 limited infarct size in the post-MI group by 53%, and the extent of this protection was not different from that we have reported for hearts without previous infarcts (i.e. 45% reduction of infarct size). These results suggest that enhanced NCX expression does not necessarily increase myocardial vulnerability to myocardial stunning and infarction.