Regional and global myocardial ischemia and reperfusion have been demonstrated to induce expression of the stress response protein heat shock 70 (HSP70) and of immediate early genes, c-jun, c-fos, and c-myc. Because of the models that have been utilized, it has not been possible to discriminate whether this response is the consequence of ischemia, reperfusion, or abnormal hemodynamic stress superimposed on stunned myocardium. In a nonworking isolated and blood-perfused rat heart model, we evaluated the mRNAs for c-fos, c-myc, and hsp70. The heart was subjected to varying periods of ischemia and reperfusion. Significant increases in hsp70 and c-fos were observed, which increased with longer periods of ischemia. No significant increase in c-myc was measured. In addition, mRNA encoding the Ca2+/glucose responsive stress protein GRP78 was evaluated. No increase in this early response gene was noted despite the use of a model associated with cellular calcium loading. Based on these observations, we suggest that the induction of hsp70 and c-fos is the consequence of ischemia and reperfusion and not dependent upon an early hypertrophy response such as would be observed in afterload mismatching or on calcium loading. Further investigations are necessary to isolate the effects of ischemia from those of reperfusion.