Postinfarct remodeling impairs mechanisms of ischemic preconditioning. We examined whether myocardial response to activation of the erythropoietin (EPO) receptor is modified by postinfarct remodeling. Four weeks after induction of myocardial infarction (MI) by coronary ligation in post-MI group (post-MI) or a sham operation in sham group (sham), rat hearts were isolated and subjected to 25-min global ischemia/2-h reperfusion. Infarct size was expressed as a percentage of risk area (i.e., left ventricle) from which scarred infarct was excluded (%I/R). The heart weight was 15% larger in post-MI, but there was no intergroup difference in plasma EPO levels or myocardial EPO receptor levels. EPO infusion (5 U/ml) significantly reduced %I/R from 59.9 +/- 4.1 to 36.2 +/- 4.2 in sham and from 58.1 +/- 5.0 to 35.2 +/- 4.0 in post-MI. This EPO-induced protection was sensitive to a phosphatidylinositol 3-kinase (PI3K) inhibitor, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), in sham. However, neither LY294002 nor wortmannin inhibited the EPO-induced protection in post-MI. Phosphorylation of Janus kinase 2 by EPO was attenuated and phosphorylation of Akt was not detected in post-MI. A guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one, and a mitochondrial ATP-sensitive K(+) channel (mitoK(ATP) channel) blocker, 5-hydroxydecanoate, inhibited EPO-induced protection in both sham and post-MI. Suppressor of cytokine signaling (SOCS)-1 protein level was higher by 50% in post-MI than in sham, although SOCS-3 levels were similar. These findings suggest that postinfarct remodeling disrupts cellular signaling from the EPO receptor to PI3K, presumably by increased SOCS-1. However, in the remodeled myocardium, lack of PI3K/Akt activation by the EPO receptor seems to be compensated by a mechanism upstream of the guanylyl cyclase-mitoK(ATP) channel pathway to achieve EPO-induced protection.