OBJECTIVE: We tested whether ischemic postconditioning (IPostC) is protective in remodeled myocardium. METHODS: Post-myocardial infarct (MI)-remodeled hearts after permanent coronary artery ligation and one kidney one clip (1K1C) hypertensive hearts of male Wistar rats were exposed to 40 min of ischemia followed by 90 min of reperfusion. IPostC was induced by six cycles of 10 s reperfusion interspersed by 10 s of no-flow ischemia. Activation of reperfusion injury salvage kinases was measured using Western blotting and in vitro kinase activity assays. RESULTS: IPostC prevented myocardial damage in both MI-remodeled and 1K1C hearts, as measured by decreased infarct size and lactate dehydrogenase release, and improved function. The reduction in infarct size and the recovery of left ventricular contractility achieved by IPostC was less in 1K1C hearts, but was unchanged in MI-remodeled hearts when compared to healthy hearts. In contrast, the recovery of inotropy was unaffected in 1K1C hearts, but was less in MI-remodeled hearts. Inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway with LY294002 abolished the protective effects of IPostC on both disease models and healthy hearts. Western blot analysis in conjunction with in vitro kinase activity assays identified protein kinase B (PKB)/Akt but not p42/p44 extracellular-signal regulated kinase 1/2 (ERK1/2) as the predominant kinase in IPostC-mediated cardioprotection in remodeled hearts. IPostC increased phosphorylation of the PKB/Akt downstream targets eNOS, GSK3beta, and p70S6K in remodeled hearts. CONCLUSION: Our results offer evidence that IPostC mediates cardioprotection in the remodeled rat myocardium primarily via activation of the PI3K-PKB/Akt reperfusion injury salvage kinase pathway.