Background:We have recently reported that heme oxygenase-1 (HO-1) is involved in ischemic preconditioning-mediated cardioprotection by promoting nitric oxide (NO) release into diabetic rat heart (DRH). The upregulation of HO-1 decreases the endothelin-1 (ET-1) production, which is a negative regulator of NO. In diabetes, the level of HO-1 is reduced while the level of ET-1 gets elevated. Thus, the present analysis was aimed to explore the concept of HO-1 and ET-1 in the abrogated cardioprotective role of ischemic post conditioning (IPOC) in the DRH. Materials and Methods: To explore the concept, a selective HO-1 inducer hemin, 18 hrs prior and a selective ETA receptor antagonist BQ-123, one week prior, were administered to DRH before isolation. DRH was removed and then mounted on Langendorff's apparatus, subjected to 10 min stabilization followed by 30 min ischemia. IPOC had been induced by four cycles of 5 min reperfusion along with 5 min ischemia followed by further 120 min of reperfusion. The extent of the infarct was measured and the coronary effluent was tested for the LDH, CK-MB and NO release. Results: In DRH, cardioprotection mediated by the IPOC was significantly attenuated. Hemin and BQ-123 reinstated the impact of IPOC in DRH and also increased the release of NO. In BQ-123 pre-treated diabetic rat, the administration of hemin was unable to produce the additive cardioprotective effect of IPOC. Conclusion: Thus, it is suggested that hemin and BQ-123 restore the attenuated cardioprotective effect of IPOC in the DRH, which may be due to increased NO release.