BACKGROUND: Diabetes mellitus (DM) is a risk factor for cardiovascular diseases, specifically, the ischemic heart diseases (IHD). The renin-angiotensin system (RAS) affects the heart directly and indirectly. However, its role in the protection of the heart against I/R injury is not completely understood. The aim of the current study was to evaluate the efficacy of the angiotensin-converting enzyme (ACE) inhibitor and Angiotensin II receptor (AT1R) blocker or a combination thereof in protection of the heart from I/R injury. METHODS: Hearts isolated from adult male Wistar rats ( = 8) were subjected to high glucose levels; acute hyperglycemia or streptozotocin (STZ)-induced diabetes were used in this study. Hearts were subjected to I/R injury, treated with Captopril, an ACE inhibitor; Losartan, an AT1R antagonist; or a combination thereof. Hemodynamics data were measured using a suitable software for that purpose. Additionally, infarct size was evaluated using 2,3,5-Triphenyltetrazolium chloride (TTC) staining. The levels of apoptosis markers (caspase-3 and -8), antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT), nitric oxide synthase (eNOS), and glucose transporter type 4 (GLUT-4) protein levels were evaluated by Western blotting. Pro-inflammatory and anti-inflammatory cytokines levels were evaluated by enzyme-linked immunosorbent assay (ELISA). RESULTS: Captopril and Losartan alone or in combination abolished the effect of I/R injury in hearts subjected to acute hyperglycemia or STZ-induced diabetes. There was a significant ( < 0.05) recovery in hemodynamics, infarct size, and apoptosis markers following the treatment with Captopril, Losartan, or their combination. Treatment with Captopril, Losartan, or their combination significantly ( < 0.05) reduced pro-inflammatory cytokines and increased GLUT-4 protein levels. CONCLUSIONS: The blockade of the RAS system protected the diabetic heart from I/R injury. This protection followed a pathway that utilizes GLUT-4 to decrease the apoptosis markers, pro-inflammatory cytokines, and to increase the anti-inflammatory cytokines. This protection seems to employ a pathway which is not involving ERK1/2 and eNOS.