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Introduction: This study was to observe the effects of vasonatrin peptide (VNP) on myocardial ischemia/reperfusion (MI/R)-induced injury in diabetic rats.Methods: The high-fat diet-fed streptozotocin rat model (type 2 diabetic model) was developed and MI/R (30 min/4 hrs) was performed.Results: Treatment of diabetic rats with VNP (100 μg/kg i.v.) improved ±LVdP/dt and reduced infarct size and apoptosis (n=8,P<0.05).MI/R induced obvious endoplasmic reticulum (ER) stress (increased GRP78/Chop levels) in diabetic myocardium.VNP significantly reduced GRP78/Chop levels and subsequently increased Akt/ERKl/2 signaling.VNPs these effects were mimicked by 8-Br-cGMP and inhibited by KT-5823.Overexpression of PKG in neonatal rat cardiomyocytes reduced ER stress and increased Akt/ERK1/2 after hypoxia/reoxygenation.Silencing PKG expression with small interfering RNA enhanced ER stress and reduced Akt/ERK1/2 signaling.Conclusion:VNP confers cardioprotection against MI/R by inhibiting the ER stress and resultant enhancing the cell survival signaling in diabetic rats