Abstract: AIM To investigate the effects of vasonatrin peptide (VNP) on myocardial ischemia/reperfusion (MI/R) injury in diabetic rats and to elucidate its mechanisms. METHODSHigh-fat diet and low-dose streptozotocin (STZ, 25 mg/kg, i.p.) injection induced diabetic Sprague Dawley rats with random blood glucose level >11.1 mmol/L 1 week later. Left anterior descending coronary artery was ligated for 30 min and reperfused for 4 h to establish the in vivo model of ischemia-reperfusion. RESULTSVNP treatment (100 μg/kg, i.v., 10 min before R) significantly improved ±LV dP/dtmax and LVSP and reduced LVEDP, apoptosis index, caspase-3 activity, plasma CK and LDH activities. Moreover, VNP inhibited endoplasmic reticulum (ER) stress by suppressing GRP78 and CHOP. These effects were mimicked by 8-Br-cGMP, a cGMP analogue but were inhibited by KT-5823, a selective inhibitor of PKG. In addition, pretreatment of DM rats with TUDCA, a specific inhibitor of ER stress, did not further promote the cardioprotective effect of VNP. CONCLUSIONVNP protects diabetic heart against MI/R injury by inhibiting ER stress via cGMP-PKG signaling pathway. These results suggest that VNP may have some potential therapeutic value for diabetic patients with ischemic heart disease.