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The opposite effects of nitric oxide donor, S‐nitrosoglutathione, on myocardial ischaemia/reperfusion injury in diabetic and non‐diabetic mice

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Clinical and Experimental Pharmacology and Physiology

Published online on


Nitric oxide is a potent anti‐apoptotic and cardioprotective molecule in healthy animals. However, recent study demonstrates that overexpression of eNOS exacerbates the liver injury in diabetic animals. whether diabetes may also alter NO's biologic activity in ischaemic/reperfused heart remains unknown. The present experiment was designed to determine whether the nitric oxide donor, S‐nitrosoglutathione, may exert different effects on diabetic and non‐diabetic myocardial ischaemia/reperfusion (MI/R) injury. Diabetic state was induced in mice by multiple intraperitoneal injections of low‐dose streptozotocin (STZ). The control or diabetic mice were subjected to 30 minutes ischaemia and 3 or 24 hours reperfusion. At 10 minutes before reperfusion, diabetic and non‐diabetic mice were received an intraperitoneal injection of S‐nitrosoglutathione (GSNO, a nitric oxide donor, 1 μmol/kg). GSNO attenuated MI/R injury in non‐diabetic mice, as measured by improved cardiac function, reduced infarct size and decreased cardiomyocyte apoptosis. In contrast, GSNO failed to attenuate but, rather, aggravated the MI/R injury in diabetic mice. Mechanically, the diabetic heart exhibited an increased nitrative/oxidative stress level, as measured by peroxynitrite formation, compared with non‐diabetic mice. Co‐administration of GSNO with EUK134 (a peroxynitrite scavenger) or MnTE‐2‐PyP5 (a superoxide dismutase mimetic) or Apocynin (a NADPH oxidase inhibitor) 10 minutes before reperfusion significantly decreased the MI/R‐induced peroxynitrite formation and the MI/R injury. Collectively, the present study for the first time demonstrated that diabetes may cause superoxide overproduction, increase NO inactivation and peroxynitrite formation, and thus convert GSNO from a cardioprotective molecule to a cardiotoxic molecule.