Protective effects of diazoxide and its 24 derivatives on myocardial ischemia injury

Objective To evaluate the protective effects of diazoxide and its derivatives(2001~2024)against ischemic injury on cardiomyocytes.by establishing a hypoxia/reoxygenation model and on myocardial ischemia induced by isoproteronol(ISO)in mice,making preparation for finding new anti-myocardial ischemia drugs.Methods 48 Kunming mice underwent subcutaneous injection of isoproterenol(ISO)20 mg/kg once a day for 2 days so as to establish animal model of myocardiac ischemia and then divided into equal groups:model group,underging gastric perfusion of,2010 1 mg/kg group,undergoing gastric perfusion of dimethyl sulfoxide solution bid for 7 d;2010 1,2,and 3 mg/kg groups,undergoing gastric perfusion of 2010 1,2,or 3 mg/kg bid for 7 d;and 2023 1,2,or 3 mg/kg bid for 7 days.Since 5 h after the first administration these mice underwent subcutaneous injection of ISO 20 mg/kg once a day for 2 days.Another 24 mice were divided into 2 equal groups:normal saline(NS)control group,undergoing gastric perfusion of NS and then subcutaneous injection of NS,solvent control group,undergoing gastric perfusion of dimethyl sulfoxide solution.and then subcutaneous injection of dimethyl sulfoxide solution.Two hours after the last subcutaneous injection of NS or ISO the mice were killed with their hearts taken out to undergo pathological examination.The content of creatine kinase(CK)in serum was detected.Results The vitality of the rat cardiomyocytes was remarkably improved in the diazoxide,2013,2023,and 2024 of the concentrations of 10 and 100 μmol/L,2022 of the concentration of 10 μmol/L,and 2010 of the concentration of 100 μmol/L significantly increased compared with the other groups.The serum CK level of the model group was significantly higher than that of the solvent control group(P0.01).The serum CK levels of the 2023 1 and 3 mg/kg subgroups,2010 3 and 9 mg/kg subgroups,and diazolun 1 and 3 mg/kg subgroups were all significantly lower than that of model group(all P0.05).There was no significant difference in the CK level between the NS control group and solvent control group.Pathological changes could be seen in the myocardium of the model group and injury-solvent group.And the pathological canges of the 2010 3 and 9 mg/kg subgroups,2023 1,3,and 9 mg/kg subgroups,and diazolon 3 and 9 mg/kg subgroups were all very mild compared with the other groups.Conclusion 2010 and 2023 have remarkable protective effects on the ventricular cardiomyocytes.