Abstract

Objective To study the effect and possible mechanism of diazoxide on myocardial ischemia/reperfusion (I/R) injury in diabetic rats, and the influence of insulin intervention which aims to maintain blood sugar levels within the normal range on the protective function of cardiomyocytes. Methods 126 health male Sprague-Dawley (SD) rats were intraperitoneally injected with one dose of 60 mg/kg streptozotocin (STZ) to reproduce diabetic model. The diabetic rats were randomly divided into seven groups, with 18 rats in each group. Myocardial I/R model was established by 30 minutes ligation of the left anterior descending branch of the coronary artery, and 120 minutes blood circulation recover. Sham group was only threaded without ligation. Rats in I/R group, diazoxide group (DZ group), and Ottawa vine penicillin (WNT) group were infused intravenously with 2 mL of 0.1% dimethyl sulphoxide (DMSO), DZ (7 mg/kg), and WNT (15 μg/kg), respectively, after 25 minutes of ischemia. Sham group was only injected with 2 mL of 0.1% DMSO. DZ+WNT group was infused with WNT 5 minutes before the injection of DZ. Insulin intervention (RI) group received a continuous insulin infusion to maintain the blood sugar at the level of 4-6 mmol/L. RI+DZ group was infused with DZ after ischemia for 25 minutes based on blood sugar control. Hemodynamic parameters in each group were monitored continuously. The pathological changes of myocardium were observed with hematoxylin and eosin (HE) staining. The expressions of phosphorylated protein kinase B (p-Akt) and phosphorylated glycogen synthase kinase-3β (p-GSK-3β) were determined by Western Blot. Results Compared with sham group, the cardiac functions of the intervention groups were significantly decreased, and severe myocardial injury was observed. Compared with I/R group, the cardiac functions of intervention groups were not obviously improved. However, after insulin intervention by which blood sugar was maintained within normal range, the cardiac function and myocardial injury were further aggravated. Compared with sham group (the expression value of sham group was set as 1), the expressions of p-Akt in other groups including I/R group, DZ group, RI group, and RI+DZ group showed no statistically significant difference (gray value: 1.07±0.09, 1.03±0.07, 1.07±0.07, 1.02±0.08 vs. 1.00, all P > 0.05). However, the expressions of p-Akt were decreased in WNT group and DZ+WNT group as compared with those of sham group and I/R group (gray value: 0.54±0.06, 0.51±0.05 vs. 1.00 and 1.07±0.09, all P 0.05). However, the expression of pGSK-3β was increased in RI group, RI+DZ group as compared with sham group and I/R group (gray value: 1.68±0.08, 1.70±0.05 vs. 1.00 and 0.97±0.08, all P < 0.05), and it was significantly higher in RI+DZ group than that of DZ group (gray value: 1.70±0.05 vs. 1.00±0.11, P < 0.05). Conclusions Diazoxide after myocardial injury could not protect the myocardium from I/R injury in diabetic rats, and did not trigger the activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Insulin intervention by which blood sugar was maintained within the normal range exacerbates myocardial I/R injury in diabetic rats. Key words: Diabetes; Diazoxide; Ischemia/reperfusion, myocardial; Insulin

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