Diabetes and hyperglycemia impair activation of mitochondrial K-ATP channels

Hyperglycemia is an important predictor of cardiovascular mortality in pati ents with diabetes. We investigated the hypothesis that diabetes or acute h yperglycemia attenuates the reduction of myocardial infarct size produced b y activation of mitochondrial ATP-regulated potassium (K-ATP) channels. Acu tely instrumented barbiturate-anesthetized dogs were subjected to a 60-min period of coronary artery occlusion and 3 h of reperfusion. Myocardial infa rct size (triphenyltetrazolium chloride staining) was 25 +/- 1, 28 +/- 3, a nd 25 +/- 1% of the area at risk (AAR) for infarction in control, diabetic (3 wk after streptozotocin-alloxan), and hyperglycemic (15% intravenous dex trose) dogs, respectively. Diazoxide (2.5 mg/kg iv) significantly decreased infarct size (10 +/- 1% of AAR, P< 0.05) but did not produce protection in the presence of diabetes (28 +/- 5%) or moderate hyperglycemia (blood gluc ose 310 +/- 10 mg/dl; 23 +/- 2%). The dose of diazoxide and the degree of h yperglycemia were interactive. Profound (blood glucose 574 +/- 23 mg/dl) bu t not moderate hyperglycemia blocked the effects of high-dose (5.0 mg/kg) d iazoxide [26 +/- 3, 15 +/- 3 (P< 0.05), and 11 +/- 2% (P< 0.05), respective ly]. There were no differences in systemic hemodynamics, AAR, or coronary c ollateral blood flow (by radioactive microspheres) between groups. The resu lts indicate that diabetes or hyperglycemia impairs activation of mitochond rial K-ATP channels.