Diabetes and hyperglycemia impair activation of mitochondrial K(ATP) channels.
Hyperglycemia is an important predictor of cardiovascular mortality in patients with diabetes. We investigated the hypothesis that diabetes or acute hyperglycemia attenuates the reduction of myocardial infarct size produced by activation of mitochondrial ATP-regulated potassium (K(ATP)) channels. Acutely instrumented barbiturate-anesthetized dogs were subjected to a 60-min period of coronary artery occlusion and 3 h of reperfusion. Myocardial infarct size (triphenyltetrazolium chloride staining) was 25 +/- 1, 28 +/- 3, and 25 +/- 1% of the area at risk (AAR) for infarction in control, diabetic (3 wk after streptozotocin-alloxan), and hyperglycemic (15% intravenous dextrose) 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 glucose 310 +/- 10 mg/dl; 23 +/- 2%). The dose of diazoxide and the degree of hyperglycemia were interactive. Profound (blood glucose 574 +/- 23 mg/dl) but not moderate hyperglycemia blocked the effects of high-dose (5.0 mg/kg) diazoxide [26 +/- 3, 15 +/- 3 (P < 0.05), and 11 +/- 2% (P < 0.05), respectively]. There were no differences in systemic hemodynamics, AAR, or coronary collateral blood flow (by radioactive microspheres) between groups. The results indicate that diabetes or hyperglycemia impairs activation of mitochondrial K(ATP) channels.
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. jkerstan@mcw.edu
J R
JR
Kersten
M W
MW
Montgomery
T
T
Ghassemi
E R
ER
Gross
W G
WG
Toller
P S
PS
Pagel
D C
DC
Warltier
D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D002245:Carbon Dioxide / Q000097:blood; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003981:Diazoxide / Q000494:pharmacology; D004285:Dogs; D004699:Endocardium / Q000187:drug effects / Q000503:physiopathology; D006339:Heart Rate; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology*; D008565:Membrane Proteins / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology*; D010100:Oxygen / Q000097:blood; D015221:Potassium Channels; D014665:Vasodilator Agents / Q000494:pharmacology; D016277:Ventricular Function, Left
D001786:Blood Glucose; D008565:Membrane Proteins; D015221:Potassium Channels; D014665:Vasodilator Agents; C117780:mitochondrial K(ATP) channel; D002245:Carbon Dioxide; D003981:Diazoxide; D010100:Oxygen