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Cardioprotection by glucose-insulin-potassium: dependence on K_ATP channel opening and blood glucose concentration before ischemia

Departments of ¹Anesthesiology, ²Division of Cardiovascular Diseases, Department of Medicine, and ³Pharmacology and Toxicology, the Medical College of Wisconsin and the Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee 53226; and the Department of Biomedical Engineering, ⁴Marquette University, Milwaukee, Wisconsin 53201

Submitted 5 February 2004 ; accepted in final form 19 March 2004

We tested the hypothesis that glucose-insulin-potassium (GIK)-induced protection against myocardial infarction depends on ATP-dependent K⁺ (K_ATP) channel activation and is abolished by hyperglycemia before the ischemia. Dogs were subjected to a 60-min coronary artery occlusion and 3-h reperfusion in the absence or presence of GIK (25% dextrose; 50 IU insulin/l; 80 mM/l KCl infused at 1.5 ml·kg^–1·h^–1) beginning 75 min before coronary artery occlusion or 5 min before reperfusion. The role of K_ATP channels was evaluated by pretreatment with glyburide (0.1 mg/kg). The efficacy of GIK was investigated with increases in blood glucose (BG) concentrations to 300 or 600 mg/dl or experimental diabetes (alloxan/streptozotocin). Infarct size (IS) was 29 ± 2% of the area at risk in control experiments. GIK decreased (P < 0.05) IS when administered beginning 5 min before reperfusion. This protective action was independent of BG (13 ± 2 and 12 ± 2% of area at risk; BG = 80 or 600 mg/dl, respectively) but was abolished in dogs receiving glyburide (30 ± 4%), hyperglycemia before ischemia (27 ± 4%), or diabetes (25 ± 3%). IS was unchanged by GIK when administered before ischemia independent of BG (31 ± 3, 27 ± 2, and 35 ± 3%; BG = 80, 300, and 600 mg/dl, respectively). The insulin component of GIK promotes cardioprotection by K_ATP channel activation. However, glucose decreases K_ATP channel activity, and this effect predominates when hyperglycemia is present before ischemia.

diabetes; hyperglycemia; myocardial infarction

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