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

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/1; 80 mM/1 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 +/- 14%), 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.