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/l; 80 mM/l KCl infused at 1.5 ml x kg(-1) x 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.
LaDisa
John F
JF
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Krolikowski
John G
JG
Pagel
Paul S
PS
Warltier
David C
DC
Kersten
Judy R
JR
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D004285:Dogs; D004334:Drug Administration Schedule; D005947:Glucose / Q000008:administration & dosage*; D005905:Glyburide / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000008:administration & dosage* / Q000097:blood; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000150:complications / Q000503:physiopathology; D009994:Osmolar Concentration; D011188:Potassium / Q000008:administration & dosage*; D015221:Potassium Channels / Q000378:metabolism*
D001786:Blood Glucose; D002316:Cardiotonic Agents; D007004:Hypoglycemic Agents; D007328:Insulin; D015221:Potassium Channels; C030396:glucose-insulin-potassium cardioplegic solution; D000255:Adenosine Triphosphate; D005947:Glucose; D011188:Potassium; D005905:Glyburide