EVIDENCE FOR THE INVOLVEMENT OF THE ATP-SENSITIVE POTASSIUM CHANNEL IN A NOVEL MODEL OF HYPOXIC PRECONDITIONING IN DOGS

Objectives: The major aims of the present study were to determine if a 5 min period of hypoxic (pO(2) = 30-40 mmHg) buffer perfusion of the left anterior descending (LAD) coronary artery 10 min prior to a 60-min LAD occlusion produces myocardial preconditioning (PC) and to determine if hypoxic PC is mediated via activation of ATP-sensitive potassium channels (K-ATP). Normoxic (pO(2) = 500-600 mmHg) buffer perfusion served as a control. Methods: Barbital-anesthetized dogs were subjected to 60 min of LAD occlusion followed by 3 h of reperfusion. Hypoxic PC was produced by 5 min of LAD perfusion with hypoxic buffer followed by 10 min of blood reperfusion prior to a 60-min occlusion. A sham PC group, elicited by 5 min of LAD perfusion with normoxic buffer, served as a control. A final group of animals was treated with glibenclamide (0.3 mg/kg i.v.), a specific K-ATP channel antagonist, 15 min prior to hypoxic PC and 3 mu M Of glibenclamide was also added to the hypoxic buffer. Transmural myocardial blood flow (TMBF, mi/min/100 g) was determined by radioactive microspheres 30 min after the initiation of the prolonged 60-min occlusion and infarct size (IF/AAR) as a percent of the area at risk (AAR) was determined by triphenyltetrazolium staining. Results: There were no significant differences between groups in hemodynamics, AAR, or TMBF. Five minutes of perfusion with hypoxic buffer prior to the 60-min occlusion produced a marked reduction in myocardial infarct size as compared to control animals (control, 30 +/- 7 to 9 +/- 2%, hypoxic PC, P < 0.05). Five minutes of perfusion with normoxic buffer had no effect on infarct size (30 +/- 6%) and pretreatment with glibenclamide completely blacked the protective effect of hypoxic PC (31 +/- 7%). Conclusions: These results support the hypothesis that a brief period of hypoxic buffer perfusion can precondition the heart and that this cardioprotective effect is dependent on the opening of myocardial K-ATP channels.