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 (pO2 = 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 (KATP). Normoxic (pO2 = 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 KATP channel antagonist, 15 min prior to hypoxic PC and 3 microM of glibenclamide was also added to the hypoxic buffer. Transmural myocardial blood flow (TMBF, ml/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 blocked 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 KATP channels.