Effects of mitochondrial KATP modulators on cardioprotection induced by chronic high altitude hypoxia in rats

Objectives: Adaptation of rats to intermittent high altitude hypoxia increases the tolerance of their hearts to acute ischemia/reperfusion injury. Our aim was to examine the role of mitochondrial ATP-sensitive potassium channels (K-ATP) in this form of protection. Methods: Adult male Wistar rats were exposed to hypoxia of 5000 in in a barochamber for 8 h/day, 5 days a week; the total number of exposures was 24-32. A control group was kept under normoxic conditions (200 m). Infarct size (tetrazolium staining) was measured in anesthetized open-chest animals subjected to 20-min regional ischemia (coronary artery occlusion) and 4-h reperfusion. Isolated perfused hearts were used to assess the recovery of contractile function following 20-min global ischemia and 40-min reperfusion. In the open-chest study, a selective mitochondrial K-ATP blocker, 5-hydroxydecanoate (5 mg/kg), or openers, diazoxide (10 mg/kg) or BMS-191095 ( 10 mg/kg), were administered into the jugular vein 5 and 10 min before occlusion, respectively. In the isolated heart study, 5-hydroxydecanoute (250 mumol/l) or diazoxide (50 mumol/l) were added to the perfusion medium 5 or 10 min before ischemia, respectively. Results: fit the control normoxic group, infarct size occupied 62.2 +/- 2.0% of the area at risk as compared with 52.7 +/- 2.5% in the chronically hypoxic group (P < 0.05). Post-ischemic recovery or contractile function (dP/dt) reached 60.0 +/- 3.9% of the pre-ischemic value and it was improved to 72.4 +/- 1.2% by adaptation to hypoxia (P < 0.05). While 5-hydroxydecanoate completely abolished these protective effects of chronic hypoxia, it had no appreciable influence in normoxic groups. In contrast, diazoxide significantly increased the recovery of contractile function and reduced infarct size in normoxic groups only. The later effect was also observed following treatment with BMS-191095. Conclusion: The results suggest that opening of mitochondrial K-ATP channels is involved in the cardioprotective mechanism conferred by long-term adaptation to intermittent high altitude hypoxia. (C) 2002 Elsevier Science B.V. All rights reserved.