Are ATP-sensitive potassium channels (KATP) implicated in hypoxic preconditioning?

Objective: To explain why intermittent hypoxia (IH) but not chronic hypoxia (CH) confer myocardial protection against reoxygenation injury we studied the consequences of a specific activator of mitochondrial KATP (diazoxide) and a non-specific inhibitor (glibenclamide) on myocardial performance after exposure to IH or CH.

Methods: Male 5-week old rats were housed under normoxia (N, FiO₂=0.21, n=24), CH (FiO₂=0.10, n=24) or IH (as CH but with 1h/day exposure to room air, n=24). Hearts were perfused for 30-min with cristalloid hypoxic buffer (PO₂=67mmHg), followed by 30-min of (re)oxygenation (PO₂=670mmHg). All 3 groups were subdivided in treatment with: a) diazoxide (100 microM), b) glibenclamide (3 microM) or c) placebo.

Results: At the end of the reoxygenation diazoxide determined lower End-Diastolic Pressure (EDP 2.8±0.5 vs. 7.7±0.5mmHg, p<0.001) and higher Left Ventricular Developed Pressure x Heart Rate (LVDPxHR 20.4±1.5 vs. 12.1±2.0mmHg.beats/min, p<0.001) in CH hearts. Glibenclamide increased EDP in IH (3.54±0.72 vs. 6.08±1.00mmHg, p<0.05) and improved myocardial systolic performance in CH (LVDPxHR 12.12±1.58 vs. 22.26±1.50mmHg.beats/min, p<0.01).

Conclusions: These results suggest that: 1) the activation of mitochondrial KATP improved the myocardial contractility in CH during reoxygenation; 2) the inhibition of KATP enhanced the myocardial systolic performance of CH hearts; 3) the inhibition of KATP didn’t reduce the protection offered by IH. The effects of KATP activator suggest the implication of KATP channels in myocardial protection observed in IH hearts. The use of KATP inhibitor doesn’t provide definitive response about the role of KATP in hypoxic preconditioning of myocardium.