HYPOXIA-INDUCED ACTIVATION OF K-ATP CHANNELS LIMITS ENERGY DEPLETION IN THE GUINEA-PIG HEART

The functional role of ATP-dependent potassium channels (K-ATP) in hyp oxic cardiac failure was investigated in isolated guinea pig hearts wi th glibenclamide and rimalkalim as inhibitor and activator, respective ly. Monophasic action potential duration at 90% of repolarization (MAP (90)), left ventricular function, and cardiac energy status ((31)Pp nu clear magnetic resonance spectroscopy) were measured during normoxic ( 95% O-2) and hypoxic (20% O-2) perfusion. In normoxic hearts, 1 mu M g libenclamide did not affect MAP(90), left ventricular function, and co ronary flow (n = 4). In contrast, rimalkalim rapidly shortened MAP(90) and left ventricular pressure (LVP) in a dose-dependent fashion (e.g. , by 60.2 +/- 3.5 and 80.8 +/- 8.2%, respectively, with 0.6 mu M rimal kalim). This latter effect was reversed by 1 mu M glibenclamide (n = 4 ). With hypoxic perfusion, a reduction in LVP was observed, along with a shortening of the action potential (MAPS,; 202 +/- 13 vs. 164 +/ 9 ms) and an increase in coronary flow. Glibenclamide (1 mu M) reversed the MAP(90) shortening and the increase in coronary flow. In addition, glibenclamide increased LVP transiently (n = 4). When coronary flow o f hypoxic hearts was kept constant, however, glibenclamide elicited a sustained positive inotropic effect (n = 7). After glibenclamide, an i ncrease in LVP from 54 +/- 4 to 64 +/- 3 mmHg was observed, along with a reduction in the free energy change of ATP hydrolysis from -54.5 +/ - 1.9 to -52.9 +/- 0.2 kJ/mol and a further increase in the coronary v enous adenosine from 269 +/- 48 to 1,680 +/- 670 nmol/l. In contrast, 0.1 mu M rimalkalim further shortened the action potential of hypoxic hearts and caused a major reduction of systolic force. This was accomp anied by a partial restoration of the free energy change of ATP hydrol ysis (-55.8 +/- 0.7 kJ/ mel) and a decrease in venous adenosine (157 27 nmol/l). Our results suggest that K-ATP channels are activated dur ing hypoxia when there are only small changes in cytosolic ATP. This c hannel activation contributes to the downregulation of contractile for ce. These findings are consistent with the hypothesis that hypoxia-ind uced activation of K-ATP channels constitutes a protective mechanism t hat conserves the cardiac energy status under conditions of insufficie nt O-2 supply.