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 hypoxic cardiac failure was investigated in isolated guinea pig hearts with glibenclamide and rimalkalim as inhibitor and activator, respectively. Monophasic action potential duration at 90% of repolarization (MAP(90)), left ventricular function, and cardiac energy status ((31)Pp nuclear magnetic resonance spectroscopy) were measured during normoxic (95% O-2) and hypoxic (20% O-2) perfusion. In normoxic hearts, 1 mu M glibenclamide did not affect MAP(90), left ventricular function, and coronary 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 rimalkalim). 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 of hypoxic hearts was kept constant, however, glibenclamide elicited a sustained positive inotropic effect (n = 7). After glibenclamide, an increase 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 venous 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 accompanied by a partial restoration of the free energy change of ATP hydrolysis (-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 during hypoxia when there are only small changes in cytosolic ATP. This channel activation contributes to the downregulation of contractile force. These findings are consistent with the hypothesis that hypoxia-induced activation of K-ATP channels constitutes a protective mechanism that conserves the cardiac energy status under conditions of insufficient O-2 supply.