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Activation of ATP-Sensitive Potassium Channels in Hypoxic Cardiac Failure Is not Mediated by Adenosine-1 Receptors in the Isolated Rat Heart

Background: Hypoxic cardiac failure is accompanied by action potential shortening, which in part might be a consequence of opening of cardiac ATP-sensitive potassium channels (KMp channels). Coupling of the adenosine-1 receptor (A-1 receptor) to these channels has been described; however, the interaction of A-I-receptors and KMP channels in different models of ischemia is still under debate. The hypothesis as to whether A-1 receptors are involved in hypoxic K,, channel-activation in the saline-perfused rat heart was tested. Methods and Results: Pharmacologic modulation of the KTP channel by Glibenclamide (inhibitor) and Rimalkalim (activator) and of the A-1 receptor by R(-)-N6-(1-methyl-2-phenylethyl)-adenosine (R(-)-PIA, agonist) and 1,3-diethyl-3,7-dihydro-8-phenyl-purine-2,6-dione (DPX, antagonist) at different oxygen tensions (95% 02 and 20% 02) was performed in isolated Langendorff-rat hearts. Peak systolic pressure (PSP, intraventricular balloon), duration of monophasic action potential (epicardial suction electrode, time to 67% of repolarization: MAP67%), coronary flow, and heart rate (HR) were registered. Hypoxic perfusion resulted in a significant reduction of PSP (from 106 ±1 to 56 ± mmHg, P < 0.005) and shortening of MAP67% (from 37 ± to 25 ± ms, P < 0.005). With application of 1 pM Glibenclamide, MAP67% returned to normoxic values and PSP increased to 78 ± mmHg (P < 0.005 vs hypoxia). In normoxia, 2 pM Rimalkalin resulted in reduction of MAP67%/ and PSP, which was reversed by Glibenclamide. Application of 0.1 pM R(-)-PIA in normoxia resulted in a decrease of HR (from 235 ±6/min to 75 +41/min, P < 0.005), which was accompanied by an increase of PSP from 96 ± to 126 ± mmHg (P < 0.05) without changes in MAP67%. These effects were reversible by 1 MM DPX and remained unaffected by application of 1 PM Glibenclamide. Application of 1 pM DPX in hypoxia had no effect on the measured parameters. Conclusion: In isolated rat hearts, the K,p channel-system is activated in hypoxic cardiac failure and contributes to action potential shortening and reduced contractile performance. These effects seem to be independent of the A- I receptor in this model.