ADENOSINE A(1) RECEPTOR BLOCKADE DOES NOT ABOLISH THE CARDIOPROTECTIVE EFFECTS OF THE ADENOSINE TRIPHOSPHATE-SENSITIVE POTASSIUM CHANNEL OPENER BIMAKALIM

There has been controversy regarding whether ATP-sensitive potassium c hannel activation protects hearts through adenosine A(1) receptor acti vation or the converse. We addressed this issue by determining the eff ect of the adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-diprop ylxanthine (DPCPX) on the cardioprotective activity of the ATP-sensiti ve potassium channel opener bimakalim. In isolated rat hearts subjecte d to 25 min of global ischemia and 30 min of reperfusion, bimakalim si gnificantly reduced lactate dehydrogenase release and improved postisc hemic recovery of contractile function. Bimakalim increased the time t o the onset of ischemic contracture (EC(25) = 1.2 mu M), compared with vehicle, and 10 mu M DPCPX had no effect on this protective action (E C(25) = 1.1 mu M). The 10 mu M concentration of DPCPX was sufficient t o abolish the bradycardic and cardioprotective effects of the adenosin e A(1) receptor agonist (R)-(-)-N-6-(2-phenylisopropyl)adenosine. DPCP X alone had no effect on the severity of ischemia/reperfusion damage. Glyburide completely abolished the cardioprotective effects of bimakal im. Bimakalim (1 mu g/kg, intracoronarily) given over four periods of 5 min, interspersed with 10-min drug-free periods, before a 60-min occ lusion and 3-hr reperfusion significantly reduced infarction size in a nesthetized dogs (25 +/- 5 and 8 +/- 2% of the left ventricular area a t risk for vehicle- and bimakalim-treated groups, respectively). DPCPX had no effect on the infarction-sparing activity of bimakalim (9 +/- 3% of the left ventricular area at risk). The protective effect of bim akalim was not accompanied by marked hemodynamic changes or by changes in regional myocardial blood flow. The results of this study suggest that the cardioprotective effects of ATP-sensitive potassium channel o peners are not dependent on adenosine A(1) receptor activation in rat or dog models of ischemia.