Vol. 280, Issue 2, 533-540, 1997

Adenosine A₁ Receptor Blockade Does Not Abolish the Cardioprotective Effects of the Adenosine Triphosphate-sensitive Potassium Channel Opener Bimakalim

Garrett J. Gross, David A. Mei, Paul G. Sleph and Gary J. Grover

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin (G.J.Gross, D.A.M.), and Department of Cardiovascular Biochemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey (P.G.S., G.J.Grover)

There has been controversy regarding whether ATP-sensitive potassium channel activation protects hearts through adenosine A₁ receptor activation or the converse. We addressed this issue by determining the effect of the adenosine A₁ receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) on the cardioprotective activity of the ATP-sensitive potassium channel opener bimakalim. In isolated rat hearts subjected to 25 min of global ischemia and 30 min of reperfusion, bimakalim significantly reduced lactate dehydrogenase release and improved postischemic recovery of contractile function. Bimakalim increased the time to the onset of ischemic contracture (EC₂₅ = 1.2 µM), compared with vehicle, and 10 µM DPCPX had no effect on this protective action (EC₂₅ = 1.1 µM). The 10 µM concentration of DPCPX was sufficient to abolish the bradycardic and cardioprotective effects of the adenosine A₁ receptor agonist (R)-()-N⁶-(2-phenylisopropyl)adenosine. DPCPX alone had no effect on the severity of ischemia/reperfusion damage. Glyburide completely abolished the cardioprotective effects of bimakalim. Bimakalim (1 µg/kg, intracoronarily) given over four periods of 5 min, interspersed with 10-min drug-free periods, before a 60-min occlusion and 3-hr reperfusion significantly reduced infarction size in anesthetized dogs (25 ± 5 and 8 ± 2% of the left ventricular area at 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 bimakalim 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 openers are not dependent on adenosine A₁ receptor activation in rat or dog models of ischemia.