Abstract
There has been controversy regarding whether ATP-sensitive potassium channel activation protects hearts through adenosine A1receptor 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)-(−)-N 6-(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.
Footnotes
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Send reprint requests to: Gary J. Grover, Ph.D., Department of Cardiovascular Biochemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, NJ 08543-4000.
- Abbreviations:
- AAR
- anatomic area at risk
- ANCOVA
- analysis of covariance
- ANOVA
- analysis of variance
- DMSO
- dimethylsulfoxide
- DPCPX
- 8-cyclopentyl-1,3-dipropylxanthine
- EDP
- end diastolic pressure
- KATP
- ATP-sensitive potassium channels
- LAD
- left anterior descending coronary artery
- LDH
- lactate dehydrogenase
- LVDP
- left ventricular developed pressure
- (R)-PIA
- (R)-(−)-N 6-(2-phenylisopropyl)adenosine
- Received July 3, 1996.
- Accepted October 4, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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