Glibenclamide antagonizes adenosine A1 receptor-mediated cardioprotection in stunned canine myocardium.

Abstract

BACKGROUND The main objective of the present study was to determine the role of adenosine in the development of myocardial stunning following multiple, brief periods of coronary artery occlusion as well as the subtype of adenosine receptor (A1 or A2) involved. A second objective was to determine if there was an interaction between the adenosine A1 receptor and the ATP-dependent K channel (KATP). METHODS AND RESULTS The effects of the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and agonist cyclopentyladenosine (CPA), the selective A2 receptor agonist CGS 21680, and the KATP channel blocker glibenclamide on myocardial stunning produced by repetitive coronary artery occlusions were studied in barbital-anesthetized dogs. Regional segment function was measured with sonomicrometry. Under control conditions, six 5-minute periods of coronary occlusion interspersed with 10-minute periods of reperfusion and ultimately followed by 2 hours of reperfusion produced regional segment dysfunction. Pretreatment with intravenous infusion of CPA (2.0 micrograms.kg-1.min-1) improved percent segment shortening throughout reperfusion, whereas pretreatment with DPCPX (1.0 mg/kg i.v. bolus) significantly worsened the recovery of postischemic contractile function. In contrast, neither DPCPX nor CPA had any effect on the recovery of contractile function when administered before the second coronary occlusion. Furthermore, pretreatment with CGS 21680 (0.2 micrograms.kg-1.min-1) did not affect the recovery of percent segment shortening. In addition, pretreatment with a low dose of glibenclamide (0.1 mg/kg) had no effect on percent segment shortening by itself but completely abolished the beneficial effect of CPA. Importantly, the effects of the various agents on percent segment shortening were independent of difference in systemic hemodynamics, collateral blood flow, or ischemic bed size. CONCLUSIONS These results suggest that stimulation of myocardial adenosine A1 receptors, particularly when induced by the initial coronary artery occlusion, is cardioprotective during repetitive, brief periods of coronary artery occlusion and that these beneficial actions may be partially mediated via a glibenclamide-sensitive mechanism, possibly opening of myocardial KATP channels.