LOSS OF MYOCARDIAL PROTECTION FROM ISCHEMIC PRECONDITIONING FOLLOWINGCHRONIC EXPOSURE TO R(-)-N-6-(2-PHENYLISOPROPYL)ADENOSINE IS RELATED TO DEFECT AT THE ADENOSINE A(1) RECEPTOR

Exogenously administered adenosine agonist will protect myocardium aga inst infarction during ischemia. However, longterm exposure to adenosi ne agonists is associated with loss of this protection. To determine w hy this protection is lost, isolated, perfused rabbit hearts were stud ied after administration of R(-)-N-6-(2-phenylisopropyl)adenosine (PIA ), 0.25 mg/ h IP, for 3-4 days to intact animals. All hearts experienc ed 30 min of regional ischemia and 120 min of reperfusion. Control gro ups 1 and 2 were untreated. In group 1 this ischemia/reperfusion was t he only intervention, whereas group 2 hearts were preconditioned with a cycle of 5 min global ischemia/10 min reperfusion preceding the 30 m in regional ischemia. Groups 3-5 had been chronically exposed to PIA. Group 3 hearts had 1 preconditioning ischemia/reperfusion cycle before the prolonged ischemia. Group 4 received a 5 min infusion of 0.1 mu m ol/Lphenylephrine in lieu of global ischemia, whereas group 5 was inst ead treated with 1 mu mol/L carbachol. Infarct size averaged 32% of th e risk zone in group 1, whereas ischemic preconditioning limited infar ction to 8.2% in group 2. Prolonged exposure of group 3 hearts to PIA resulted in the inability of preconditioning with 5 min global ischemi a to protect (28.7 +/- 4.4% infarction). However, protection was resto red by either phenylephrine, an agonist of alpha(1)-adrenergic recepto rs which couple to G(q) and stimulate PKC, or carbachol, an agonist of M-2-muscarinic receptors which couple instead to G(i) as do adenosine A(1) receptors (5.2 +/- 1.7% and 9.2 +/- 2.1% infarction, resp.). The refore, cross tolerance to ischemic preconditioning develops after chr onic PIA infusion. Since both the G(i) and the PKC components of the p reconditioning pathway were shown to be intact, tolerance must have be en related to downregulation or desensitization of the A(1) adenosine receptor.