AN ADENOSINE-A1-RECEPTOR AGONIST, R(-)-N-(2-PHENYLISOPROPYL)-ADENOSINE (PIA), BUT NOT ADENOSINE ITSELF, ACTS AS A THERAPEUTIC PRECONDITIONING-MIMETIC AGENT IN RABBITS

Objective: A preconditioning mimetic agent could be useful therapy for cardiac ischaemic events; stimulation of adenosine receptors has been proposed as a preconditioning mediator. The ability of adenosine-receptor activation to mimic ischaemic preconditioning was tested in an in vivo rabbit model. Methods: Adenosine (15 mg, a maximally tolerated dose, n=10) was infused over six minutes via a coronary artery and compared with saline (n=12) in anaesthetised rabbits. Five minutes after infusion, a coronary artery was occluded for 40 minutes followed by three hours of reperfusion. In a second study, preischaemic intravenous treatment with adenosine (25 mg.kg(-1), n=9), or an A(1)-adenosine agonist, R(-)-N-(2-phenylisopropyl)-adenosine (PIA, 900 mu g.kg(-1), n=12), were compared with saline (n=12), when given before 40 minutes of coronary artery ligation and three hours of reperfusion in anaesthetised rabbits. Results: Intracoronary adenosine reduced mean arterial pressure during infusion (48(3) nu 80(4) mm Hg, control, p<0.001); however, infusion regional myocardial blood flow was significantly higher in adenosine treated hearts (5.00(0.90) nu 2.30(0.26) ml.min(-1) g(-1), p<0.02) in the region later to become ischaemic. During occlusion ischaemic blood flow was similar in both groups as was the size of the ischaemic risk region, expressed as a % of the left ventricle (42(3)% adenosine and 37(3)% control, NS). Intracoronary adenosine treatment failed to reduce infarct size (52(5)% of the risk zone nu 57(7)% in controls, NS). In the second protocol, heart rate immediately after treatment was reduced by both intraveous adenosine (26%) and PIA (22%) nu control, indicating atrial A(1) receptor activation. Treatment with PIA resulted in a significant reduction in ultimate infarct size compared with saline (38(5)% of risk region nu 57(5)%, p<0.05). Adenosine, however, failed to reduce infarct size (50(8)%, NS nu saline). There were no differences between area at risk or myocardial blood flow among groups. Conclusion: The adenosine agonist PIA but not adenosine itself might be a useful adjunctive therapy.