1029-19 Enhancement of Endogenous Adenosine Protects Rabbit Cardiac Myocytes from ischemic Injury

Myocardial ischemia induces adenosine (ADO) formation that limits injury. Amplification of ADO levels (via exogenous ADO, ischemic preconditioning, or an ARA, etc) provides more protection. A new novel orally-active ARA GP531 (5-amino-1-B-D-[5-benzylamino-5-deoxy ribofuranosyl]imidazole-4 carboxamide) augments ADO levels specifically during periods of ATP breakdown, eg. ischemia, so its effect on cardiac myocytes was evaluated. Rabbit myocytes paced at 1 Hz were exposed to a simulated ischemic buffer containing (mM) 2′-deoxyglucose (20), NaCN (1), Na-Iactate (20), and K+ (10) at pHo 6.6 (37°C) for 8min followed by 15min reperfusion in non-ischemic buffer. Changes of myocyte length were monitored with an optical-video edge recording system, and hypercontracture was the index of irreversible cell injury. In the absence of GP-1-531, 58±7% (cells studied=132) of the myocytes developed hypercontracture, and the surviving myocytes contracted at 43±9% of pre-ischemic levels. GP531 had no effect on myocytes basal function but reduced cell hypercontracture to 49±5% (0.5μM, cells=134, P=NS). 35±5% (5μM, cells=157, p<0.05). and 34±7% (50μM, cells=139, P<0.05), respectively, and the surviving myocytes contracted at 66±5% of pre-ischemic levels (p<0.05 vs untreated controlsl. Moreover, GP531-induced cardioprotection was blocked by the nonselective adenosine-receptor antagonist, 8-SPT (100μM). although GP0531 itself did not bind to adenosine receptors. Thus, GP0531 protects rabbit cardiac myocytes from ischemia-reperfusion injury by a mechanism involving enhancement of local ADO and activation of ADO receptors selectively during ischemia