Selective [A.sub.2A] adenosine receptor activation reduces ischemia-reperfusion injury in rat kidney

Okusa, Mark D., Joel Linden, Timothy Macdonald, and Liping Huang. Selective [A.sub.2A] adenosine receptor activation reduces ischemia-reperfusion injury in rat kidney. Am. J. Physiol. 277 (Renal Physiol. 46): F404-F412, 1999.--[A.sub.2A] adenosine receptors ([A.sub.2A]-ARs) are known modulators of renal hemodynamics and potent inhibitors of inflammation. We sought to determine whether selective activation of [A.sub.2A]-Ars protects kidneys from ischemia-reperfusion injury. The ester derivative of DWH-146 (DWH-146e), a selective [A.sub.2A] agonist, was found to be more potent and selective for [A.sub.2A]-ARs than the prototype compound CGS-21680. Osmotic minipumps were implanted subcutaneously to infuse into rats either vehicle or DWH-146e (0.004 [Micro]g [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-1]), during and after ischemia-reperfusion injury. Following 24 and 48 h of reperfusion, the rise in serum creatinine and blood urea nitrogen for vehicle-treated rats was substantially elevated compared with DWH-146e-treated rats. Histological examination revealed widespread tubular epithelial necrosis and vascular congestion in the outer medulla of vehicle-treated compared with DWH-146e-treated animals. ZM-241385, a selective [A.sub.2A] antagonist, blocked the protective effect of DWH-146e. Delaying administration of DWH-146e until the initiation of reperfusion also decreased serum creatinine. We conclude that 1) selective [A.sub.2A]-AR activation by DWH-146e reduces ischemia-reperfusion injury in rat kidneys, 2) the effect of DWH-146e is [A.sub.2A] receptor mediated, and 3) the protective effects are mediated by preventing injury during the reperfusion period. acute renal failure; ischemia; inflammation; DWH-146 ester; ZM-241385