Enhanced protection from renal ischemia: Reperfusion injury with A(2A)-adenosine receptor activation and PDE 4 inhibition

Background. We previously demonstrated in rats and mice that agonists of A( 2A)-adenosine receptors (A(2A)-ARs) reduce renal injury following ischemia- reperfusion. We now extend these studies and examine the effects of ATL-146 e (formerly DWH-146e), an A(2A)-AR agonist, and rolipram, a type IV phospho diesterase (PDE 4) inhibitor, on murine renal injury following ischemia-re perfusion. Methods. C57BL/6 mice were treated with rolipram, ATL-146e, or both compoun ds combined and were subjected to renal ischemia for 32 minutes and reperfu sion for 24 to 48 hours. In vitro studies were performed on suspended and a dhering human neutrophils. Results. Continuous delivery of rolipram or ATL-146e during reperfusion red uced renal injury in a dose-dependent manner. Maximal protection was observ ed when ATL-146e was infused for six hours during reperfusion. Elevated pla sma creatinine and myeloperoxidase activity produced by ischemia-reperfusio n were reduced by rolipram (0.1 ng/kg/min) and ATL-146e (10 ng/kg/min) by u p to approximately 60% and 70%, respectively. Go-infusion of both compounds produced a maximum reduction of plasma creatinine of approximately 90% and myeloperoxidase activity. In vitro studies on suspended and adhering human neutrophils demonstrated that selective stimulation of A(2A)-ARs by ATL-14 6e increased cAMP accumulation, reduced oxidative activity of activated neu trophils, and decreased activated neutrophil adherence. These responses wer e potentiated by rolipram. Conclusions. We conclude that the combined infusion of ATL-146e and rolipra m leads to enhanced renal tissue protection from ischemia-reperfusion by me chanisms that may include reduced neutrophil adherence/recruitment and rele ase of reactive oxygen species.