Enhanced protection from renal ischemia:: Reperfusion injury with A2A-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-146e (formerly DWH-146e), an A(2A)-AR agonist, and rolipram, a type IV phosphodiesterase (PDE 4) inhibitor, on murine renal injury following ischemia-re perfusion. Methods. C57BL/6 mice were treated with rolipram, ATL-146e, or both compounds combined and were subjected to renal ischemia for 32 minutes and reperfusion for 24 to 48 hours. In vitro studies were performed on suspended and adhering human neutrophils. Results. Continuous delivery of rolipram or ATL-146e during reperfusion reduced renal injury in a dose-dependent manner. Maximal protection was observed when ATL-146e was infused for six hours during reperfusion. Elevated plasma creatinine and myeloperoxidase activity produced by ischemia-reperfusion were reduced by rolipram (0.1 ng/kg/min) and ATL-146e (10 ng/kg/min) by up 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-146e increased cAMP accumulation, reduced oxidative activity of activated neutrophils, and decreased activated neutrophil adherence. These responses were potentiated by rolipram. Conclusions. We conclude that the combined infusion of ATL-146e and rolipram leads to enhanced renal tissue protection from ischemia-reperfusion by mechanisms that may include reduced neutrophil adherence/recruitment and release of reactive oxygen species.