Enhanced protection from renal ischemia-reperfusion [correction of 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-146e (formerly DWH-146e), an A(2A)-AR agonist, and rolipram, a type IV phosphodiesterase (PDE 4) inhibitor, on murine renal injury following ischemia-reperfusion.


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. Co-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.
Okusa
M D
MD
Department of Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, USA. mdo7y@virginia.edu
Linden
J
J
Huang
L
L
Rosin
D L
DL
Smith
D F
DF
Sullivan
G
G
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000009:adverse effects*; D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000378:metabolism*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D009195:Peroxidase / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D011687:Purines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism*; D016897:Respiratory Burst / Q000187:drug effects; D020889:Rolipram / Q000494:pharmacology
C431129:ATL 146e; D003509:Cyclohexanecarboxylic Acids; D010726:Phosphodiesterase Inhibitors; D058906:Purinergic P1 Receptor Agonists; D011687:Purines; D017382:Reactive Oxygen Species; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D000242:Cyclic AMP; D009195:Peroxidase; D017868:Cyclic AMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram