Selective A(2A) adenosine receptor activation reduces skin pressure ulcer formation and inflammation.
Activation of A(2A) adenosine receptors (A(2A)-AR) by ATL-146e (formerly DWH-146e) prevents inflammatory cell activation and adhesion. Recurrent ischemia-reperfusion (I/R) of the skin results in pressure ulcer formation, a major clinical problem. ATL-146e was evaluated in a novel reproducible rat model of pressure ulcer. A 9-cm(2) region of dorsal rat skin was cyclically compressed at 50 mmHg using a surgically implanted metal plate and an overlying magnet to generate reproducible tissue necrosis. Osmotic minipumps were implanted into 24 rats divided into four equal groups to infuse vehicle (control), ATL-146e (0.004 microg x kg(-1) x min(-1)), ATL-146e plus an equimolar concentration of A(2A) antagonist, ZM-241385, or ZM-241385 alone. Each group received 10 I/R cycles. In non-I/R-treated skin, ATL-146e has no effect on blood flow. I/R-treated skin of the ATL-146e group compared with the vehicle group had 65% less necrotic area, 31% less inhibition of average skin blood flow, and fewer extravasated leukocytes (23 +/- 3 vs. 49 +/- 6 per 500 microm(2)). These data suggest that ATL-146e, acting via an A(2A)-AR, reduces leukocyte infiltration and is a potent prophylactic for I/R injury in skin.
Peirce
S M
SM
Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908, USA.
Skalak
T C
TC
Rieger
J M
JM
Macdonald
T L
TL
Linden
J
J
D000818:Animals; D002460:Cell Line; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D003872:Dermatitis / Q000517:prevention & control*; D004338:Drug Combinations; D006801:Humans; D007511:Ischemia / Q000473:pathology; D007962:Leukocytes / Q000473:pathology; D008297:Male; D009336:Necrosis; D003668:Pressure Ulcer / Q000517:prevention & control*; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000502:physiology*; D012016:Reference Values; D012039:Regional Blood Flow / Q000187:drug effects; D015427:Reperfusion Injury / Q000473:pathology; D012867:Skin / Q000098:blood supply / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
C431129:ATL 146e; D003509:Cyclohexanecarboxylic Acids; D004338:Drug Combinations; D011687:Purines; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385