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 DW H-146e) prevents inflammatory cell activation and adhesion. Recurrent ische mia-reperfusion (I/R) of the skin results in pressure ulcer formation, a ma jor clinical problem. ATL-146e was evaluated in a novel reproducible rat mo del of pressure ulcer. A 9-cm(2) region of dorsal rat skin was cyclically c ompressed at 50 mmHg using a surgically implanted metal plate and an overly ing magnet to generate reproducible tissue necrosis. Osmotic minipumps were implanted into 24 rats divided into four equal groups to infuse vehicle (c ontrol), ATL-146e (0.004 mug . kg(-1) . min(-1)), ATL-146e plus an equimola r concentration of A(2A) antagonist, ZM-241385, or ZM-241385 alone. Each gr oup 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 ve hicle group had 65% less necrotic area, 31% less inhibition of average skin blood flow, and fewer extravasated leukocytes (23 +/- 3 vs. 49 +/- 6 per 5 00 mum(2)). These data suggest that ATL-146e, acting via an A(2A)-AR, reduc es leukocyte infiltration and is a potent prophylactic for I/R injury in sk in.