ANTIINFLAMMATORY EFFECTS OF AN ADENOSINE KINASE INHIBITOR - DECREASEDNEUTROPHIL ACCUMULATION AND VASCULAR LEAKAGE

Adenosine inhibits neutrophil function, but also causes cardiovascular side effects when administered systemically. To regulate local adenos ine concentrations and minimize toxicity, a novel adenosine kinase inh ibitor, GP-1-515, was tested in several acute inflammation models in r ats. GP-1-515 inhibited carrageenan-induced rat paw swelling in a dose -dependent manner (maximum inhibition, 47 +/- 3%). In a rat skin lesio n model, GP-1-515 significantly reduced cutaneous neutrophil infiltrat ion following an intradermal injection of carrageenan or zymosan-activ ated plasma, or induction of a reverse passive Arthus reaction. This a ction appeared to be mediated by endogenous adenosine, inasmuch as a s pecific A2 adenosine receptor antagonist reversed the effect. GP-1-515 also decreased vascular leakage induced by carrageenan (which is part ly neutrophil dependent) and by the neutrophil-independent mediators h istamine and bradykinin. Inhibition of leakage was reversed by co-admi nistration of adenosine receptor antagonists. Treatment with anti-infl ammatory doses of GP-1-515 had no effect on heart rate or blood pressu re. in conclusion, GP-1-515 significantly reduced both neutrophil infi ltration and vascular leakage through the release of endogenous adenos ine without evidence of cardiovascular side effects.