Anti-inflammatory effects of an adenosine kinase inhibitor. Decreased neutrophil accumulation and vascular leakage.

Abstract

Adenosine inhibits neutrophil function, but also causes cardiovascular side effects when administered systemically. To regulate local adenosine concentrations and minimize toxicity, a novel adenosine kinase inhibitor, GP-1-515, was tested in several acute inflammation models in rats. GP-1-515 inhibited carrageenan-induced rat paw swelling in a dose-dependent manner (maximum inhibition, 47 +/- 3%). In a rat skin lesion model, GP-1-515 significantly reduced cutaneous neutrophil infiltration following an intradermal injection of carrageenan or zymosan-activated plasma, or induction of a reverse passive Arthus reaction. This action appeared to be mediated by endogenous adenosine, inasmuch as a specific A2 adenosine receptor antagonist reversed the effect. GP-1-515 also decreased vascular leakage induced by carrageenan (which is partly neutrophil dependent) and by the neutrophil-independent mediators histamine and bradykinin. Inhibition of leakage was reversed by co-administration of adenosine receptor antagonist. Treatment with anti-inflammatory doses of GP-1-515 had no effect on heart rate or blood pressure. In conclusion, GP-1-515 significantly reduced both neutrophil infiltration and vascular leakage through the release of endogenous adenosine without evidence of cardiovascular side effects.