adenosine-kinase and Skin-Diseases

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.

Topics: Adenosine Kinase; Animals; Anti-Inflammatory Agents, Non-Steroidal; Capillary Permeability; Carrageenan; Chemotaxis, Leukocyte; Edema; Hemodynamics; Male; Neutrophils; Rats; Rats, Inbred Strains; Ribonucleosides; Skin Diseases