title: 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.
authors.affiliation: Gensia, Inc., San Diego, CA 92121, USA.
authors.forename: S
authors.initials: S
authors.lastname: Rosengren
authors.forename: G W
authors.initials: GW
authors.lastname: Bong
authors.forename: G S
authors.initials: GS
authors.lastname: Firestein
mesh_terms: D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects*; D002351:Carrageenan / Q000037:antagonists & inhibitors; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004487:Edema / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009504:Neutrophils / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012263:Ribonucleosides / Q000494:pharmacology*; D012871:Skin Diseases / Q000473:pathology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D012263:Ribonucleosides; C087698:GP 1-515; D002351:Carrageenan; D000248:Adenosine Kinase