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INFLAMMATION AND IMMUNOPHARMACOLOGY

Investigation into the Potential Anti-Inflammatory Effects of Endothelin Antagonists in a Murine Model of Experimental Monosodium Urate Peritonitis

The William Harvey Research Institute, Charterhouse Square, London, United Kingdom (S.J.G., C.W.L.); and Department of Experimental Medicine, Second University of Naples, Naples, Italy (S.J.G., C.D.F., F.R., M.D.A.)

Endothelin (ET)-1 has been detected in many inflammatory pathologies, including rheumatoid arthritic patients, asthma, and ischemic-reperfusion injury. In this study, we have investigated the effect of a panel of different ET-1 antagonists displaying different selectivities for the receptors in a murine model of experimental inflammatory peritonitis. Systemic treatment of mice with the ETA antagonist C₃₃H₄₄N₆O₅, N-[N-[-N(hexahydro-1H-azepin-1-yl)carbonyl]-L-leucyl]-1-methyl-D-tryptophyl]-3-(2-pyridinyl)-D-alanine (FR139317) inhibited neutrophil accumulation. However, a greater degree of inhibition was observed with the ETB antagonist C₃₄H₅₁N₅O₇, N-cis-2,6-dimethylpiperidinocarbonyl-b-tBu-Ala-D-Trp(1-methoxycarbonyl)-D-Nle-OH (BQ-788) and the ET(A and B) antagonist C₅₂H₆₅N₇O₁₀, N-acetyl--[10,11-dihydro-5H-dibenzo-[a,d]cycloheptadien-5-yl]-D-Gly-Leu-Asp-lle-lle-Trp (PD145065); all these effects occurred without altering peripheral blood cell counts. Release of the CXC chemokine KC was significantly reduced by the FR139317 and PD145065 but not by BQ-788. Evaluation of the therapeutic potential of these antagonists showed that PD145065 inhibited neutrophil migration and KC release, whereas the others caused a nonsignificant reduction in these parameters. Parameters of endothelial cell activation showed that urate-stimulated interleukin-1 release was inhibited by BQ-788 and PD145065 but not by FR139317, whereas ET-1 was only inhibited by the mixed antagonist. A different scenario was observed with respect to release of the CXC chemokine KC with FR139317 and PD145065 being effective, whereas with a marker of polymorphonuclear activation the ETA and mixed antagonist inhibited adhesion molecule expression. These data show that ET-1 antagonists elicit different mechanisms of actions in the way they display their antimigratory effects in a murine model of monosodium urate crystal peritonitis.

Address correspondence to: Dr. Stephen J. Getting, Department of Biochemical Pharmacology, The William Harvey Research Institute, Charterhouse Square, London EC1M 6BQ, UK. E-mail: s.j.getting{at}qmul.ac.uk