Abstract
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-α-[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-1β 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.
Footnotes
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This work was supported by the Arthritis Research Campaign UK (Grant G0571). S.J.G. is also a recipient of the Visiting Fellowship of the Second University of Naples.
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DOI: 10.1124/jpet.104.065573.
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ABBREVIATIONS: MSU, monosodium urate; PMN, polymorphonuclear; ET, endothelin; FR139317, C33H44N6O5, N-[N-[-N(hexahydro-1H-azepin-1-yl)carbonyl]-l-leucyl]-1-methyl-d-tryptophyl]-3-(2-pyridinyl)-d-alanine); BQ-788, C34H51N5O7, N-cis-2,6-dimethylpiperidinocarbonyl-b-tBu-Ala-d-Trp(1-methoxycarbonyl)-d-Nle-OH; PD145065, C52H65N7O10, N-acetyl-α-[10,11-dihydro-5H-dibenzo[a,d]cycloheptadien-5-yl]-d-Gly-Leu-Asp-lle-lle-Trp; MØ, macrophage; ELISA, enzyme-linked immunosorbent assay; PBS, phosphate-buffered saline; IL, interleukin; EIA, enzyme immunoassay; PAF, platelet-activating factor; LUI135252, darusentan; IRL-1038, H-Cys-Val-Tyr-Phe-Cys-His-Leu-Asp-Ile-Ile-Trp-OH; SB209670, (+)-(1s,2R,3S)-3-()-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indene-2-carboxylic acid.
- Received January 16, 2004.
- Accepted March 2, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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Investigation into the Potential Anti-Inflammatory Effects of Endothelin Antagonists in a Murine Model of Experimental Monosodium Urate Peritonitis
