Investigation into the potential anti-inflammatory effects of endothelin antagonists in a murine model of experimental monosodium urate peritonitis.
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-alpha-[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-1beta 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.
Department of Biochemical Pharmacology, The William Harvey Research Institute, Charterhouse Square, London, UK. s.j.getting@qmul.ac.uk
Stephen J
SJ
Getting
Clara
C
Di Filippo
Connie W
CW
Lam
Francesco
F
Rossi
Michele
M
D'Amico
D000818:Animals; D001381:Azepines / Q000494:pharmacology / Q000627:therapeutic use*; D018925:Chemokines / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D010538:Peritonitis / Q000139:chemically induced / Q000188:drug therapy*; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D010972:Platelet Activating Factor / Q000378:metabolism; D013997:Time Factors; D014527:Uric Acid
D001381:Azepines; D018925:Chemokines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007211:Indoles; D007375:Interleukin-1; D009842:Oligopeptides; D010880:Piperidines; D010972:Platelet Activating Factor; C079574:FR 139317; C082887:PD 145065; D014527:Uric Acid; C086539:BQ 788