title: Potent anti-inflammatory and antinociceptive activity of the endothelin receptor antagonist bosentan in monoarthritic mice.
abstract: BACKGROUND
  Endothelins are involved in tissue inflammation, pain, edema and cell migration. Our genome-wide microarray analysis revealed that endothelin-1 (ET-1) and endothelin-2 (ET-2) showed a marked up-regulation in dorsal root ganglia during the acute phase of arthritis. We therefore examined the effects of endothelin receptor antagonists on the development of arthritis and inflammatory pain in monoarthritic mice.
  
  
  METHODS
  Gene expression was examined in lumbar dorsal root ganglia two days after induction of antigen-induced arthritis (AIA) using mRNA microarray analysis. Effects of drug treatment were determined by repeated assessment of joint swelling, pain-related behavior, and histopathological manifestations during AIA.
  
  
  RESULTS
  Daily oral administration of the mixed ET(A) and ET(B) endothelin receptor antagonist bosentan significantly attenuated knee joint swelling and inflammation to an extent that was comparable to dexamethasone. In addition, bosentan reduced inflammatory mechanical hyperalgesia. Chronic bosentan administration also inhibited joint swelling and protected against inflammation and joint destruction during AIA flare-up reactions. In contrast, the ET(A)-selective antagonist ambrisentan failed to promote any detectable antiinflammatory or antinociceptive activity.
  
  
  CONCLUSIONS
  Thus, the present study reveals a pivotal role for the endothelin system in the development of arthritis and arthritic pain. We show that endothelin receptor antagonists can effectively control inflammation, pain and joint destruction during the course of arthritis. Our findings suggest that the antiinflammatory and antinociceptive effects of bosentan are predominantly mediated via the ET(B) receptor.
authors.affiliation: Institute of Pharmacology and Toxicology, University Hospital, Friedrich Schiller University, Drackendorfer Str. 1, 07747 Jena, Germany.
authors.forename: Anne-Katja
authors.initials: AK
authors.lastname: Imhof
authors.forename: Laura
authors.initials: L
authors.lastname: Glück
authors.forename: Mieczyslaw
authors.initials: M
authors.lastname: Gajda
authors.forename: Rolf
authors.initials: R
authors.lastname: Bräuer
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Schaible
authors.forename: Stefan
authors.initials: S
authors.lastname: Schulz
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D018771:Arthralgia / Q000188:drug therapy*; D001169:Arthritis, Experimental / Q000188:drug therapy*; D000077300:Bosentan; D004195:Disease Models, Animal; D004487:Edema / Q000188:drug therapy; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D059225:Nociception / Q000187:drug effects; D010666:Phenylpropionates / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D055502:Secondary Prevention; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D010666:Phenylpropionates; D011724:Pyridazines; D013449:Sulfonamides; C467894:ambrisentan; D000077300:Bosentan