title: Fasitibant chloride, a kinin B₂ receptor antagonist, and dexamethasone interact to inhibit carrageenan-induced inflammatory arthritis in rats.
abstract: OBJECTIVE
  Bradykinin, through the kinin B₂ receptor, is involved in inflammatory processes related to arthropathies. B₂ receptor antagonists inhibited carrageenan-induced arthritis in rats in synergy with anti-inflammatory steroids. The mechanism(s) underlying this drug interaction was investigated.
  
  
  METHODS
  Drugs inhibiting inflammatory mediators released by carrageenan were injected, alone or in combination, into the knee joint of pentobarbital anaesthetized rats 30 min before intra-articular administration of carrageenan. Their effects on the carrageenan-induced inflammatory responses (joint pain, oedema and neutrophil recruitment) and release of inflammatory mediators (prostaglandins, IL-1β, IL-6 and the chemokine GRO/CINC-1), were assessed after 6 h.
  
  
  RESULTS
  The combination of fasitibant chloride (MEN16132) and dexamethasone was more effective than each drug administered alone in inhibiting knee joint inflammation and release of inflammatory mediators. Fasitibant chloride, MK571, atenolol, des-Arg⁹-[Leu⁸]-bradykinin (B₂ receptor, leukotriene, catecholamine and B₁ receptor antagonists, respectively) and dexketoprofen (COX inhibitor), reduced joint pain and, except for the latter, also diminished joint oedema. A combination of drugs inhibiting joint pain (fasitibant chloride, des-Arg⁹-[Leu⁸]-bradykinin, dexketoprofen, MK571 and atenolol) and oedema (fasitibant chloride, des-Arg⁹-[Leu⁸]-bradykinin, MK571 and atenolol) abolished the respective inflammatory response, producing inhibition comparable with that achieved with the combination of fasitibant chloride and dexamethasone. MK571 alone was able to block neutrophil recruitment.
  
  
  CONCLUSIONS
  Bradykinin-mediated inflammatory responses to intra-articular carrageenan were not controlled by steroids, which were not capable of preventing bradykinin effects either by direct activation of the B₂ receptor, or through the indirect effects mediated by release of eicosanoids and cytokines.
authors.affiliation: Department of Pharmacology, Menarini Ricerche S.p.A., Florence, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Valenti
authors.forename: Sandro
authors.initials: S
authors.lastname: Giuliani
authors.forename: Cecilia
authors.initials: C
authors.lastname: Cialdai
authors.forename: Manuela
authors.initials: M
authors.lastname: Tramontana
authors.forename: Carlo Alberto
authors.initials: CA
authors.lastname: Maggi
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D065094:Bradykinin B2 Receptor Antagonists; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000627:therapeutic use*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004487:Edema / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D007596:Joints / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D020024:Leukotriene Antagonists / Q000627:therapeutic use; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects; D009952:Ornithine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011422:Propionates / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000627:therapeutic use*; D013582:Synovial Fluid / Q000276:immunology / Q000378:metabolism
chemical_list: C506838:(4-amino-5-(4-(4-(2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido)tetrahydro-2H-4-pyranoylcarbonyl)piperazino)-5-oxopentyl)(trimethyl)ammonium; D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D065094:Bradykinin B2 Receptor Antagonists; D016207:Cytokines; D018836:Inflammation Mediators; D020024:Leukotriene Antagonists; D011422:Propionates; D011804:Quinolines; D013449:Sulfonamides; C059141:verlukast; D003907:Dexamethasone; D009952:Ornithine