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Therapeutic effects of the endothelin receptor antagonist Ro 48-5695 in the TNBS/DNBS rat model of colitis.

AbstractOBJECTIVE:
Endothelins can act as polyfunctional cytokines. It is therefore possible that endothelins could play an active role in gut inflammation. Elevated levels of endothelin-1 have been reported in ulcerative colitis and Crohn's disease. The aim of this study was to establish the therapeutic effect of a 'new' endothelin receptor antagonist Ro 48-5695 in an animal model of inflammatory bowel disease. This study compares the effect of Ro 48-5695 on colonic damage induced by two haptens: trinitrobenzenesulphonic (TNBS) or dinitrobenzenesulphonic acid (DNBS).
METHODS:
Colitis was induced by intra-rectal administration of TNBS or DNBS. After TNBS/DNBS injury, rats were treated with 10.0, 3.0, 1.0 or 0.3 mg/kg of Ro 48-5695 orally, daily for 5 days. On day 6 post-hapten treatment, colonic tissues were removed and examined in a blinded fashion for macroscopic damage (damage score) and myeloperoxidase (MPO) activity. Stool consistency and adhesions were also measured.
RESULTS:
Oral administration of Ro 48-5695 almost completely prevented TNBS-induced damage at a dose of 10 mg/kg. The same dose in this model also had a therapeutic effect as measured by MPO and incidence of diarrhoea and adhesions. In DNBS-induced colonic damage, Ro 48-5695 was more potent and at 1.0 and 3.0 mg/kg decreased the damage score by 50 and 60% respectively; also the incidence of adhesions and diarrhoea was significantly reduced. However, MPO activity in this model was affected only by the highest dose of Ro 48-5695 tested (3.0 mg/kg) where it was reduced by 48%.
CONCLUSIONS:
These data provide evidence for the involvement of endothelins in the pathophysiology of inflammatory bowel disease and support the possibility of exploring a new therapeutic approach.
AuthorsI Padol, J Q Huang, C M Hogaboam, R H Hunt
JournalEuropean journal of gastroenterology & hepatology (Eur J Gastroenterol Hepatol) Vol. 12 Issue 3 Pg. 257-65 (Mar 2000) ISSN: 0954-691X [Print] England
PMID10750644 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Benzenesulfonates
  • Endothelin Receptor Antagonists
  • Endothelin-1
  • Ro 48-5695
  • Sulfonamides
  • dinitrobenzenesulfonic acid
  • Trinitrobenzenesulfonic Acid
  • Peroxidase
Topics
  • Animals
  • Benzenesulfonates
  • Colitis, Ulcerative (chemically induced, etiology, therapy)
  • Disease Models, Animal
  • Endothelin Receptor Antagonists
  • Endothelin-1 (physiology)
  • Inflammatory Bowel Diseases (chemically induced, etiology, therapy)
  • Male
  • Peroxidase (metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Sulfonamides (therapeutic use)
  • Trinitrobenzenesulfonic Acid

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