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

Objective Endothelins can act as polyfunctional cytokines. It is therefore possible that endothelins could play an active role in gut inflammation. El evated levels of endothelin-1 have been reported in ulcerative colitis and Crohn's disease. The aim of this study was to establish the therapeutic eff ect of a 'new' endothelin receptor antagonist Ro 48-5695 in an animal model of inflammatory bowel disease, This study compares the effect of Ro 48-569 5 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, co lonic tissues were removed and examined in a blinded fashion for macroscopi c damage (damage score) and myeloperoxidase (MPO) activity. Stool consisten cy 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 adhe sions. In ONES-induced colonic damage, pc 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. Howeve r, MPO activity in this model was affected only by the highest dose of Ro 4 8-5695 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 possib ility of exploring a new therapeutic approach. Eur J Gastroenterol Hepatol 12:257-265 (C) 2000 Lippincott Williams & Wilkins.