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. 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.
Padol
I
I
Intestinal Disease Research Programme, McMaster University, Hamilton, Ontario, Canada.
Huang
J Q
JQ
Hogaboam
C M
CM
Hunt
R H
RH
D000818:Animals; D001557:Benzenesulfonates; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000209:etiology / Q000628:therapy*; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000209:etiology / Q000628:therapy; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000627:therapeutic use*; D014302:Trinitrobenzenesulfonic Acid
D001557:Benzenesulfonates; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; C118553:Ro 48-5695; D013449:Sulfonamides; C007488:dinitrobenzenesulfonic acid; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase