Protective effect of the tachykinin NK2 receptor antagonist nepadutant in acute rectocolitis induced by diluted acetic acid in guinea pigs

We have evaluated the potential protective activity of nepadutant, a select ive tachykinin NK, receptor antagonist, in a model of acute rectocolitis in duced by an enema with 7.5% acetic acid in guinea-pigs. The injury was quan tified visually by using a macroscopic injury score, and histologically by using a necrosis score. In addition, changes in myeloperoxidase activity, a marker for neutrophil infiltration, and plasma protein extravasation were evaluated. The injury caused by 7.5% acetic acid was mild, affecting the su perficial layers and producing a strong edema of the submucosa. A single ad ministration of nepadutant (0.3-10 mg/kg s.c., 1 h before acetic acid) mark edly reduced the macroscopic damage and necrosis score and the increase in plasma protein extravasation induced by 7.5% acetic acid in the early phase of the injury. Single administration of nepadutant (3 mg/kg s.c.) reduced the macroscopic score and myeloperoxidase activity at the top (24 h) of inf lammation. Repeated administration (3 mg/kg s.c. three times during 24 h) o r cc-administration of the tachykinin NK, receptor antagonist MEN 11467 (3 mg/kg s.c.) did not enhance the antiulcer effect obtained with the single t reatment with nepadutant. These data suggest the involvement of tachykinin NK, receptors in the first phases of inflammation induced by acetic acid. ( C) 2000 Harcourt Publishers Ltd.