The aim of this study was to evaluate the effect of
MEN 11467 (1R,2S)-2-N[1(H)indol-3-yl-carbonyl]-1-N{N-(p-tolylacetyl)-N-(meth yl)-D-3(2-Naphthyl)alanyl}diaminocyclohexane), a new potent
tachykinin NK1 receptor antagonist, in an experimental model of acute
rectocolitis induced by an
enema with 7.5%
acetic acid in guinea-pigs. This effect was compared to that of
mesalazine (5-amino-
2-hydroxybenzoic acid). The injury was quantified 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 superficial layers and producing a strong
edema of the submucosa. A single administration of
MEN 11467 (0.3-10 mg/kg s.c., I h before
acetic acid) reduced the macroscopic damage and
necrosis score and the increase in
plasma protein extravasation induced by 7.5%
acetic acid in the early acute phase of the injury (death at 2.5 h).
Mesalazine (100 mg/kg p.o., 1 h before) reduced the macroscopic score but not the
plasma protein extravasation. Repeated administration of
MEN 11467 (1-3 mg/kg s.c., -1, +6 and +23 h after 7.5%
acetic acid) reduced the macroscopic score and
myeloperoxidase activity but not the
plasma protein extravasation induced in the late phase of acute injury (death at 24 h). At this time
mesalazine markedly reduced the macroscopic score,
myeloperoxidase activity and
plasma protein extravasation induced by 7.5%
acetic acid. These results suggest a greater involvement of
tachykinin NK1 receptors in the early phase than in the late phase of colonic
inflammation in response to chemical injury.