Effect of MEN 11467, a new tachykinin NK1 receptor antagonist, in acute rectocolitis induced by acetic acid in guinea-pigs

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-(methyl)-D-3(2-Naphthyl) an yl)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 usin g a macroscopic injury score and histologically by using a necrosis score. In addition, changes in myeloperoxidase activity, a marker for neutrophil i nfiltration, and plasma protein extravasation were evaluated. The injury ca used by 7.5% acetic acid was mild, affecting the superficial layers and pro ducing a strong edema of the submucosa. A single administration of MEN 1146 7 (0.3-10 mg/kg s.c., 1 h before acetic acid) reduced the macroscopic damag e and necrosis score and the increase in plasma protein extravasation induc ed 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 11 467 (1-3 mg/kg s.c., -1, +6 and +23 h after 7.5% acetic acid) reduced the m acroscopic score and myeloperoxidase activity but not the plasma protein ex travasation induced in the late phase of acute injury (death at 24 h). At t his time mesalazine markedly reduced the macroscopic score, myeloperoxidase activity and plasma protein extravasation induced by 7.5% acetic acid. The se 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. (C) 1999 Elsevier Science B.V. All rights reserved.