CP-96,345, A SUBSTANCE-P ANTAGONIST, INHIBITS RAT INTESTINAL RESPONSES TO CLOSTRIDIUM-DIFFICILE TOXIN-A BUT NOT CHOLERA-TOXIN

Toxin A from Clostridium difficile mediates acute inflammatory enteroc olitis in experimental animals, while cholera toxin causes noninflamma tory secretory diarrhea. The purpose of this study was to investigate whether an antagonist to the peptide substance P, a constituent of pri mary sensory neurons known to participate in inflammatory responses, w ould inhibit toxin A-mediated enteritis in the rat ileum. Pretreatment of rats with CP-96,345 (2.5 mg per kg of body weight), a substance P antagonist, dramatically inhibited fluid secretion (P < 0.01) and mann itol permeability (P < 0.01) in ileal loops exposed to toxin A. The pr otective effects, which were dose dependent, caused a significant redu ction of inflammation in the lamina propria, reduction of the necrosis of intestinal epithelial cells, and complete inhibition of toxin A-me diated release of rat mast cell protease II, a specific product of rat mucosal mast cells. An inactive enantiomer of the substance P antagon ist, CP-96,344, had no effect. In contrast, pretreatment with CP-96,34 5 had no inhibitory effect on the intestinal effects caused by adminis tration of cholera toxin into the ileal loops. From these data, we con clude that the peptide substance P is involved in the secretory and in flammatory effects of toxin A but not of cholera toxin.