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

被引:243
作者
POTHOULAKIS, C
CASTAGLIUOLO, I
LAMONT, JT
JAFFER, A
OKEANE, JC
SNIDER, RM
LEEMAN, SE
机构
[1] BOSTON UNIV,SCH MED,DEPT PHARMACOL & EXPTL THERAPEUT,BOSTON,MA 02118
[2] BOSTON UNIV,SCH MED,DEPT PATHOL,BOSTON,MA 02118
关键词
D O I
10.1073/pnas.91.3.947
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Toxin A from Clostridium difficile mediates acute inflammatory enterocolitis in experimental animals, while cholera toxin causes noninflammatory secretory diarrhea. The purpose of this study was to investigate whether an antagonist to the peptide substance P, a constituent of primary sensory neurons known to participate in inflammatory responses, would 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 mannitol permeability (P < 0.01) in ileal loops exposed to toxin A. The protective effects, which were dose dependent, caused a significant reduction of inflammation in the lamina propria, reduction of the necrosis of intestinal epithelial cells, and complete inhibition of toxin A-mediated release of rat mast cell protease II, a specific product of rat mucosal mast cells. An inactive enantiomer of the substance P antagonist, CP-96,344, had no effect. In contrast, pretreatment with CP-96,345 had no inhibitory effect on the intestinal effects caused by administration of cholera toxin into the ileal loops. From these data, we conclude that the peptide substance P is involved in the secretory and inflammatory effects of toxin A but not of cholera toxin.
引用
收藏
页码:947 / 951
页数:5
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