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Oxidant-evoked release of acetylcholine from enteric neurons of the rat colon

TS Gaginella, MB Grisham, DB Thomas, R Walsh and C Moummi

Searle Research and Development, Skokie, Illinois.

In the presence of halides, granulocytes generate hypochlorous acid and, subsequently, chlorinated amines (chloramines). These lipophilic, potent reactive oxygen metabolites may contribute to the mucosal pathophysiology associated with inflammatory bowel disease. A common symptom of inflammatory bowel disease is mucosal secretion of fluid and electrolytes, leading to diarrhea. Because acetylcholine (Ach) can stimulate colonic fluid secretion, we determined the effect of monochloramine (NH2Cl) on Ach release by mucosal/submucosal nerves. Mucosa from the rat colon was separated from outer muscle layers and minced before incubation with [14C]choline to label stores of Ach in cholinergic neurons. Release of [14C]Ach was evoked with NH2Cl in the absence and presence of 5-aminosalicylic acid, glutathione, nordihydroguaiarectic acid or the cyclooxygenase inhibitor piroxicam. NH2Cl produced concentration-related increases in [14C] Ach release into the medium; greater than 100% over base line was observed at 0.5 mM. Glutathione inhibited the NH2Cl-evoked release in a concentration- dependent fashion. Release induced by 0.1 mM NH2Cl was abolished by 5- aminosalicylic acid and significantly inhibited by nordihydroguaiarectic acid. Piroxicam also prevented the effect of NH2Cl on release of [14C] Ach. None of these agents alone had any effect on base line [14C]Ach release. Tetrodotoxin (5 microM) did not significantly inhibit the NH2Cl-evoked transmitter release. We conclude that NH2Cl, at concentrations believed to exist in inflamed tissue, causes the release of Ach from mucosal/submucosal nerves primarily through nonspecific neural membrane injury. Endogenous prostaglandins, possibly liberated as a consequence of the injury, may be involved in the Ach release process.

Volume 263, Issue 3, pp. 1068-1073, 12/01/1992
Copyright © 1992 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1992 by the American Society for Pharmacology and Experimental Therapeutics.