Proabsorptive and prosecretory roles for nitric oxide in cholera toxin induced secretion.

BACKGROUND: Cholera toxin causes small intestinal hypersecretion by inducing a coordinated response from enterocytes, enterochromaffin cells, enteric neurones, and the vascular supply. Nitric oxide has been implicated in the function of these separate components. AIMS: To explore the role of nitric oxide in the totality of cholera toxin induced secretion in vivo.
METHODS: One group of adult male Wistar rats was treated with the nitric oxide synthase inhibitors NG-nitro-L-arginine methyl ester (L-NAME; subcutaneously or intraluminally), NG-methyl-L-arginine (L-NMA), or 7-nitroindazole. A second group of rats was treated with L-arginine (intraperitoneally or intraluminally) or D-arginine. The small intestine was isolated between two cannulae and instilled with 75 microg cholera toxin or saline for two hours. Small intestinal perfusion of a plasma electrolyte solution containing [14C]-PEG was undertaken to determine net water and electrolyte movement. After the experiment macroscopic and microscopic intestinal appearances were noted and jejunal 5-hydroxytryptamine concentrations were determined.
RESULTS: Both L-arginine and L-NAME induced secretion in the basal state, but only when administered intraluminally. Systemically applied L-NAME caused a dose dependent reduction in cholera toxin induced secretion. This was paralleled by L-NMA but not by 7-nitroindazole or by intraluminally applied L-NAME. Systemically applied L-NAME caused notable cyanosis of the intestine, consistent with mesenteric ischaemia, but no microscopic abnormalities. Systemically applied L-arginine but not D-arginine also reduced cholera toxin induced secretion and inhibited 5-hydroxytryptamine release.
CONCLUSION: Nitric oxide has a duality of roles in cholera toxin induced secretion, acting both as an absorbagogue and a secretagogue. Its mechanisms of action include the maintenance of mucosal perfusion and enterochromaffin cell stabilisation.