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 n eurones, and the vascular supply. Nitric oxide has been implicated in the f unction of these separate components. Aims-To explore the role of nitric oxide in the totality of cholera toxin i nduced secretion in vivo. Methods-One group of adult male Wistar rats was treated with the nitric oxi de synthase inhibitors N-G-nitro-L-arginine methyl ester (L-NAME; subcutane ously or intraluminally), N-G-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 mu g cholera toxin or saline for two hours. Small intestinal perfusion of a plasma electrolyte solution containing [C- 14]-PEG was undertaken to determine net water and electrolyte movement. Aft er the experiment macroscopic and microscopic intestinal appearances were n oted and jejunal 5-hydroxytryptamine concentrations were determined. Results-Both L-arginine and L-NAME induced secretion in the basal state, bu t only when administered intraluminally. Systemically applied L-NAME caused a dose dependent reduction in cholera toxin induced secretion. This was pa ralleled 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. S ystemically applied L-arginine but not D-arginine also reduced cholera toxi n induced secretion and inhibited 5-hydroxytryptamine release. Conclusion-Nitric oxide has a duality of roles in cholera toxin induced sec retion, acting both as an absorbagogue and a acting both as an absorbagogue ana a Secretagogue. Its mechanisms of action include the maintenance of mu cosal perfusion and enterochromaffin cell stabilisation.