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.


OBJECTIVE
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.


CONCLUSIONS
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.
Turvill
J L
JL
Digestive Diseases Research Centre, St Bartholomew's and the Royal London School of Medicine and Dentistry, Turner Street, London E1 2AD, UK.
Mourad
F H
FH
Farthing
M J
MJ
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D002772:Cholera Toxin / Q000494:pharmacology*; D004573:Electrolytes / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D014867:Water / Q000378:metabolism
D004573:Electrolytes; D004791:Enzyme Inhibitors; D014867:Water; D009569:Nitric Oxide; D002772:Cholera Toxin; D001120:Arginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester