The role of
nitric oxide in intestinal fluid and
electrolyte secretion depends upon whether the conditions under study are physiological or pathophysiological. In physiological conditions, endogenous
nitric oxide seems to be a proabsorptive molecule, based on the findings that
nitric oxide synthase inhibitors reverse net fluid absorption to net secretion in mice, rats, guinea pigs, rabbits, and dogs. This proabsorptive mode involves the enteric nervous system, the suppression of
prostaglandin formation, and the opening of basolateral K+ channels. However, in some pathophysiological states
nitric oxide synthase may be produced at higher concentrations that are capable of evoking net secretion. Thus
nitric oxide synthase contributes to the diarrheal response in trinitrobenzene
sulfonic acid-induced
ileitis in guinea pigs and is the mediator of the
laxative action of several intestinal
secretagogues including
castor oil,
phenolphthalein,
bisacodyl,
magnesium sulfate,
bile salts, senna, and cascara in the rat. Corresponding with the in vivo results,
nitric oxide-donating compounds or
nitric oxide itself stimulate
chloride secretion in the guinea pig and rat intestine in vitro. Exceptions are the
diarrhea produced by bacterial
enterotoxins in the rat, in which
nitric oxide seems to have a proabsorptive role, and the mouse ileum in vitro, in which
nitric oxide-donating compounds produce a net proabsorptive effect on basal ion transport. Several endogenous
secretagogues (
substance P,
5-hydroxytryptamine,
interleukin-1beta), which are important mediators of the
inflammatory bowel diseases, act, at least in part, through the liberation of
nitric oxide. Clinical studies have shown that
nitric oxide is elevated in several
inflammatory bowel diseases and other secretory conditions including
ulcerative colitis,
Crohn's disease,
toxic megacolon,
diverticulitis, infectious
gastroenteritis, and infantile
methemoglobinemia. However, the determination of
nitric oxide in secretory
diarrhea per se does not give conclusive information on the
nitric oxide contribution to clinical secretory
diarrhea.