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.