Current roles of nitric oxide in gastrointestinal disorders.

It has been confusing as to what roles nitric oxide (NO) has in different physiological and pathological mechanisms in various diseases. In the gastrointestinal tract, NO can be either protective or deleterious in different disorders. This depends on what type of nitric oxide synthase (NOS) is involved in these pathological conditions. Constitutive NOS (cNOS) is responsible for production of NO in physiological context. In contrast, inducible NOS (iNOS) produces NO in pathophysiological circumstances. NO is implicated in mechanisms maintaining the integrity of the gastric epithelium. In this connection, it regulates gastric blood flow and directly stimulates gastric mucus secretion by activating soluble guanylate cyclase. A blockade of NO production resulted in an impairment of the vascular response and the subsequent alkaline flux in the lumen. This would impair the restitution process. Endogenous NO also contributes to the inhibition of acid secretion in the stomach. Indeed the adverse action of cigarette smoking on ulcer healing is largely dependent on the deficiency of cNOS and a subsequent depression of gastric blood flow and angiogenesis. To this end, NO may act as a crucial signal to promote endothelial cell differentiation into vascular tubes. In experimental colitis, NO derived from iNOS, together with other free radicals contribute significantly to the inflammatory response in the colon. It is also involved in the ulcerogenic effect of passive smoking on colitis. The mechanism is likely mediated through the interaction with superoxide to produce peroxynitrite, a strong oxidizing agent that initiates lipid peroxidation. In conclusion, NO in low concentration derived from cNOS is cytoprotective by directly acting as an inducer of defense responses in the gastrointestinal tract. However, higher concentrations of NO from iNOS exhibit toxic effects through nitrosative and oxidative stress.