New issues about nitric oxide and its effects on the gastrointestinal tract

Over the last years the important role of nitric oxide (NO) as endogenous m odulator of numerous physiological functions has been shown. NO is involved in the regulation of blood flow, maintenance of vascular tone, control of platelet aggregation, and modulation of the activity of the mastocytes. It also plays a key role as neurotransmitter in the central and peripheric ner vous system (non adrenergic non colinergic, NANC, neurons), in the nervous control of the cerebral blood flow and in the neuroendocrine regulation or synaptic plasticity. However, NO shows a dual behavior: at physiological co ncentrations, released through the constitutive synthase (cNOS), it regulat es house-keeping functions, whereas its overproduction by the inducible iso enzyme (iNOS) exhibits cytotoxic activity because interacting with reactive species producing peroxinitrites (ONOO.) and other compounds, which are hi ghly damaging for the tissues. In the gastrointestinal tract (GIT) NO participates in the modulation of th e smooth musculature tone, such as the regulation of intestinal peristaltis m, gastric emptying and antral motor activity. It also regulates acid and g astric mucus secretion, alkaline production, and is involved in the mainten ance of mucosal blood flow. In physiological conditions, NO acts as an endo genous mediator modulating both, the repairing and integrity of the tissues , and exhibits gastroprotective properties against different types of aggre ssive agents. However, high concentrations of NO are related to numerous pa thological processes of GIT including peptic ulcer, chronic gastritis, gast rointestinal cancer, bacterial gastroenteritis, celiac or chronic inflammat ory bowel diseases. Recently, this hypothesis that cNOS is always beneficia l and iNOS is always deleterious, has been questioned, since that a series of data suggest that the increase of cNOS activity could be responsible for the derived pathological changes and, by contrast, NO liberated by the ind ucible isoenzyme might play a repairing effect in certain pathological diso rders. The pharamceutical industry is really interested in proving the clinical be nefits of the mediator. Numerous NO-donor drugs, nitrite derivatives, have been frequently used in the cardiovascular diseases due to their vasodilati ng properties, which allow an enhancement of coronary blood flow. More rece ntly, the protective effect of NO against non-steroidal antiinflammatory dr ugs (NSAID)-gastroenteropathy has been shown, because its vasodilating and antioxidant properties render it a potentially useful agent. Different NSAI D, including acetyl salicylic acid, diclofenac or naproxen, have been formu lated by attaching a NO releasing-moiety. These NO-NSAID, antiinflammatorie s combined with precursors of the mediator, or with inhibitors of the induc ible synthase, are currently being evaluated. However, although the pharmac otherapeutical possibilities of NO are considerable, it is necessary to elu cidate the exact mechanisms derived from simulation/inhibition of the isoen zymes in order to determine the clinical utility of NO-donors.