Role of Nitric Oxide in Physiology and Pathology of the Gastrointestinal Tract

Abstract

In this paper the physiological role of NO and isoforms of NOS in the gastrointestinal tract and the involvement of NO in pathological processes of digestive tract as well as the perspective of therapeutic use of NO-donating drugs and selective inhibitors of phosphodiesterase in the treatment of gastric diseases were presented.

Comparison between 3-Nitrooxyphenyl acetylsalicylate (NO-ASA) andO2-(acetylsalicyloxymethyl)-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (NONO-ASA) as Safe Anti-Inflammatory, Analgesic, Antipyretic, Antioxidant Prodrugs

“…NO-NSAIDs were designed based on the assumption that NO (a potent vasodilator and inhibitor of leukocyte adherence to the gastric vascular endothelium) released from them would mimic most of the beneficial biological effects attributed to prostaglandins in the gastrointestinal tract (Martin and Wallace, 2006;Stanek et al, 2008). This approach effectively yielded safer anti-inflammatory, analgesic, antipyretic, and chemopreventive prodrugs in which the NO donor moiety is organic nitrate (-ONO 2 ) (Wallace et al, 1994).…”

Signal Transduction Underlying the Inhibitory Mechanism of Fluoxetine on Electrical Field Stimulation Response in Rat Ileal Smooth Muscle

“…In the GI tract, NO is released from the neurons of the ENS by neuronal isoform of NO synthase (nNOS). The relaxation of GI SMCs is mainly controlled by the nNOS-derived NO [21,22]. However, inhibition with L-NAME enhanced the effect of FLX on EFS-induced contraction (fig.…”

“…NO is synthesized from NO synthase on demand [22]. After its release from the wall of the gut, it diffuses on the cell membrane of the SMC and controls the smooth muscles' relaxation [21,35]. In the guinea pig ileum, NO is released from the myenteric plexus when stimulated by electric field and induced relaxation [36,37].…”

Post-translational regulation of neuronal nitric oxide synthase: implications for sympathoexcitatory states

“…Despite the beneficial roles of NO as the neuromodulator, as a messenger and in host defense mechanism, a dysregulated production of NO can give rise to pathological conditions. The modulations in NOS and NO metabolism leads to either decreased the production of NO, which is linked to cardiovascular diseases [35, 36, 37, 39], erectile dysfunction (ED) [51] and gastrointestinal disorders [52] or excess of NO which is related to tumor progression [53] and neurodegenerative diseases[30]. Therefore, the regulation of nNOS activity is strictly controlled to perform the variety of functions, which dictate the specificity of NO signaling and influence on the activity of neurons in regions of the CNS involved in autonomic regulation such as PVN and RVLM.…”

“…The importance of these molecules as critical regulator/s of nNOS function suggests that these molecules or their interactions may be the rational therapeutic targets in pathologies associated with dysregulation of nNOS. As literature[30, 35, 36, 37, 52, 53] suggest that NO is a Janus-faced molecule having two contrasting aspects, and incongruous release of this mediator has been linked to a number of pathologies, therefore, a fine regulation of nNOS within specific key brain nuclei such as the PVN is critical for maintaining cardiovascular homeostasis. The knowledge of isoform-specific structural features of the catalytic site, characterization of the interactions with modulating intracellular proteins and application of modern inhibitor design approaches in combination with mutagenesis should result in novel nNOS selective targeting with discrete pharmacological effects.…”