Nitric Oxide Is Essential for Generating the Minute Rhythm Contraction Pattern in the Small Intestine, Likely via ICC-DMP

Abstract

Nitrergic nerves have been proposed to play a critical role in the orchestration of peristaltic activities throughout the gastrointestinal tract. In the present study, we investigated the role of nitric oxide, using spatiotemporal mapping, in peristaltic activity of the whole ex vivo mouse intestine. We identified a propulsive motor pattern in the form of propagating myogenic contractions, that are clustered by the enteric nervous system into a minute rhythm that is dependent on nitric oxide. The cluster formation was abolished by TTX, lidocaine and nitric oxide synthesis inhibition, whereas the myogenic contractions, occurring at the ICC-MP initiated slow wave frequency, remained undisturbed. Cluster formation, inhibited by block of nitric oxide synthesis, was fully restored in a highly regular rhythmic fashion by a constant level of nitric oxide generated by sodium nitroprusside; but the action of sodium nitroprusside was inhibited by lidocaine indicating that it was relying on neural activity, but not rhythmic nitrergic nerve activity. Hence, distention-induced activity of cholinergic nerves and/or a co-factor within nitrergic nerves such as ATP is also a requirement for the minute rhythm. Cluster formation was dependent on distention but was not evoked by a distention reflex. Block of gap junction conductance by carbenoxolone, dose dependently inhibited, and eventually abolished clusters and contraction waves, likely associated, not with inhibition of nitrergic innervation, but by abolishing ICC network synchronization. An intriguing feature of the clusters was the presence of bands of rhythmic inhibitions at 4–8 cycles/min; these inhibitory patches occurred in the presence of tetrodotoxin or lidocaine and hence were not dependent on nitrergic nerves. We propose that the minute rhythm is generated by nitric oxide-induced rhythmic depolarization of the musculature via ICC-DMP.

17β-Estradiol Suppresses Gastric Inflammatory and Apoptotic Stress Responses and Restores nNOS-Mediated Gastric Emptying in Streptozotocin (STZ)-Induced Diabetic Female Mice

“…NO-mediated relaxation has been reported as the predominant component that is severely compromised in female rodent models of diabetic Gp, specifically within the proximal regions of the stomach, colon, and intestinal smooth muscle [ 4 , 40 , 41 ]. Human and animal studies suggest that NO depletion due to nNOS dysfunction and expression may lead to delayed GE in diabetes and high oxidative stress conditions [ 4 ].…”

Clinical significance of small bowel manometry patterns suggestive of intestinal obstruction

“…In a recent study using an ex-vivo animal model, minute rhythm was induced by intestinal distension and found to be dependent on cholinergic nerves of the enteric nervous system and nitric oxide. 23 In one third of cases, the origin of the minute rhythm pattern could not be determined and finally fell into the undetermined category. Interestingly in this group of patients, constipation was more prevalent than in the rest of the patients with the MRP or PSC patterns.…”

“…In analogy to organic occlusion, the MRP and PSC patterns in patients with intestinal neuropathy may be a reaction to a downstream functional obstruction. In a recent study using an ex‐vivo animal model, minute rhythm was induced by intestinal distension and found to be dependent on cholinergic nerves of the enteric nervous system and nitric oxide 23 …”

“…In a recent study using an ex‐vivo animal model, minute rhythm was induced by intestinal distension and found to be dependent on cholinergic nerves of the enteric nervous system and nitric oxide. 23 …”

Common Pathophysiological Mechanisms and Treatment of Diabetic Gastroparesis

“…25 (4) The ICC of the deep muscular plexus, which can produce stimulus-dependent pacemaker activity, can be used to coordinate small bowel segmentation and cluster propulsion actions. 26 (5) In the pyloric region of the colon and the stomach, respectively, the ICC of submucosa and submucosal plexus are located at the interface between the submucosal connective tissue and the innermost circular muscle layer. 27 (6) The connective tissue below the mesothelium contains ICC-SS, which are stellate, multi-processed cells.…”