Integrative Control of Gastrointestinal Motility by Nitric Oxide

Abstract

In the gastrointestinal (GI) tract, nitric oxide (NO) has been shown over the last 25 years to exert a prominent function as inhibitory neurotransmitter. Apart from the regulation of secretion and resorption, NO from nitrergic neurons has been demonstrated to be crucial for GI smooth muscle relaxation and motility. In fact, several human diseases such as achalasia, gastroparesis, slow transit constipation or Hirschsprung's disease may involve dysfunctional nitrergic signaling. Most of NO's effects as neurotransmitter are mediated by NO-sensitive guanylyl cyclase (NO-GC) and further transduced by cGMP-dependent mechanisms. In contrast to the vascular system where NO from the endothelium induces relaxation by acting on NO-GC solely in smooth muscle cells, GI tissues contain several different NO-GCexpressing cell types that include smooth muscle cells, interstitial cells of Cajal and fibroblast-like cells. Based on this diverse localization of the NO receptor, the exact pathway(s) leading to NO-induced relaxation are still unknown. Global and cell-specific knockout mouse strains have been generated that lack enzymes participating in nitrergic signaling. These animals have been helpful in examining the role of NO in smooth muscle of the GI tract. Here, we discuss the current knowledge on NO-mediated mechanisms in the relaxation of GI smooth muscle in stomach, small and large intestine including sphincters. Special focus is placed on the integration of nitrergic signals by specialized cell types within the gut smooth muscle layers.

Soluble Guanylate Cyclase Stimulators and Activators

“…NO released from nitrergic neurons in the GI tract is an important regulator of GI smooth muscle relaxation and motility (Groneberg et al 2016). Mice lacking sGC develop fatal GI obstruction (Friebe et al 2007).…”

“…There is strong evidence that dysfunctional nitrergic signaling is involved in GI motility disorders such as achalasia, gastroparesis, slow transit constipation, and Hirschsprung's disease. sGC is found in several cell types in the GI tract, including smooth muscle cells, interstitial cells of Cajal (ICC), and fibroblast-like cells; smooth muscle and ICC-specific sGC knockouts have increased understanding of the roles of sGC in each cell type in the regulation of intestinal peristalsis (Groneberg et al 2016).…”

Age-dependent Role of Cilostazol on Cold Restraint Stress-induced Gastric Ulceration in Female Rats

“…NO is a potent vasorelaxant mediator involved in the control of gastric blood flow and contributes to the maintenance of gastric mucosal integrity [32]. It was evident that the gastroprotective effect of NO mostly due to the maintenance of blood flow around the ulcer and increase PGE2 production [33].…”

A case study of 10 patients administered HBOC‐201 in high doses over a prolonged period: outcomes during severe anemia when transfusion is not an option

“…Many GI side effects stem from the roles that NO plays in motility of the alimentary canal, 35–37 as well as in stomach churning and small and large intestine peristalsis . Consequently, disruption of NO bioavailability by cell‐free HBOCs can cause GI side effects that resolve with the rapid clearance of a product from the circulation.…”