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.
Keywords: Guanylyl cyclase, cGMP, relaxation, interstitial cells of Cajal, smooth muscle, knockout mice, enteric
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