Pharmacological characterization of the nitrergic innervation of the stomach.
Proximal gastric relaxation is a vago-vagal reflex upon food intake. The efferent neurons involved at the level of the stomach are nonadrenergic noncholinergic. Deficient proximal gastric relaxation is observed in a portion of patients with functional dyspepsia, while exaggerated relaxation might contribute to the development of gastroesophageal reflux disease via triggering of transient lower esophageal sphincter relaxations. Nitric oxide (NO) is mediating, together with vasoactive intestinal polypeptide (VIP) as parallel cotransmitter, the nonadrenergic noncholinergic neurotransmission of the proximal stomach. Evidence for a sequential link between VIP as neurotransmitter and muscular NO generation was obtained when studied in isolated gastric smooth muscle cells; inducible NO synthase seems expressed. The endogenous gastric nitrergic neurotransmitter is not sensitive to superoxide anion generators and NO scavengers, that reduce the relaxation to exogenous NO. This is not due to the release of a nerve-derived hyperpolarizing factor in addition of NO, nor to binding to thiols, but Cu/Zn superoxide dismutase is involved in the protection of endogenous NO versus superoxide anions and scavenging. The release of NO from gastric nitrergic neurons is not sensitive to negative feedback but is inhibited via presynaptic alpha 2-adrenoceptors. Nitric oxide functionally antagonizes acetylcholine in the smooth muscle cells but does not influence the release of acetylcholine at the cholinergic varicosities. Stimulating or inhibiting the gastric nitrergic neurons might be a target for drug therapy in functional dyspepsia or gastro-esophageal reflux, respectively.
Lefebvre
R A
RA
Heymans Institute of Pharmacology, Ghent University, De Pintelaan 185, B-9000 Gent.
D004415:Dyspepsia / Q000209:etiology*; D016166:Free Radical Scavengers; D005764:Gastroesophageal Reflux / Q000209:etiology; D006801:Humans; D009126:Muscle Relaxation; D009434:Neural Pathways / Q000473:pathology*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism* / Q000502:physiology; D013270:Stomach / Q000294:innervation* / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism
D016166:Free Radical Scavengers; D018377:Neurotransmitter Agents; D009569:Nitric Oxide; D014660:Vasoactive Intestinal Peptide; D013482:Superoxide Dismutase