Pyloric sphincter dysfunction in nNOS-/- and W/Wv mutant mice: animal models of gastroparesis and duodenogastric reflux.
OBJECTIVE
Nitrergic nerves and interstitial cells of Cajal (ICC) have been implicated in the regulation of pyloric motility. The purpose of these studies was to define their roles in pyloric function in vivo.


METHODS
Pyloric sphincter manometry was performed in wild-type controls, neuronal nitric oxide synthase-deficient (nNOS(-/-)) mice, and ICC-deficient W/W(v) mice, and the effect of deafferented cervical vagal stimulation was examined.


RESULTS
Mice showed a distinct approximately 0.6-mm-wide zone of high pressure at the antroduodenal junction, representing the pyloric sphincter. In wild-type controls, the pylorus exhibited tonic active pressure of 12.4 +/- 1.6 mm Hg with superimposed phasic contractions. The motility indices, minute motility index, and total myogenic activity were reduced by vagal stimulation, and the reduction was antagonized by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). In nNOS(-/-) mice, pyloric basal tone, minute motility index, and total myogenic activity were not significantly different from those in controls, but vagal stimulation paradoxically increased pyloric motility. In contrast, the W/W(v) mice had significantly reduced resting pyloric pressure that was suppressed by vagal stimulation in an L-NAME-sensitive manner. The stomachs of fasted nNOS(-/-) mice showed solid food residue and bezoar formation, while W/W(v) mice showed bile reflux.


CONCLUSIONS
In nNOS(-/-) mice, loss of nitrergic pyloric inhibition leads to gastric stasis and bezoars. In contrast, basal pyloric hypotension with normal nitrergic inhibition predisposes W/W(v) mice to duodenogastric bile reflux.
Sivarao
Digavalli V
DV
Department of Veterans Affairs Medical Center, Center for Swallowing and Motility Disorders, West Roxbury, Massachusetts 02132, USA.
Mashimo
Hiroshi
H
Goyal
Raj K
RK
D000818:Animals; D001630:Bezoars / Q000235:genetics / Q000503:physiopathology; D001646:Bile; D004383:Duodenogastric Reflux / Q000235:genetics / Q000503:physiopathology*; D004386:Duodenum / Q000502:physiology; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005746:Gastric Emptying / Q000502:physiology; D005769:Gastrointestinal Motility / Q000502:physiology; D018589:Gastroparesis / Q000235:genetics / Q000503:physiopathology*; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D008365:Manometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011708:Pylorus / Q000294:innervation / Q000503:physiopathology*; D014630:Vagus Nerve / Q000502:physiology
D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D019331:NG-Nitroarginine Methyl Ester