Pyloric sphincter dysfunction in nNOS-/- and W/Wv mutant mice: animal models of gastroparesis and duodenogastric reflux.

Abstract

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. 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. 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. 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.