Lower Esophageal Sphincter Is Achalasic in nNOS(-/-) and Hypotensive in W/W(v) Mutant Mice

Gastroenterology. 2001 Jul;121(1):34-42. doi: 10.1053/gast.2001.25541.

Abstract

Background and aims: It has been proposed that nitrergic nerves mediate lower esophageal sphincter (LES) relaxation with intramuscular interstitial cells of Cajal (ICC-IM) as an intermediary. Dysfunction of the nitrergic pathway has been shown to cause LES hypertension and impaired relaxation in achalasia. We determined whether mice with neuronal nitric oxide synthase gene disruption (nNOS(-/-)) and W/W(v) mice lacking ICC-IM have achalasia-like LES dysfunction.

Methods: Intraluminal manometry using a customized micro-sized catheter assembly was performed in anesthetized mice. Basal LES pressure and swallow- and vagal-evoked LES relaxations were quantified in wild-type, Nomega-nitro-L-arginine methyl ester HCl salt (L-NAME)-treated, nNOS(-/-), and W/W(v) mice.

Results: Wild-type mouse LES maintained a basal pressure (24 +/- 3 mm Hg; N = 8) and relaxed normally to swallow (87% +/- 3%; N = 8) and vagal stimulation (91% +/- 4% mm Hg; N = 6). Pretreatment with L-NAME (100 mg/kg, intravenously) attenuated LES relaxation to both stimuli (P < 0.05). The LES in nNOS(-/-) was significantly hypertensive (36 +/- 5 mm Hg; N = 10; P < 0.05) with a markedly impaired relaxation (P < 0.05). In contrast, W/W(v) mouse LES was significantly hypotensive (11 +/- 2 mm Hg; N = 6; P < 0.05) with normal relaxation that was blocked by L-NAME.

Conclusions: nNOS(-/-) mice have LES hypertension with impaired relaxation resembling achalasia. In contrast, W/W(v) mice have hypotensive LES with unimpaired relaxation, suggesting that ICC-IM do not play a role in nitrergic neurotransmission.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Deglutition / drug effects
  • Esophageal Achalasia / genetics*
  • Esophagogastric Junction / drug effects
  • Esophagogastric Junction / physiology*
  • Female
  • Male
  • Manometry
  • Mice
  • Mice, Inbred C57BL
  • NG-Nitroarginine Methyl Ester
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type I

Substances

  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type I
  • Nos1 protein, mouse
  • NG-Nitroarginine Methyl Ester