Lower esophageal sphincter is achalasic in nNOS(-/-) and hypotensive in W/W-V mutant mice

Background & Aims: It has been proposed that nitrergic nerves mediate lower esophageal sphincter (LES) relaxation with intramuscular interstitial cell s of Cajal (ICC IM) as an intermediary. Dysfunction of the nitrergic pathwa y has been shown to cause LES hypertension and impaired relaxation in achal asia. We determined whether mice with neuronal nitric oxide synthase gene d isruption (nNOS(-/-)) and W/W-v mice lacking ICC-IM have achalasia-like LES dysfunction. Methods: Intraluminal manometry using a customized micro-size d catheter assembly was performed in anesthetized mice. Basal LES pressure and swallow- and vagal-evoked LES relaxations were quantified in wild-type, N omega -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-NAM E (100 mg/kg, intravenously) attenuated LES relaxation to both stimuli (P < 0.05). The LES in nNOS(-/-) was significantly hypertensive (36 +/- 5 mm HS ; N = 10; P < 0.05) with a markedly impaired relaxation (P < 0.05). In cont rast, 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 ac halasia. In contrast, W/W-v mice have hypotensive LES with unimpaired relax ation, suggesting that ICC-IM do not play a role in nitrergic neurotransmis sion.