Lower esophageal sphincter is achalasic in nNOS-/- and hypotensive in W/WV mutant mice

Background & 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, 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-NAME (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 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.