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

Abstract

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/Wv 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]ω-nitro-L-arginine methyl ester HCl salt (L-NAME)-treated, nNOS-/-, and W/Wv 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/Wv 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/Wv mice have hypotensive LES with unimpaired relaxation, suggesting that ICC-IM do not play a role in nitrergic neurotransmission.