Lower esophageal sphincter is achalasic in nNOS(-/-) and hypotensive in W/W(v) mutant mice.
OBJECTIVE
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.
Sivarao
D V
DV
Center for Swallowing and Motility Disorders, Department of Veterans Affairs Medical Center, 1400 VFW Parkway, West Roxbury, Massachusetts 02132, USA.
Mashimo
H L
HL
Thatte
H S
HS
Goyal
R K
RK
D000818:Animals; D003679:Deglutition / Q000187:drug effects; D004931:Esophageal Achalasia / Q000235:genetics*; D004943:Esophagogastric Junction / Q000187:drug effects / Q000502:physiology*; D005260:Female; D008297:Male; D008365:Manometry; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I
D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D019331:NG-Nitroarginine Methyl Ester