Murine genetic deficiency of neuronal nitric oxide synthase (nNOS(-/-) ) and interstitial cells of Cajal (W/W(v) ): Implications for achalasia?
OBJECTIVE
Nitric oxide (NO) is an important inhibitory mediator of esophageal function, and its lack leads to typical features of achalasia. In contrast, the role of intramuscular interstitial cells of Cajal (ICC-IM) and vasoactive intestinal peptide (VIP) in lower esophageal sphincter (LES) function is still controversial. Therefore, we examined the function and morphology of the LES in vivo in NO-deficient (nNOS(-/-) ), ICC-IM-deficient (W/W(v) )-, and wild-type (WT) mice.


METHODS
Esophageal manometry was performed with a micro-sized transducer catheter to quantify LES pressure, swallow evoked LES relaxation, and esophageal body motility. The LES morphology was examined by semiquantitative analysis of the immunoreactivity (reduction grade I-IV) of neuronal NOS (nNOS), ICC-IM, and VIP and their correlation with esophageal function.


RESULTS
nNOS(-/-) in comparison to WT mice showed a significantly higher LES mean resting pressure with an impaired swallow induced relaxation, whereas W/W(v) mice had a hypotensive LES with decreased relaxation. W/W(v) and nNOS(-/-) mice demonstrated differing degrees of tubular esophageal dysfunction. The reduced immunoreactivity of nNOS correlated with an increased LES pressure and decreased LES relaxation, respectively. Cajal-cell reduction correlated with impaired LES relaxation, whereas VIP reduction revealed no correlation with esophageal function.


CONCLUSIONS
The reduction of ICC-IM and nNOS can cause dysfunction of the LES and esophageal peristalsis, whereas VIP reduction seems to have no effect. ICC-IM and nNOS deficiency might be independent relevant causes of esophageal dysfunction similar to that seen in human achalasia.
Department of Gastroenterology, German Diagnostic Clinic, Wiesbaden, Germany.
Michaela
M
Müller
Sebastian
S
Colcuc
Daniel G
DG
Drescher
Alexander J
AJ
Eckardt
Harald
H
von Pein
Christian
C
Taube
Johannes
J
Schumacher
Henning R
HR
Gockel
Carl C
CC
Schimanski
Hauke
H
Lang
Ines
I
Gockel
D000818:Animals; D004931:Esophageal Achalasia / Q000209:etiology* / Q000503:physiopathology; D049630:Esophageal Sphincter, Lower / Q000503:physiopathology; D005260:Female; D017353:Gene Deletion; D006801:Humans; D056885:Interstitial Cells of Cajal / Q000502:physiology*; D008297:Male; D008365:Manometry; D008815:Mice, Inbred Strains; D009569:Nitric Oxide / Q000502:physiology; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency* / Q000235:genetics*; D010528:Peristalsis; D014660:Vasoactive Intestinal Peptide / Q000502:physiology
D009569:Nitric Oxide; D014660:Vasoactive Intestinal Peptide; D052248:Nitric Oxide Synthase Type I
achalasia; interstitial cells of Cajal; lower esophageal sphincter; nitric oxide; vasoactive intestinal peptide