COLONIC MOTILITY

Interstitial cells of Cajal are involved in the afferent limb of the rectoanal inhibitory reflex

F de Lorijn¹, W J de Jonge², T Wedel³, J M Vanderwinden³, M A Benninga¹, G E Boeckxstaens²

¹ Department of Paediatric Gastroenterology and Nutrition, Emma Children’s Hospital, Amsterdam, the Netherlands
² Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, the Netherlands
³ Laboratoire de Neurophysiologie, Faculté de Médecine, Université Libre de Bruxelles, Brussels, Belgium

Correspondence to:
Correspondence to:
Dr G E Boeckxstaens
Department of Gastroenterology and Hepatology, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; g.e.boeckxstaens{at}amc.uva.nl

Background and aims: Interstitial cells of Cajal (ICC) have been shown to be involved in nitrergic neurotransmission of the lower oesophageal sphincter and pylorus. Here we studied the role of ICC and nitric oxide (NO) in the inhibitory neurotransmission of the murine internal anal sphincter (IAS).

Methods: The rectoanal inhibitory reflex, rectal compliance, and relaxation of the isolated IAS to electrical stimulation were measured in controls, KIT ^W/KIT ^Wv mice, and neuronal NO synthase (nNOS) deficient mice. In addition, we evaluated the effect of blockade of nNOS using N-nitro-L-arginine methyl ester. Distribution of nNOS positive neurones and ICC in the IAS was assessed immunohistochemically.

Results: KIT positive ICC were present in a dense network in the IAS of controls but not in KIT ^W/KIT^Wv mice. Relaxation of IAS muscle strips induced by electrical stimulation was diminished in nNOS^–/– mice but not in KIT ^W/KIT ^Wv mice. Blockade of NOS reduced the relaxation of IAS muscle strips in both mice. Relaxation of the IAS to rectal distension was significantly diminished in KIT ^W/KIT ^Wv mice and nNOS deficient mice. In concert, in vivo blockade of NOS attenuated the relaxation of the IAS in controls. No significant difference in compliance was found.

Conclusion: The inhibitory innervation of the IAS and the rectoanal inhibitory reflex are mediated by NO and the rectoanal inhibitory reflex requires an intact network of ICC in the IAS. Thus both loss of nitrergic innervation and deficiency of ICC lead to impaired anal relaxation and may play an important role in rectal evacuation disorders.

Abbreviations: IAS, internal anal sphincter; ICC, interstitial cells of Cajal; nNOS, neuronal nitric oxide synthase; NO, nitric oxide; RAIR, rectoanal inhibitory reflex; L-NAME, N-nitro-L-arginine methyl ester; LOS, lower oesophageal sphincter; TBS-TX, Tris buffered saline-Triton X; NHS, normal horse serum; NANC, non-adrenergic non-cholinergic; SNP, sodium nitroprusside; ATP, 5'-adenosine triphosphate

Keywords: interstitial cells of Cajal; nitric oxide; anal sphincter; anorectal manometry; rectoanal inhibitory reflex

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