title: Dominant role of interstitial cells of Cajal in nitrergic relaxation of murine lower oesophageal sphincter.
abstract: Oesophageal achalasia is a disease known to result from reduced relaxation of the lower oesophageal sphincter (LES). Nitric oxide (NO) is one of the main inhibitory transmitters. NO-sensitive guanylyl cyclase (NO-GC) acts as the key target of NO and, by the generation of cGMP, mediates nitrergic relaxation in the LES. To date, the exact mechanism of nitrergic LES relaxation is still insufficiently elucidated. To clarify the role of NO-GC in LES relaxation, we used cell-specific knockout (KO) mouse lines for NO-GC. These include mice lacking NO-GC in smooth muscle cells (SMC-GCKO), in interstitial cells of Cajal (ICC-GCKO) and in both SMC/ICC (SMC/ICC-GCKO). We applied oesophageal manometry to study the functionality of LES in vivo. Isometric force studies were performed to monitor LES responsiveness to exogenous NO and electric field stimulation of intrinsic nerves in vitro. Cell-specific expression/deletion of NO-GC was monitored by immunohistochemistry. Swallowing-induced LES relaxation is strongly reduced by deletion of NO-GC in ICC. Basal LES tone is affected by NO-GC deletion in either SMC or ICC. Lack of NO-GC in both cells leads to a complete interruption of NO-induced relaxation and, therefore, to an achalasia-like phenotype similar to that seen in global GCKO mice. Our data indicate that regulation of basal LES tone is based on a dual mechanism mediated by NO-GC in SMC and ICC whereas swallow-induced LES relaxation is mainly regulated by nitrergic mechanisms in ICC.
authors: Physiologisches Institut I, Universität Würzburg, Würzburg, Germany.
authors: Dieter
authors: D
authors: Groneberg
authors: Eugen
authors: E
authors: Zizer
authors: Barbara
authors: B
authors: Lies
authors: Barbara
authors: B
authors: Seidler
authors: Dieter
authors: D
authors: Saur
authors: Martin
authors: M
authors: Wagner
authors: Andreas
authors: A
authors: Friebe
mesh_terms: D000818:Animals; D049630:Esophageal Sphincter, Lower / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D056885:Interstitial Cells of Cajal / Q000378:metabolism* / Q000502:physiology; D007537:Isometric Contraction; D051379:Mice; D008810:Mice, Inbred C57BL; D009126:Muscle Relaxation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase
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