title: Interstitial cells of Cajal modulate the tone of the human internal anal sphincter in vitro.
abstract: BACKGROUND
  Interstitial cells of Cajal, expressing the proto-oncogene c-kit, have been shown to regulate the spontaneous activity of the gastrointestinal tract. They have been described in the human internal anal sphincter; however, their function is still unclear.
  
  
  OBJECTIVE
  We examined the effects of the c-kit tyrosine kinase inhibitor imatinib mesylate on sphincter strips to investigate the function of the interstitial cells.
  
  
  METHODS
  This was a case series study.
  
  
  METHODS
  This was a single-center study conducted at the University of Oxford.
  
  
  METHODS
  Internal anal sphincter strips were collected from 10 patients undergoing abdominoperineal resection or proctectomy and mounted in organ bath. Responses to electrical field stimulation and chemical agents were monitored in the absence of drugs and after the administration of increasing doses of imatinib mesylate. Immunohistochemistry was performed to identify interstitial cells.
  
  
  METHODS
  The role of the interstitial cells in the internal anal sphincter was assessed.
  
  
  RESULTS
  Imatinib mesylate significantly reduced the tone and the spontaneous activity of the strips. In the absence of drugs, the tone generated was 147.7 ± 33.0 mg/mg of tissue. Administration of ≥5 μM of imatinib mesylate caused a dose-dependent reduction in the tone. Strips exhibited spontaneous activity characterized by intermittent low-amplitude contractions superimposed on basal tone (135.6 ± 4.6 contractions in 10 minutes). Imatinib mesylate significantly reduced the number of contractions at concentration >5 μM. No differences were observed in the responses to electrical field stimulation, carbachol, or phenylephrine. Immunohistochemistry showed c-kit-positive cells.
  
  
  CONCLUSIONS
  This study was limited by the relatively small number of patients enrolled and thus the difficulty of finding human tissue for laboratory studies.
  
  
  CONCLUSIONS
  Our results suggest that the interstitial cells modulate the tone and the spontaneous activity of the internal anal sphincter. This provides a foundation for new approaches to preclinical and clinical research. Moreover, these cells may represent a target for drugs inhibiting the c-kit receptor and provide a new approach for treating anorectal diseases.
authors: 1Department of Surgery, University of Siena, Siena, Italy 2Department of Pharmacology, University of Oxford, Oxford, United Kingdom 3Department of Colorectal Surgery, Churchill Hospital, Oxford, United Kingdom.
authors: Bruno
authors: B
authors: Lorenzi
authors: Alison F
authors: AF
authors: Brading
authors: Neil J McC
authors: NJ
authors: Mortensen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001003:Anal Canal / Q000166:cytology* / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D004558:Electric Stimulation; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007124:Immunoenzyme Techniques; D056885:Interstitial Cells of Cajal / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D001549:Benzamides; C000715470:MAS1 protein, human; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit