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NEUROREGULATION AND MOTILITY

Hydrogen peroxide contributes to motor dysfunction in ulcerative colitis

¹Departments of Medicine and ²Surgery, Rhode Island Hospital and Brown Medical School, Providence, Rhode Island 02903; ³Department of Medicine, Division of Biomolecular Medicine, Boston University School of Medicine, Boston, Massachusetts 02118; and ⁴Division of Gastroenterology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106

Submitted 24 September 2003 ; accepted in final form 10 December 2003

Ulcerative colitis (UC) affects colonic motor function, but the mechanism responsible for this motor dysfunction is not well understood. We have shown that neurokinin A (NKA) may be an endogenous neurotransmitter mediating contraction of human sigmoid colonic circular muscle (HSCCM). To elucidate factors responsible for UC motor dysfunction, we examined the role of hydrogen peroxide (H₂O₂) in the decrease of NKA-induced response of HSCCM. As previously demonstrated, NKA-induced contraction or Ca²⁺ increase of normal muscle cells is mediated by release of Ca²⁺ from intracellular stores, because it was not affected by incubation in Ca²⁺-free medium (CFM) containing 200 µM BAPTA. In UC, however, CFM reduced both cell contraction and NKA-induced Ca²⁺ increase, suggesting reduced Ca²⁺ release from intracellular stores. In normal Ca²⁺ medium, NKA and KCl caused normal Ca²⁺ signal in UC cells but reduced cell shortening. The decreased Ca²⁺ signal and contraction in response to NKA or thapsigargin were partly recovered in the presence of H₂O₂ scavenger catalase, suggesting involvement of H₂O₂ in UC-induced dysmotility. H₂O₂ levels were higher in UC than in normal HSCCM, and enzymatically isolated UC muscle cells contained much higher levels of H₂O₂ than normal cells, which were significantly reduced by catalase. H₂O₂ treatment of normal cells in CFM reproduced the reduction of NKA-induced Ca²⁺ release observed in UC cells. In addition, H₂O₂ caused a measurable, direct release of Ca²⁺ from intracellular stores. We conclude that H₂O₂ may contribute to reduction of NKA-induced Ca²⁺ release from intracellular Ca²⁺ stores in UC and contribute to the observed colonic motor dysfunction.

neurokinin A; calcium; smooth muscle; human; colon

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