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1 Department of Medicine, Rhode Island Hospital and Brown Medical School, Providence, RI, USA; Department of Surgery, Rhode Island Hospital and Brown Medical School, Providence, RI, USA
2 Department of Surgery, Rhode Island Hospital and Brown Medical School, Providence, RI, USA
3 Department of Medicine, Division of Biomolecular Medicine, Boston University School of Medicine, Boston, MA, USA
4 Division of Gastroenterology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
* To whom correspondence should be addressed. E-mail: Weibiao_Cao{at}brown.edu.
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 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, as it was not affected by incubation in Ca2+-free medium containing 200µM BAPTA (CFM). 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 the 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.
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