Hydrogen peroxide contributes to motor dysfunction in ulcerative colitis.
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 (H(2)O(2)) in the decrease of NKA-induced response of HSCCM. As previously demonstrated, NKA-induced contraction or Ca(2+) increase of normal muscle cells is mediated by release of Ca(2+) from intracellular stores, because it was not affected by incubation in Ca(2+)-free medium (CFM) containing 200 microM BAPTA. In UC, however, CFM reduced both cell contraction and NKA-induced Ca(2+) increase, suggesting reduced Ca(2+) release from intracellular stores. In normal Ca(2+) medium, NKA and KCl caused normal Ca(2+) signal in UC cells but reduced cell shortening. The decreased Ca(2+) signal and contraction in response to NKA or thapsigargin were partly recovered in the presence of H(2)O(2) scavenger catalase, suggesting involvement of H(2)O(2) in UC-induced dysmotility. H(2)O(2) levels were higher in UC than in normal HSCCM, and enzymatically isolated UC muscle cells contained much higher levels of H(2)O(2) than normal cells, which were significantly reduced by catalase. H(2)O(2) treatment of normal cells in CFM reproduced the reduction of NKA-induced Ca(2+) release observed in UC cells. In addition, H(2)O(2) caused a measurable, direct release of Ca(2+) from intracellular stores. We conclude that H(2)O(2) may contribute to reduction of NKA-induced Ca(2+) release from intracellular Ca(2+) stores in UC and contribute to the observed colonic motor dysfunction.
Cao
Weibiao
W
Dept. of Medicine, Brown Medical School and Rhode Island Hospital, 593 Eddy St., SWP-510, Providence, RI 02903, USA. Weibiao_Cao@brown.edu
Vrees
Matthew D
MD
Kirber
Michael T
MT
Fiocchi
Claudio
C
Pricolo
Victor E
VE
D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002374:Catalase / Q000494:pharmacology; D003093:Colitis, Ulcerative / Q000503:physiopathology*; D012809:Colon, Sigmoid / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D015288:Neurokinin A / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology
D011189:Potassium Chloride; D015288:Neurokinin A; D006861:Hydrogen Peroxide; D002374:Catalase; D002118:Calcium