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1 Department of Medicine, Rhode Island Hospital and Brown University, Providence, RI, USA
2 Department of Medicine, Division of Biomolecular Medicine, Boston University School of Medicine, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: Piero_Biancani{at}brown.edu.
We have previously reported that induction of acute experimental esophagitis by repeated perfusion of HCl may affect the release of intracellular Ca2+ stores. We therefore measured cytosolic Ca2+ levels in response to a maximally effective dose of ACh in Fura 2AM-loaded LES circular muscle cells and examined the contribution of H2O2 to the reduction in Ca2+ signal. In normal cells ACh-induced Ca2+ increase was the same in normal and Ca2+ free medium and was abolished by the PIP2-specific phospholipase C inhibitor U73122, confirming that the initial ACh-induced contraction depends on Ca2+ release from intracellular stores through production of IP3. In esophagitis, LES cells ACh induced Ca2+ increase was significantly lower in normal Ca2+ medium than in normal cells and was further reduced (~70%) when the cells were incubated in Ca2+ free medium. This reduction was partially reversed by the H2O2 scavenger catalase. Measurements of H2O2 in LES circular muscle showed significantly higher levels in esophagitis than in normal animals. When normal LES cells were incubated with H2O2, ACh-induced Ca2+ increase was significantly reduced both in normal Ca2+ and in Ca2+ free medium, and similar to those observed in the esophagitis animals. Similarly, the initial ACh-induced contraction was also reduced in normal cells incubated with H2O2. H2O2, when applied to cells at sufficiently high concentration, produced a visible and prolonged Ca2+ signal in normal cells. In addition, H2O2-induced cell contraction was sensitive to depletion of stores by thapsigargin and, conversely, H2O2 reduced thapsigargin-induced contraction suggesting that thapsigargin and H2O2 may operate through similar mechanisms. Measurements of Ca2+-ATPase activity indicate that both H2O2 and thapsigargin a caused a reduction in Ca2+-ATPase activity, confirming similarity of mechanism of action. We conclude that H2O2 may be at least partly responsible for impairment of Ca2+ release in acute experimental esophagitis by inhibiting Ca2+uptake and refilling of Ca2+ stores.
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