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Vol. 283, Issue 3, 1293-1304, 1997
Department of Pharmacology, Chung Ang University Pharmacy College,
Seoul 156-756, Korea (U.D.S.),
Department of Medicine, Rhode Island
Hospital and Brown University School of Medicine, Providence, Rhode
Island (K.M.H., W.C., J.B., P.B),
Department of Medicine, VA Medical
Center and Brown University School of Medicine, Providence, Rhode
Island (H.R.) and
Kangnam General Hospital, Public Corporation, Seoul,
135-090, Korea (N.K.)
In single cells, isolated by enzymatic digestion from the circular
muscle layer of the lower esophageal sphincter (LES), acute experimental esophagitis (AE) alters signal transduction in response to
a maximally effective dose of acetylcholine. In normal LES contraction
was inhibited by M3
M1 or M2
antagonists. In AE inhibition by M2 antagonists increased
significantly so that contraction was inhibited by M3 > M2 > M1 antagonists. In normal cells
permeabilized by saponin, contraction was antagonized by antibodies
against Gq/11, by the phosphatidylinositol-specific
phospholipase C (PI-PLC) antagonist U 73122, but not by the
phosphatidylcholine-specific phospholipase C (PC-PLC) inhibitor D609,
or by the phospholipase D pathway inhibitor propranolol. In AE
contraction was reduced by Gq/11 and Gi3
antibodies and by U73122, propranolol and D609. After thapsigargin
treatment of normal cells to reduce intracellular Ca++
stores, contraction was inhibited by M2 and M3
antagonists, by antibodies against Gq/11 and
Gi3, by U73122, D609 and propranolol, suggesting that
depletion of Ca++ stores reproduces the changes induced by
AE. We conclude that in normal LES smooth muscle cells
acetylcholine-induced contraction is mediated by M3
receptors linked to Gq/11 and PI-PLC, whereas in AE,
contraction through this pathway is reduced, perhaps because of
reduction in Ca++ stores, and a second pathway is activated
by M2 receptors linked to Gi3, PC-PLC and
phospholipase D.
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