Leukotriene D 4–induced contraction of cat esophageal and lower esophageal sphincter circular smooth muscle

Abstract

Background & Aims: In esophageal circular muscle, acetylcholine activates phosphatidylcholine-specific phospholipases C and D and phospholipase A 2, producing diacylglycerol and arachidonic acid, which cause contraction by interacting synergistically to activate protein kinase C. In a model of acute esophagitis, leukotriene D 4 (LTD 4) contributes to acetylcholine-induced contraction. We examined intracellular signaling in LTD 4-induced contraction. Methods: Esophageal and lower esophageal sphincter (LES) cells, isolated by enzymatic digestion, were contracted by LTD 4 in the absence or presence of inhibitors. Permeabilization by saponin allowed use of G-protein antibodies and heparin. Results: Esophageal contraction was inhibited by pertussis toxin, G i3 antibodies, D609 (phosphatidylcholine-specific phospholipase C inhibitor), propranolol (phospholipase D pathway inhibitor), and chelerythrine (protein kinase C antagonist) but not W7 (calmodulin antagonist). LES contraction was unaffected by pertussis toxin. It was inhibited by G q antibodies, U-73122 (phosphatidylinositol-specific phospholipase C inhibitor), heparin (inositol 1,4,5-trisphosphate inhibitor), and W7 and reduced by D609. Conclusions: In the esophagus, LTD 4 activates a protein kinase C–dependent pathway through pertussis toxin–sensitive G i3 proteins and phosphatidylcholine-specific phospholipase. In the LES, LTD 4 activates a calmodulin-dependent pathway through pertussis toxin–insensitive G q proteins and phosphatidylinositol-specific phospholipase C. The intracellular pathways activated by LTD 4 in the esophagus and the LES are similar to those activated by acetylcholine and other agonists. GASTROENTEROLOGY 1998;115:919-928