Leukotrienes in acetylcholine-induced contraction of esophageal circular smooth muscle in experimental esophagitis

Background & Aims: Phospholipase A(2) (PLA(2)) participates in acetylcholine (ACh)-induced contraction of esophageal circular smooth muscle. Because PLA(2), arachidonic acid, and its metabolites are involved in inflammatory responses, their role after induction of experimental esophagitis was examined. Methods: Experiments were performed in esophageal smooth muscle cells (ESO) isolated by enzymatic digestion from the circular layer of normal and esophagitis animals. Content of peptidoleukotrienes (leukotriene [LT] C-4, LTD4, and LTE4) was measured in esophageal circular muscle tissue. Results: The cytosolic PLA(2) antagonist trifluoromethyl ketone analogue of arachidonic acid inhibited ACh-induced contraction of normal and esophagitis ESO. Inhibition by secreted PLA(2) antagonists AM5 and MJ33 was significantly greater in esophagitis ESO. The lipoxygenase inhibitor nordihydro-guaiaretic acid and the LTD4 antagonist ICI 198,615 inhibited ACh-induced contraction of esophagitis but not of normal ESO. Secreted PLA(2) and LTD4 contracted normal ESO more than esophagitis ESO. However, in esophagitis, ESO contraction was increased by threshold diacylglycerol concentration. Resting levels of LTs were greater in esophagitis than in normal circular esophageal muscle and increased in response to ACh in esophagitis but not in normal esophageal muscle. Conclusions: Esophagitis shifts the signal transduction pathway activated by ACh. Esophagitis increased the contribution of secreted PLA(2) and of LTs to ACh-induced contraction.