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NEUROREGULATION AND MOTILITY

Inflammation induced changes in arachidonic acid metabolism in cat LES circular muscle

Department of Medicine, Rhode Island Hospital and Brown University, Providence, Rhode Island

Submitted 22 July 2004 ; accepted in final form 9 November 2004

Myogenic lower esophageal sphincter (LES) tone is maintained by arachidonic acid metabolites, such as PGF₂ and thromboxane A₂/B₂. Experimental esophagitis in cat reduces LES in vivo pressure and in vitro tone. Because IL-1 may mediate esophagitis-associated reduction in ACh release in esophagus, we examined whether IL-1 may also play a role in esophagitis-induced reduction of LES tone. A cat model of experimental esophagitis was obtained by repeated esophageal perfusion with HCl (Biancani P, Barwick K, Selling J, and McCallum R. Gastreonterology 87: 8–16, 1984 and Sohn UD, Harnett KM, Cao W, Rich H, Kim N, Behar J, and Biancani P. J Pharmacol Exp Ther 283: 1293–1304, 1997.). LES circular muscle strips were examined in muscle chambers as previously described (Biancani P, Billett G, Hillemeier C, Nissenshon M, Rhim BY, Sweczack S, and Behar J. Gastroenterology 103: 1199–1206, 1992). Levels of inflammatory mediators were measured. IL-1 levels were higher in esophagitis than in normal LES. IL-1 reduced normal LES tone, and the reduction was reversed by catalase, suggesting a role of H₂O₂. This was confirmed by IL-1-induced production of H₂O₂ in normal LES and elevated H₂O₂ levels in esophagitis. H₂O₂ by itself is sufficient to explain the changes that occur in the muscle, reducing its ability to contract. H₂O₂ increased PGE₂ in normal LES, and PGE₂ levels were elevated in esophagitis LES, whereas PGF₂ levels were unchanged. H₂O₂ also increased levels of 8-isoprostanes, stable prostaglandin-like compounds formed by free radical-induced peroxidation of arachidonic acid, and 8-isoprostane levels were elevated in esophagitis. The PGF₂ analog 8-iso-PGF₂ caused little contraction of LES strips but reduced PGF₂ binding and contraction of normal LES. In esophagitis, PGF₂ binding and contraction were reduced in LES, suggesting that isoprostanes may contribute to reduction in tone in esophagitis. The data suggest that, in esophagitis, IL-1 causes production of H₂O₂. H₂O₂ increases PGE₂, which relaxes the LES, and 8-iso-F₂, which blocks PGF₂-mediated contraction.

smooth muscle; contraction; tone; signal transduction; hydrogen peroxide; cytokines; lower esophageal sphincter

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