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HORMONES AND SIGNALING

Platelet-activating factor and prostaglandin E₂ impair esophageal ACh release in experimental esophagitis

¹Rhode Island Hospital and Brown University, Providence, Rhode Island; and ²Case Western Reserve University, Cleveland, Ohio

Submitted 21 January 2005 ; accepted in final form 9 May 2005

ACh is a neurotransmitter in cat esophageal circular muscle, as atropine nearly abolishes contraction of in vitro circular muscle strips in response to electric field stimulation (EFS) (5, 12). Experimental esophagitis reduced EFS- but not ACh-induced contraction of esophageal circular muscle, suggesting that esophagitis impairs neurotransmitter release. Because IL-1 and IL-6 are produced in esophagitis and reproduce these changes in normal esophageal muscle (12), we examined the role of IL-1 and IL-6 in this motor dysfunction. IL-1, IL-6 (12), H₂O₂, PGE₂, and platelet-activating factor (PAF) were elevated in esophagitis specimens. Normal muscle incubated (2 h) in IL-1 and IL-6 had increases in H₂O₂, PGE₂, and PAF levels. H₂O₂ contributed to increased PGE₂ and PAF, as the increase was partially (60–80%) reversed by the H₂O₂ scavenger catalase. EFS-induced [³H]ACh release from muscle strips significantly (42%) decreased in esophagitis and after 2 h incubation in PGE₂ and in PAF C-16. Similarly, EFS-induced but not ACh-induced muscle contraction decreased in esophagitis and after incubation in PGE₂ and PAF C-16. Finally, in normal muscle strips treated with IL-1 electrical field stimulation (EFS)-induced contraction was partially restored by indomethacin or by the PAF antagonist CV3988 and was completely restored by the combination of CV3988 and indomethacin, whereas in strips treated with IL-6, EFS-induced contraction was partially restored by the PAF antagonist CV3988 and not affected by indomethacin. We conclude that IL-1-induced production of H₂O₂ causes formation of PGE₂ and PAF that inhibit ACh release from esophageal cholinergic neurons without affecting ACh-induced contraction of esophageal circular muscle. IL-6 causes production of H₂O₂, PAF, and other unidentified inflammatory mediators.

inflammation; smooth muscle contraction; reactive oxygen species

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