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) (4, 10). Induction of experimental esophagitis by perfusion with HCl 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 (10), we examined the role of IL-1 and IL-6 in this motor dysfunction. In addition to IL-1, IL-6 (10), H₂O₂, PGE₂ and PAF were elevated in esophagitis specimens. Normal muscle incubated (2-hr) in IL-1 and IL-6 had increases in H₂O₂, PGE₂ and PAF levels similar to those of esophagitis specimens. H₂O₂ contributed to increased PGE₂ and PAF, as the increase was partially (60-80%) reversed by the H₂O₂ scavenger catalase. EFS-induced ³[H]ACh release from muscle strips significantly (42%) decreased in esophagitis, and after 2-hr incubation in PGE₂ and in PAF C-16, suggesting that their increase may contribute to reduced ³[H]ACh release. 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, 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 H₂O₂causes formation of PGE₂ and PAF which 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.