Platelet-activating factor and prostaglandin E2impair esophageal ACh release in experimental esophagitis

Abstract

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-1β and IL-6 are produced in esophagitis and reproduce these changes in normal esophageal muscle ( 12 ), we examined the role of IL-1β and IL-6 in this motor dysfunction. IL-1β, IL-6 ( 12 ), H2O2, PGE2, and platelet-activating factor (PAF) were elevated in esophagitis specimens. Normal muscle incubated (2 h) in IL-1β and IL-6 had increases in H2O2, PGE2, and PAF levels. H2O2contributed to increased PGE2and PAF, as the increase was partially (60–80%) reversed by the H2O2scavenger catalase. EFS-induced [3H]ACh release from muscle strips significantly (42%) decreased in esophagitis and after 2 h incubation in PGE2and in PAF C-16. Similarly, EFS-induced but not ACh-induced muscle contraction decreased in esophagitis and after incubation in PGE2and PAF C-16. Finally, in normal muscle strips treated with IL-1β 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-1β-induced production of H2O2causes formation of PGE2and 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.