Mechanism of leukotriene D4 stimulation of Cl- secretion in rat distal colon in vitro.

Lipoxygenase metabolites of arachidonic acid have been implicated as mediators of inflammation in inflammatory bowel disease (IBD). To assess their role in regulation of electrolyte transport, we investigated the effect of leukotriene D4 (LTD4) on ion transport across isolated rat colonic mucosa under voltage-clamp conditions. Serosal addition of LTD4 caused a dose-dependent rapid and transient increase in both short-circuit current (Isc) and potential difference, with maximal response at 1 microM. Pretreatment of the tissue with a specific LTD4 receptor antagonist (SKF-104353) inhibited these LTD4 effects. The effect of LTD4 on Isc and potential difference was also abolished by the absence of Cl- from both bathing solutions or by the presence of a Na(+)-K(+)-2Cl- cotransport inhibitor (bumetanide). A cyclooxygenase inhibitor (piroxicam) completely prevented the LTD4-induced increase in Isc. In addition, the effect of LTD4 on Isc was inhibited by either 5-hydroxytryptamine2 or 5-hydroxytryptamine3 antagonists (ketanserin and ICS-205-930, respectively). These results are consistent with a model in which LTD4 initially stimulates the synthesis from lamina propria cells of cyclooxygenase metabolites that induce electrogenic Cl- secretion, most likely via serotonergic receptors.