Neurally mediated actions of leukotrienes on ion transport in guinea pig distal colon

The effects of the sulfidopeptide leukotrienes (LT), LTC₄, LTD₄ and LTE₄ on short-circuit current (I(sc)), a measure of active ion transport, were determined in muscle-stripped mucosa sheets from the guinea pig distal colon. LTC₄ and D₄, but not E₄, evoked concentration-dependent increases in I(sc). Auto- and cross-tachyphylaxis could be demonstrated in LT actions. LTD₄ was more sensitive than LTC₄ to inhibition by the LTD₄ antagonist, 1-<2-hydroxy-3-propyl-4-<4-(1H-tetrazol-5- yl)butoxy>phenyl>ethanone, and the intracellular Ca⁺⁺ inhibitor, 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester. Mucosal LT effects were reduced in tissues pretreated with bumetanide or bathed in HCO₃^--free media. Measurements of transepithelial Na⁺ and Cl^- fluxes revealed that LTC₄ increased unidirectional and net secretory fluxes of Cl^- but had no effect on Na⁺ transport. Tetrodotoxin, atropine and indomethacin inhibited mucosal responses to LTC₄ and D₄; in addition prazosin inhibited LTD₄ effects. The results suggest that LTC₄ and D₄ evoke anion secretion by acting through distinct LT receptor populations. These effects are mediated in part by cholinergic and adrenergic submucosal neurons as well as by colonic prostanoids.