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 (1(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 Ne+ 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.