Characterization of LTC₄ effects on rabbit Heal mucosa in vitro

Summary

The effects of peptidoleukotriene C4 (LTC₄) on electrical properties and Na⁺ and Cl⁻ fluxes in the presence or absence of the LTD4/LTE4 antagonist, (2(S)-hydroxy3-(R)-carboxyethylthio)-3-[2-(8-phenyloctyl)phenyl] propanoic acid (SK&F 104353) were investigated in stripped ileal mucosa from rabbits placed in Ussing chambers. Results from this study demonstrate that serosal addition of LTC4 produces a dose-dependent increase in short-circuit current (I_sc) which is not affected by pretreatment of the tissue with SK&F 104353 (0.1 μM). The concentration of LTC4 which produced an increase in I_sc of 4 µEq/h · cm² was 181 nM in the absence of SK&F 104353 and this value did not differ significantly from the value of 212 nM in the presence of SK&F 104353 (0.1 μM). SK&F 104353 (0.1 μM) reduced the increase in I_sc elicited by LTD4 and LTE4 by > 95%. Mucosal addition of LTC4 failed to alter I_sc. The time course of the increase in I_sc in response to LTC4 is qualitatively similar to that seen with both LTD4 and LTE4. Increases in I_sc produced by LTC4 are not inhibited by removal of Ca²⁺ from the serosal bathing solution but are inhibited by pretreatment of the tissue with indomethacin (1 µM). The histamine receptor antagonist, mepyramine, reduced the change in I_sc resulting from stimulation with LTC4 by 20% while the cholinergic antagonist, atropine, and the excitable tissue Na⁺ channel blocker, tetrodotoxin, were without effect. Measurement of unidirectional and net Na⁺ and Cl⁻ fluxes revealed that LTC4 reduces Na⁺ and Cl⁻ absorption and that subsequent addition of PGEI produced no further decrease. Thus, these results indicate that LTC4 as well as LTD₄ and LTE₄ can inhibit electrolyte absorption and that the receptors involved in stimulation by LTC₄ are distinct from those responsible for the effects of LTD₄ and LTE₄.