Leukotriene C4 enhances the contraction of porcine tracheal smooth muscle through the activation of Y‐27632, a rho kinase inhibitor, sensitive pathway

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Abstract
An unsaturated fatty acid, leukotriene C4 (LTC4), has a potent contractile effect on human airway smooth muscle, and has been implicated in the pathogenesis of human asthma. Using front‐surface fluorometry with fura‐PE3, the effect of LTC4 on the intracellular Ca2+ concentration ([Ca2+]i) and tension were investigated in porcine tracheal smooth muscle strips. The application of LTC4 induced little or no contraction despite a small and transient increase in [Ca2+]i. In the presence of LTC4, however, the contractions evoked by high K+ depolarization or a low concentration of carbachol (CCh) were markedly enhanced without inducing any changes in the [Ca2+]i levels, thus indicating that LTC4 increases the Ca2+ responsiveness of the contractile apparatus. This LTC4‐induced increase in Ca2+ responsiveness could partly be reproduced in the permeabilized preparation of tracheal smooth muscle strips. The LTC4‐induced enhancement of contraction was accompanied by an increase in myosin light chain (MLC) phosphorylation and was blocked by a rho kinase inhibitor (Y‐27632), but not by either a PKC inhibitor (calphostin C) or a tyrosine kinase inhibitor (genistein). These results indicated that, in porcine tracheal smooth muscle, LTC4 enhances the contraction by increasing the Ca2+ responsiveness of the contractile apparatus in a MLC phosphorylation dependent manner, possibly through the activation of the rho‐rho kinase pathway. British Journal of Pharmacology (2001) 132, 111–118; doi:10.1038/sj.bjp.0703780