Leukotriene C 4 enhances the contraction of porcine tracheal smooth muscle through the activation of Y‐27632, a rho kinase inhibitor, sensitive pathway

An unsaturated fatty acid, leukotriene C 4 (LTC 4 ), 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 LTC 4 on the intracellular Ca 2+ concentration ([Ca 2+ ] i ) and tension were investigated in porcine tracheal smooth muscle strips. The application of LTC 4 induced little or no contraction despite a small and transient increase in [Ca 2+ ] i . In the presence of LTC 4 , however, the contractions evoked by high K + depolarization or a low concentration of carbachol (CCh) were markedly enhanced without inducing any changes in the [Ca 2+ ] i levels, thus indicating that LTC 4 increases the Ca 2+ responsiveness of the contractile apparatus. This LTC 4 ‐induced increase in Ca 2+ responsiveness could partly be reproduced in the permeabilized preparation of tracheal smooth muscle strips. The LTC 4 ‐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, LTC 4 enhances the contraction by increasing the Ca 2+ 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