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

1. 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. 2. 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. 3. 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). 4. 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.