LTD 4 induces hyperresponsiveness to histamine but not to carbachol in bovine airway smooth muscle: Role of SR-ATPase Ca 2+ pump and tyrosine kinase pathway

Airway hyperresponsiveness is a key feature of asthma, but its mechanisms remain poorly understood. LTD4 is one of the few molecules capable to produce airway hyperresponsiveness. In this study LTD4, but not LTC4, produced a leftward displacement of the concentration-response curve to histamine in bovine airway smooth muscle strips. Neither LTC4 nor LTD4 modified the concentration-response curve to carbachol. In simultaneous measurements of intracellular Ca ([Ca]i) and contraction, histamine or carbachol produced a transient Ca peak followed by a plateau, along with a contraction. LTD4 increased the histamine-induced transient Ca peak and contraction, but did not modify responses to carbachol. Enhanced responses to histamine induced by LTD4 were not modified by staurosporine or chelerythrine, but were abolished by genistein. Western blot showed that carbachol, but not histamine, caused intense phosphorylation of ERK1/2, and that LTD4 significantly enhanced the phosphorylation induced by histamine, but not by carbachol. L-type Ca channels participation in the hyperresponsiveness to histamine was discarded because LTD4 did not modify the [Ca]i changes induced by KCl. In tracheal myocytes, LTD4 enhanced the transient Ca peak induced by histamine (but not by carbachol) and the SR Ca refilling. Genistein abolished this last LTD4 effect. Partial blockade of the SR-ATPase Ca pump with cyclopiazonic acid reduced the Ca transient peak induced by histamine but not by carbachol. These results suggested that LTD4 induces hyperresponsiveness to histamine through activation of the tyrosine kinase pathway and an increasing SR-ATPase Ca pump activity. L-type Ca channels seemed not to be involved in this phenomenon.