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LTD₄ induces hyperresponsiveness to histamine in bovine airway smooth muscle: role of SR-ATPase Ca²⁺ pump and tyrosine kinase

³Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad Universitaria and ²Laboratorio de Investigación en Autoinmunidad and ¹Departamento de Hiperreactividad Bronquial, Instituto Nacional de Enfermedades Respiratorias, México DF, México

Submitted 17 December 2003 ; accepted in final form 13 September 2004

Airway hyperresponsiveness is a key feature of asthma, but its mechanisms remain poorly understood. Leukotriene D₄ (LTD₄) is one of the few molecules capable of producing airway hyperresponsiveness. In this study, LTD₄, but not leukotriene C₄ (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 Ca²⁺ ([Ca²⁺]_i) and contraction, histamine or carbachol produced a transient Ca²⁺ peak followed by a plateau, along with a contraction. LTD₄ increased the histamine-induced transient Ca²⁺ 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 extracellular signal-regulated kinase 1/2 and that LTD₄ significantly enhanced the phosphorylation induced by histamine, but not by carbachol. L-type Ca²⁺ channel participation in the hyperresponsiveness to histamine was discarded because LTD₄ did not modify the [Ca²⁺]_i changes induced by KCl. In tracheal myocytes, LTD₄ enhanced the transient Ca²⁺ peak induced by histamine (but not by carbachol) and the sarcoplasmic reticulum (SR) Ca²⁺ refilling. Genistein abolished this last LTD₄ effect. Partial blockade of the SR-ATPase Ca²⁺ pump with cyclopiazonic acid reduced the Ca²⁺ 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 Ca²⁺ pump activity. L-type Ca²⁺ channels seemed not to be involved in this phenomenon.

asthma; intracellular calcium ion; leukotriene D₄; tyrosine kinase; extracellular signal-regulated kinase 1/2; sarcoplasmic reticulum

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