Mechanism of action of leukotriene D4 on guinea pig tracheal smooth muscle cells: roles of Ca++ influx and intracellular Ca++ release.
The effects of leukotriene D4 (LTD4) on the concentration of intracellular cytosolic free calcium ([Ca++]i) and on phosphoinositide hydrolysis were studied in cultured guinea pig tracheal smooth muscle cells. In Fura-2-loaded cells, LTD4 (10(-9)-10(-6) M) induced concentration-dependent changes in [Ca++]i consisting of a slow, transient increase followed by a sustained phase. Preincubation of cells with LTD4 receptor antagonist MK-571 (10(-6) M) blocked the increase in [Ca++]i. Similarly, LTD4-induced inositol phosphate ([3H]InsP(s) synthesis was transient, concentration-dependent and inhibited by the LTD4 antagonist. In the absence of extracellular Ca++, LTD4 failed to induce [Ca++]i increases and [3H]InsP(s) formation. Accordingly, NiCl2 completely inhibited the LTD4-stimulated [3H]InsP(s) synthesis. Nifedipine (10(-5) M) had a slight inhibitory effect on [Ca++]i increase but significantly reduced (40-50%) the [3H]lnsP(s) accumulation. These findings indicate that LTD4-stimulated inositol phosphate synthesis and [Ca++]i increases in tracheal smooth muscle cells are receptor-mediated events and are dependent on the availability of extracellular Ca++. It is suggested that Ca++ influx plays a major role in the LTD4 signal transduction mechanism.
Dumitriu
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Department of Pharmacology, Faculty of Medicine, University of Sherbrooke, Quebec, Canada.
Prié
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Bernier
S G
SG
Guillemette
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Sirois
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P
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D006168:Guinea Pigs; D006868:Hydrolysis; D017136:Ion Transport; D017998:Leukotriene D4 / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D014132:Trachea / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D010716:Phosphatidylinositols; D017998:Leukotriene D4; D001920:Bradykinin; D002118:Calcium