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1Le Bilarium, Department of Physiology and Biophysics, 2Service of Thoracic Surgery, 3Department of Pathology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Quebec, Canada
Submitted 12 April 2007 ; accepted in final form 24 July 2007
Airway smooth muscle (ASM) metabolizes arachidonic acid (AA) through various enzymatic pathways, including cytochrome P-450 (CYP-450)
-hydroxylase, which leads to the production of 20-hydroxyeicosatetraenoic acid (20-HETE). The goal of this study was to delineate the mode of action of 20-HETE in human ASM cells. Isometric tension measurements demonstrated that 20-HETE induced a concentration-dependent relaxant effect in ASM on bronchi precontracted with either methacholine or AA. Relaxing effects of 20-HETE on resting tone were prevented by 10 nM iberiotoxin (IbTx), a BKCa channel inhibitor. Microelectrode measurements showed that exogenous additions of 20-HETE (0.1–10 µM) hyperpolarized the membrane potential of human ASM cells. This concentration-dependent electrophysiological effect induced by the eicosanoid was prevented by 10 nM IbTx. Complementary experiments, using the planar lipid bilayer reconstitution technique, demonstrated that 20-HETE activated reconstituted BKCa channels at low free Ca2+ concentrations. Together, these results indicate that 20-HETE-dependent activation of BKCa channels is responsible for the hyperpolarization and controlled relaxation of ASM in human distal bronchi.
20-hydroxyeicosatetraenoic acid; organ culture; membrane potential
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