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Functional effects of 20-HETE on human bronchi: hyperpolarization and relaxation due to BK_Ca channel activation

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 BK_Ca 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 BK_Ca channels at low free Ca²⁺ concentrations. Together, these results indicate that 20-HETE-dependent activation of BK_Ca 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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