Functional effects of 20-HETE on human bronchi: hyperpolarization and relaxation due to BKCa channel activation.
Airway smooth muscle (ASM) metabolizes arachidonic acid (AA) through various enzymatic pathways, including cytochrome P-450 (CYP-450) omega-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 microM) 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 Ca(2+) 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.
Le Bilarium, Dept. of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Univ. of Sherbrooke, 3001, 12th Ave. N., Sherbrooke, J1H 5N4, QC, Canada.
Caroline
C
Morin
Marco
M
Sirois
Vincent
V
Echave
Marcio M
MM
Gomes
Eric
E
Rousseau
D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000008:administration & dosage / Q000096:biosynthesis / Q000494:pharmacology*; D066298:In Vitro Techniques; D007537:Isometric Contraction; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008051:Lipid Bilayers / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D009126:Muscle Relaxation; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009994:Osmolar Concentration; D010455:Peptides / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008051:Lipid Bilayers; D010455:Peptides; C064719:iberiotoxin; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid