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.
Morin
Caroline
C
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.
Sirois
Marco
M
Echave
Vincent
V
Gomes
Marcio M
MM
Rousseau
Eric
E
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