title: Epoxyeicosatrienoic acids, potassium channel blockers and endothelium-dependent hyperpolarization in the guinea-pig carotid artery.
abstract: 1. Using intracellular microelectrodes, we investigated the effects of 17-octadecynoic acid (17-ODYA) on the endothelium-dependent hyperpolarization induced by acetylcholine in the guinea-pig isolated internal carotid artery with endothelium. 2. In the presence of Nomega-nitro-L-arginine (L-NOARG, 100 microM) and indomethacin (5 microM) to inhibit nitric oxide synthase and cyclo-oxygenase, acetylcholine (1 microM) evoked an endothelium-dependent hyperpolarization which averaged -16.4 mV starting from a resting membrane potential of -56.8 mV. There was a negative correlation between the amplitude of the hyperpolarization and the absolute values of the resting membrane potential. 3. The acetylcholine-induced endothelium-dependent hyperpolarization was not altered by charybdotoxin (0.1 microM) or iberiotoxin (30 nM). It was partially but significantly reduced by apamin (0.5 microM) to -12.8+/-1.2 mV (n=10) or the combination of apamin plus iberiotoxin (-14.3+/-3.4mV, n=4). However, the combination of charybdotoxin and apamin abolished the hyperpolarization and under these conditions, acetylcholine evoked a depolarization (+ 7.1+/-3.7 mV, n = 8). 4. 17-ODYA (10 microM) produced a significant hyperpolarization of the resting membrane potential which averaged -59.6 mV and a partial but significant inhibition of the acetylcholine-induced endothelium-dependent hyperpolarization (-10.9 mV). 5. Apamin did not modify the effects of 17-ODYA but in the presence of charybdotoxin or iberiotoxin, 17-ODYA no longer influenced the resting membrane potential or the acetylcholine-induced hyperpolarization. 6. When compared to solvent (ethanol, 1% v/v), epoxyeicosatrienoic acids (EpETrEs) (5,6-, 8,9-, 11,12- and 14,15-EpETrE, 3 microM) did not affect the cell membrane potential and did not relax the guinea-pig isolated internal carotid artery. 7. These results indicate that, in the guinea-pig internal carotid artery, the involvement of metabolites of arachidonic acid through the cytochrome P450 pathway in endothelium-dependent hyperpolarization is unlikely. Furthermore, the hyperpolarization mediated by the endothelium-derived hyperpolarizing factor (EDHF) is probably not due to the opening of BK(Ca) channels.
authors.affiliation: Département de Diabétologie, Institut de Recherches Servier, Suresnes, France.
authors.forename: T
authors.initials: T
authors.lastname: Chataigneau
authors.forename: M
authors.initials: M
authors.lastname: Félétou
authors.forename: J
authors.initials: J
authors.lastname: Duhault
authors.forename: P M
authors.initials: PM
authors.lastname: Vanhoutte
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects* / Q000502:physiology; D018999:Charybdotoxin / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004576:Electromyography; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology; D026902:Potassium Channel Blockers
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D010455:Peptides; D026902:Potassium Channel Blockers; D018999:Charybdotoxin; C047008:17-octadecynoic acid; C064719:iberiotoxin; D015126:8,11,14-Eicosatrienoic Acid