title: Modulation of the K(+) channels encoded by the human ether-a-gogo-related gene-1 (hERG1) by nitric oxide.
abstract: The inhibition of nitric oxide synthase by N-nitro-L-arginine methyl ester (0.03-3 mM) dose-dependently reduced nitric oxide (NO(*)) levels and enhanced the outward currents carried by human ether-a-gogo-related gene-1 (hERG1) K(+) channels expressed in Xenopus laevis oocytes, whereas the increase in NO(*) levels achieved by exposure to L-arginine (0.03-10 mM) inhibited these currents. Furthermore, four NO(*) donors belonging to such different chemical classes as sodium nitroprusside (1-1000 microM), 3-morpholino-sydnonimine (100-1000 microM), (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1- ium-1, 2-diolate (NOC-18; 1-300 microM), and S-nitroso N-acetylpenicillamine (1-300 microM) dose-dependently inhibited hERG1 outward K(+) currents. By contrast, the NO(*) donor NOC-18 (0.3 mM) did not affect other cloned K(+) channels such as rat neuroblastoma-glioma K(+) channel 2, rat delayed rectifier K(+) channel 1, bovine ether-a-gogo gene, rat ether-a-gogo-related gene-2, and rat ether-a-gogo-related gene-3. The inhibitory effect of NO(*) donors on hERG1 K(+) channels was prevented by the NO(*) scavengers 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide and hemoglobin. The membrane permeable analog of cGMP, 8-bromo-cGMP (1 mM), failed to reproduce the inhibitory action of NO(*) donors on hERG1 outward currents; furthermore, the specific inhibitor of the NO(*)-dependent guanylyl cyclase, 1H-[1,2,4]oxadiazolo[4, 3-a]quinoxalin-1-one (50 microM), neither interfered with outward hERG1 K(+) currents nor prevented their inhibition by 0.3 mM NOC-18. Both L-arginine (10 mM) and NOC-18 (0.3 mM) counteracted the stimulatory effect on hERG1 outward currents induced by the radical oxygen species-generating system FeSO(4) (25 microM)/ascorbic acid (50 microM; Fe/Asc). Finally, L-arginine (10 mM) and NOC-18 (0.3 mM) inhibited both basal and Fe/Asc (0.1 mM/0.2 mM)-stimulated lipid peroxidation in X. laevis oocytes. Collectively, the present results suggest that NO(*), both endogenously produced and pharmacologically delivered, may exert in a cGMP-independent way an inhibitory effect on hERG1 outward K(+) currents via an interaction with radical oxygen species either generated under resting conditions or triggered by Fe/Asc.
authors.affiliation: Section of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, Naples, Italy. mtaglia@unina.it
authors.forename: M
authors.initials: M
authors.lastname: Taglialatela
authors.forename: A
authors.initials: A
authors.lastname: Pannaccione
authors.forename: S
authors.initials: S
authors.lastname: Iossa
authors.forename: P
authors.initials: P
authors.lastname: Castaldo
authors.forename: L
authors.initials: L
authors.lastname: Annunziato
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism; D027682:Cation Transport Proteins; D002417:Cattle; D006152:Cyclic GMP / Q000378:metabolism; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007501:Iron / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism* / Q000502:physiology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D051381:Rats; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014162:Transfection; D014982:Xenopus laevis
chemical_list: D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D020030:Nitric Oxide Donors; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D009569:Nitric Oxide; D007501:Iron; D006152:Cyclic GMP; D001205:Ascorbic Acid; D019331:NG-Nitroarginine Methyl Ester