title: sigma(2)-receptor ligand-mediated inhibition of inwardly rectifying K(+) channels in the heart.
abstract: The sigma(2)-receptor agonist, ifenprodil, was suggested as an inhibitor of G protein-coupled inwardly rectifying potassium channels. Nevertheless, an analysis of the role of sigma(2) receptors in cardiac electrophysiology has never been done. This work aims i) to identify the roles of cardiac sigma(2) receptors in the regulation of cardiac K(+) channel conductances and ii) to check whether sigma(2)-receptor agonists exhibit class III antiarrhythmic properties. The sigma(2)-receptor agonists ifenprodil, threo-ifenprodil, LNP250A [threo-8-[1-(4-hydroxyphenyl)-1-hydroxy-propan-2-yl]-1-phenyl-1,3,8-triazaspiro[4,5]decane-4-one] (a derivative of ifenprodil devoid of alpha(1)-adrenergic and N-methyl-d-aspartate glutamate receptor-blocking properties), and 1,3-di(2-tolyl)guanidine were used to discriminate the effects linked to sigma(2) receptors from those of the sigma(1) subtype, induced by (+/-)-N-allylnormetazocine (SKF-10,047). The sigma(2)-receptor antagonist 3-alpha-tropanyl-2(pCl-phenoxy)butyrate (SM-21) was employed to characterize sigma(2)-mediated effects in patch-clamp experiments. In rabbits, all sigma(2)-receptor agonists reduced phenylephrine-induced cardiac arrhythmias. They prolonged action potential duration in rabbit Purkinje fibers and reduced human ether-a-go-go-related gene (HERG) K(+) currents. (+)-SKF-10,047 was completely inactive in the last two tests. The effects of threo-ifenprodil were not antagonized by SM-21. In HERG-transfected COS-7 cells, SM-21 potentiated the ifenprodil-induced blockade of the HERG current. These data suggest that sigma(2)-receptor ligands block I(Kr) and that this effect could explain part of the antiarrhythmic properties of this ligands family. Nevertheless, an interaction with HERG channels not involving sigma(2) receptors seems to share this pharmacological property. This work shows for the first time that particular caution has to be taken toward ligands with affinity for sigma(2) receptors. The repolarization prolongation and the early-afterdepolarization can be responsible for "torsades de pointe" and sudden cardiac death.
authors: Laboratoire de Neurobiologie et de Pharmacologie Cardiovasculaire, Facultéde Médecine, INSERM U-715, 11 rue Humann, 67085 Strasbourg, France. laurent.monassier@medecine.u-strasbg.fr
authors: Laurent
authors: L
authors: Monassier
authors: Boris
authors: B
authors: Manoury
authors: Chloé
authors: C
authors: Bellocq
authors: Jacques
authors: J
authors: Weissenburger
authors: Hugues
authors: H
authors: Greney
authors: Diane
authors: D
authors: Zimmermann
authors: Jean-Daniel
authors: JD
authors: Ehrhardt
authors: Patrice
authors: P
authors: Jaillon
authors: Isabelle
authors: I
authors: Baró
authors: Pascal
authors: P
authors: Bousquet
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D019556:COS Cells; D002522:Chlorocebus aethiops; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D005260:Female; D006321:Heart / Q000187:drug effects*; D008297:Male; D010620:Phenazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D017480:Receptors, sigma / Q000819:agonists* / Q000502:physiology
chemical_list: D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010880:Piperidines; D026902:Potassium Channel Blockers; D017480:Receptors, sigma; C106107:sigma-2 receptor; D010656:Phenylephrine; C012134:SK&F 10047; D010620:Phenazocine; C010739:ifenprodil