TY - JOUR T1 - σ<sub>2</sub>-Receptor Ligand-Mediated Inhibition of Inwardly Rectifying K<sup>+</sup> Channels in the Heart JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 341 LP - 350 DO - 10.1124/jpet.107.122044 VL - 322 IS - 1 AU - Laurent Monassier AU - Boris Manoury AU - Chloé Bellocq AU - Jacques Weissenburger AU - Hugues Greney AU - Diane Zimmermann AU - Jean-Daniel Ehrhardt AU - Patrice Jaillon AU - Isabelle Baró AU - Pascal Bousquet Y1 - 2007/07/01 UR - http://jpet.aspetjournals.org/content/322/1/341.abstract N2 - The σ2-receptor agonist, ifenprodil, was suggested as an inhibitor of G protein-coupled inwardly rectifying potassium channels. Nevertheless, an analysis of the role of σ2 receptors in cardiac electrophysiology has never been done. This work aims i) to identify the roles of cardiac σ2 receptors in the regulation of cardiac K+ channel conductances and ii) to check whether σ2-receptor agonists exhibit class III antiarrhythmic properties. The σ2-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 α1-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 σ2 receptors from those of the σ1 subtype, induced by (±)-N-allylnormetazocine (SKF-10,047). The σ2-receptor antagonist 3-α-tropanyl-2(pCl-phenoxy)butyrate (SM-21) was employed to characterize σ2-mediated effects in patch-clamp experiments. In rabbits, all σ2-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 σ2-receptor ligands block IKr and that this effect could explain part of the antiarrhythmic properties of this ligands family. Nevertheless, an interaction with HERG channels not involving σ2 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 σ2 receptors. The repolarization prolongation and the early-afterdepolarization can be responsible for “torsades de pointe” and sudden cardiac death. The American Society for Pharmacology and Experimental Therapeutics ER -