Monassier Laurent, Manoury Boris, Bellocq Chloé, Weissenburger Jacques, Greney Hugues, Zimmermann Diane, Ehrhardt Jean-Daniel, Jaillon Patrice, Baró Isabelle, Bousquet Pascal
Laboratoire de Neurobiologie et de Pharmacologie Cardiovasculaire, Facultéde Médecine, INSERM U-715, 11 rue Humann, 67085 Strasbourg, France.
J Pharmacol Exp Ther. 2007 Jul;322(1):341-50. doi: 10.1124/jpet.107.122044. Epub 2007 Apr 25.
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.
σ(2)受体激动剂艾芬地尔被认为是一种G蛋白偶联内向整流钾通道的抑制剂。然而，尚未对σ(2)受体在心脏电生理学中的作用进行分析。这项工作旨在：i）确定心脏σ(2)受体在调节心脏钾通道电导中的作用；ii）检查σ(2)受体激动剂是否具有III类抗心律失常特性。使用σ(2)受体激动剂艾芬地尔、苏式-艾芬地尔、LNP250A [苏式-8-[1-(4-羟基苯基)-1-羟基-丙-2-基]-1-苯基-1,3,8-三氮杂螺[4,5]癸烷-4-酮]（一种无α(1)-肾上腺素能和N-甲基-D-天冬氨酸谷氨酸受体阻断特性的艾芬地尔衍生物）以及1,3-二(2-甲苯基)胍，以区分与σ(2)受体相关的效应和由(±)-N-烯丙基去甲左啡诺（SKF-10,047）诱导的σ(1)亚型的效应。σ(2)受体拮抗剂3-α-托烷-2-(对氯苯氧基)丁酸酯（SM-21）用于在膜片钳实验中表征σ(2)介导的效应。在兔中，所有σ(2)受体激动剂均减少了去氧肾上腺素诱导的心律失常。它们延长了兔浦肯野纤维的动作电位时程，并降低了人类醚-去极化相关基因（HERG）钾电流。(+)-SKF-10,047在最后两项测试中完全无活性。苏式-艾芬地尔的效应未被SM-21拮抗。在转染HERG的COS-7细胞中，SM-21增强了艾芬地尔诱导的HERG电流阻断。这些数据表明，σ(2)受体配体阻断I(Kr)，并且这种效应可以解释该配体家族抗心律失常特性的一部分。然而，与不涉及σ(2)受体的HERG通道的相互作用似乎也具有这种药理学特性。这项工作首次表明，对于对σ(2)受体具有亲和力的配体必须格外谨慎。复极延长和早后去极化可能是“尖端扭转型室速”和心源性猝死的原因。
