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CARDIOVASCULAR

₂-Receptor Ligand-Mediated Inhibition of Inwardly Rectifying K⁺ Channels in the Heart

Laboratoire de Neurobiologie et de Pharmacologie Cardiovasculaire, Facultéde Médecine, Inserm, U-715, Facultéde Médecine, Strasbourg, France (L.M., H.G., D.Z., J.-D.E., P.B.); Laboratoire de Pharmacologie, Facultéde Médecine St Antoine, Paris, France (J.W., P.J.); and Inserm U-533 and Institut du Thorax, Université de Nantes, Facultéde Médecine, Nantes, France (B.M., C.B., I.B.)

The ₂-receptor agonist, ifenprodil, was suggested as an inhibitor of G protein-coupled inwardly rectifying potassium channels. Nevertheless, an analysis of the role of ₂ receptors in cardiac electrophysiology has never been done. This work aims i) to identify the roles of cardiac ₂ receptors in the regulation of cardiac K⁺ channel conductances and ii) to check whether ₂-receptor agonists exhibit class III antiarrhythmic properties. The 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 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 ₂ receptors from those of the ₁ subtype, induced by (±)-N-allylnormetazocine (SKF-10,047). The ₂-receptor antagonist 3--tropanyl-2(pCl-phenoxy)butyrate (SM-21) was employed to characterize ₂-mediated effects in patch-clamp experiments. In rabbits, all 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 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 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 ₂ receptors. The repolarization prolongation and the early-afterdepolarization can be responsible for "torsades de pointe" and sudden cardiac death.

Address correspondence to: Laurent Monassier, Laboratoire de Neurobiologie et de Pharmacologie Cardiovasculaire, Facultéde Médecine, INSERM U-715, 11 rue Humann, 67085 Strasbourg, France. E-mail: laurent.monassier{at}medecine.u-strasbg.fr