title: L-364,373 (R-L3) enantiomers have opposite modulating effects on IKs in mammalian ventricular myocytes.
abstract: Activators of the slow delayed rectifier K⁺ current (IKs) have been suggested as promising tools for suppressing ventricular arrhythmias due to prolongation of repolarization. Recently, L-364,373 (R-L3) was nominated to activate IKs in myocytes from several species; however, in some studies, it failed to activate IKs. One later study suggested opposite modulating effects from the R-L3 enantiomers as a possible explanation for this discrepancy. Therefore, we analyzed the effect of the RL-3 enantiomers on IKs in ventricular mammalian myocytes, by applying standard microelectrode and whole-cell patch-clamp techniques at 37 °C. We synthesized 2 substances, ZS_1270B (right) and ZS_1271B (left), the 2 enantiomers of R-L3. In rabbit myocytes, ZS_1270B enhanced the IKs tail current by approximately 30%, whereas ZS_1271B reduced IKs tails by 45%. In guinea pig right ventricular preparations, ZS_1270B shortened APD90 (action potential duration measured at 90% repolarization) by 12%, whereas ZS_1271B lengthened it by approximately 15%. We concluded that R-L3 enantiomers in the same concentration range indeed have opposite modulating effects on IKs, which may explain why the racemic drug R-L3 previously failed to activate IKs. ZS_1270B is a potent IKs activator, therefore, this substance is appropriate to test whether IKs activators are ideal tools to suppress ventricular arrhythmias originating from prolongation of action potentials.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, H-6701 Szeged, Hungary.
authors.forename: Claudia
authors.initials: C
authors.lastname: Corici
authors.forename: Zsófia
authors.initials: Z
authors.lastname: Kohajda
authors.forename: Attila
authors.initials: A
authors.lastname: Kristóf
authors.forename: András
authors.initials: A
authors.lastname: Horváth
authors.forename: László
authors.initials: L
authors.lastname: Virág
authors.forename: Tamás
authors.initials: T
authors.lastname: Szél
authors.forename: Norbert
authors.initials: N
authors.lastname: Nagy
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Szakonyi
authors.forename: Ferenc
authors.initials: F
authors.lastname: Fülöp
authors.forename: Danina M
authors.initials: DM
authors.lastname: Muntean
authors.forename: András
authors.initials: A
authors.lastname: Varró
authors.forename: Norbert
authors.initials: N
authors.lastname: Jost
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D051668:Delayed Rectifier Potassium Channels / Q000819:agonists* / Q000037:antagonists & inhibitors*; D005260:Female; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008839:Microelectrodes; D015394:Molecular Structure; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011817:Rabbits; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D051668:Delayed Rectifier Potassium Channels; C113498:L 364373; D001569:Benzodiazepines