L-364,373 (R-L3) enantiomers have opposite modulating effects on Iks in mammalian ventricular myocytes

Claudia Corici, Zsófia Kohajda, Attila Kristóf, András Horváth, László Virág, Tamás Szél, Norbert Nagy, Zsolt Szakonyi, Ferenc Fülöp, Danina M. Muntean, András Varró, Norbert Jost

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2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)586-592
Number of pages7
JournalCanadian journal of physiology and pharmacology
Volume91
Issue number8
DOIs
Publication statusPublished - Aug 1 2013

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Keywords

  • 373
  • Antiarrhythmic drugs
  • Enantiomers
  • I activator
  • I blocker
  • L-364
  • Slow delayed rectifier potassium current

ASJC Scopus subject areas

  • Physiology
  • Pharmacology
  • Physiology (medical)

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