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

• Published in: Canadian journal of physiology and pharmacology Vol. 91; no. 8; pp. 586 - 592
• Main Authors: Corici, Claudia, Kohajda, Zsófia, Kristóf, Attila, Horváth, András, Virág, László, Szél, Tamás, Nagy, Norbert, Szakonyi, Zsolt, Fülöp, Ferenc, Muntean, Danina M., Varró, András, Jost, Norbert
• Format: Journal Article
• Language: English
• Published: 01.08.2013
• ISSN: 0008-4212; 1205-7541
• DOI: 10.1139/cjpp-2012-0407

Activators of the slow delayed rectifier K + current (I Ks ) 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 I Ks in myocytes from several species; however, in some studies, it failed to activate I Ks . 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 I Ks 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 I Ks tail current by approximately 30%, whereas ZS_1271B reduced I Ks tails by 45%. In guinea pig right ventricular preparations, ZS_1270B shortened APD 90 (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 I Ks , which may explain why the racemic drug R-L3 previously failed to activate I Ks. ZS_1270B is a potent I Ks activator, therefore, this substance is appropriate to test whether I Ks activators are ideal tools to suppress ventricular arrhythmias originating from prolongation of action potentials.