In:
Canadian Journal of Physiology and Pharmacology, Canadian Science Publishing, Vol. 91, No. 8 ( 2013-08), p. 586-592
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0008-4212
,
1205-7541
DOI:
10.1139/cjpp-2012-0407
Language:
English
Publisher:
Canadian Science Publishing
Publication Date:
2013
detail.hit.zdb_id:
2004356-9
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