Differential inhibition of cardiac and neuronal Na⁺ channels by the selective serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine

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• 作者：Carsten Stoetzer^a ; ^{stoetzer.carsten@mh-hannover.de" class="auth_mail" title="E-mail the corresponding author} ; Bastian Papenberg^a ; Thorben Doll^a ; ^b ; ^c ; ^d ; Marc Vö ; lker^a ; Joerg Heineke^b ; Marcus Stoetzer^c ; Florian Wegner^d ; Andreas Leffler^a
• 关键词：Na+ channel ; Cardiotoxicity ; Antidepressant ; Patch-clamp ; SNRI
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：15 July 2016
• 年：2016
• 卷：783
• 期：Complete
• 页码：1-10
• 全文大小：2906 K

文摘

Duloxetine and venlafaxine are selective serotonin-norepinephrine-reuptake-inhibitors used as antidepressants and co-analgesics. While venlafaxine rather than duloxetine induce cardiovascular side-effects, neither of the substances are regarded cardiotoxic. Inhibition of cardiac Na⁺-channels can be associated with cardiotoxicity, and duloxetine was demonstrated to block neuronal Na⁺-channels. The aim of this study was to investigate if the non-life threatening cardiotoxicities of duloxetine and venlafaxine correlate with a weak inhibition of cardiac Na⁺-channels.

Effects of duloxetine, venlafaxine and amitriptyline were examined on endogenous Na⁺-channels in neuroblastoma ND7/23 cells and on the α-subunits Nav1.5, Nav1.7 and Nav1.8 with whole-cell patch clamp recordings.

Tonic block of the cardiac Na⁺-channel Nav1.5 and rat-cardiomyocytes (CM) revealed a higher potency for duloxetine (Nav 1.5 IC₅₀ 14±1 µM, CM IC₅₀ 27±3 µM) as compared to venlafaxine (Nav 1.5 IC₅₀ 671±26 µM, CM IC₅₀ 452±34 µM). Duloxetine was as potent as the cardiotoxic antidepressant amitriptyline (IC₅₀ 13±1 µM). While venlafaxine almost failed to induce use-dependent block on Nav1.5 and cardiomyocytes, low concentrations of duloxetine (1, 10 µM) induced prominent use-dependent block similar to amitriptyline. Duloxetine, but not venlafaxine stabilized fast and slow inactivation and delayed recovery from inactivation. Duloxetine induced an unselective inhibition of neuronal Na⁺-channels (IC₅₀ ND7/23 23±1 µM, Nav1.7 19±2 µM, Nav1.8 29±2).

Duloxetine, but not venlafaxine inhibits cardiac Na⁺-channels with a potency similar to amitriptyline. These data indicate that an inhibition of Na⁺-channels does not predict a clinically relevant cardiotoxicity.