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The opioid oxycodone use-dependently inhibits the cardiac sodium channel NaV 1.5.

ABSTRACT: BACKGROUND AND PURPOSE:Oxycodone is a potent semi-synthetic opioid that is commonly used for the treatment of severe acute and chronic pain. However, treatment with oxycodone can lead to cardiac electrical changes, such as long QT syndrome, potentially inducing sudden cardiac arrest. Here, we investigate whether the cardiac side effects of oxycodone can be explained by modulation of the cardiac Nav 1.5 sodium channel. EXPERIMENTAL APPROACH:Heterologously expressed human Nav 1.5, Nav 1.7 (HEK293 cells) or Nav 1.8 channels (mouse N1E-115 cells) were used for whole-cell patch-clamp electrophysiology. A variety of voltage-clamp protocols were used to test the effect of oxycodone on different channel gating modalities. Human stem cell-derived cardiomyocytes were used to measure the effect of oxycodone on cardiomyocyte beating. KEY RESULTS:Oxycodone inhibited Nav 1.5 channels, concentration and use-dependently, with an IC50 of 483 ?M. In addition, oxycodone slows recovery of Nav 1.5 channels from fast inactivation and increases slow inactivation. At high concentrations, these effects lead to a reduced beat rate in cardiomyocytes and to arrhythmia. In contrast, no such effects could be observed on Nav 1.7 or Nav 1.8 channels. CONCLUSIONS AND IMPLICATIONS:Oxycodone leads to an accumulation of Nav 1.5 channels in inactivated states, with a slow time course. Although the concentrations needed to elicit cardiac arrhythmias in vitro are relatively high, some patients under long-term treatment with oxycodone as well as drug abusers and addicts might suffer from severe cardiac side effects induced by the slowly developing effects of oxycodone on Nav 1.5 channels.

SUBMITTER: Meents JE

PROVIDER: S-EPMC6016641 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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The opioid oxycodone use-dependently inhibits the cardiac sodium channel Na<sub>V</sub> 1.5.

Meents Jannis E JE Juhasz Krisztina K Stölzle-Feix Sonja S Peuckmann-Post Vera V Rolke Roman R Lampert Angelika A

British journal of pharmacology 20180607 14

<h4>Background and purpose</h4>Oxycodone is a potent semi-synthetic opioid that is commonly used for the treatment of severe acute and chronic pain. However, treatment with oxycodone can lead to cardiac electrical changes, such as long QT syndrome, potentially inducing sudden cardiac arrest. Here, we investigate whether the cardiac side effects of oxycodone can be explained by modulation of the cardiac Na<sub>v</sub> 1.5 sodium channel.<h4>Experimental approach</h4>Heterologously expressed human ...[more]

PMID: 29722437

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Project description:RationaleThe cardiac sodium channel NaV1.5, encoded by SCN5A, produces the rapidly inactivating depolarizing current INa that is responsible for the initiation and propagation of the cardiac action potential. Acquired and inherited dysfunction of NaV1.5 results in either decreased peak INa or increased residual late INa (INa,L), leading to tachy/bradyarrhythmias and sudden cardiac death. Previous studies have shown that increased cellular NAD+ and NAD+/NADH ratio increase INa through suppression of mitochondrial reactive oxygen species and PKC-mediated NaV1.5 phosphorylation. In addition, NAD+-dependent deacetylation of NaV1.5 at K1479 by Sirtuin 1 increases NaV1.5 membrane trafficking and INa. The role of NAD+ precursors in modulating INa remains unknown.ObjectiveTo determine whether and by which mechanisms the NAD+ precursors nicotinamide riboside (NR) and nicotinamide (NAM) affect peak INa and INa,Lin vitro and cardiac electrophysiology in vivo.Methods and resultsThe effects of NAD+ precursors on the NAD+ metabolome and electrophysiology were studied using HEK293 cells expressing wild-type and mutant NaV1.5, rat neonatal cardiomyocytes (RNCMs), and mice. NR increased INa in HEK293 cells expressing NaV1.5 (500 μM: 51 ± 18%, p = .02, 5 mM: 59 ± 22%, p = .03) and RNCMs (500 μM: 60 ± 26%, p = .02, 5 mM: 74 ± 39%, p = .03) while reducing INa,L at the higher concentration (RNCMs, 5 mM: -45 ± 11%, p = .04). NR (5 mM) decreased NaV1.5 K1479 acetylation but increased INa in HEK293 cells expressing a mutant form of NaV1.5 with disruption of the acetylation site (NaV1.5-K1479A). Disruption of the PKC phosphorylation site abolished the effect of NR on INa. Furthermore, NAM (5 mM) had no effect on INa in RNCMs or in HEK293 cells expressing wild-type NaV1.5, but increased INa in HEK293 cells expressing NaV1.5-K1479A. Dietary supplementation with NR for 10-12 weeks decreased QTc in C57BL/6 J mice (0.35% NR: -4.9 ± 2.0%, p = .14; 1.0% NR: -9.5 ± 2.8%, p = .01).ConclusionsNAD+ precursors differentially regulate NaV1.5 via multiple mechanisms. NR increases INa, decreases INa,L, and warrants further investigation as a potential therapy for arrhythmic disorders caused by NaV1.5 deficiency and/or dysfunction.

Dataset Information

The opioid oxycodone use-dependently inhibits the cardiac sodium channel NaV 1.5.

Publications

The opioid oxycodone use-dependently inhibits the cardiac sodium channel Na<sub>V</sub> 1.5.

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