Nitric oxide down-regulates voltage-gated Na+ channel in cardiomyocytes possibly through S-nitrosylation-mediated signaling

Abstract

Nitric oxide (NO) is produced from endothelial cells and cardiomyocytes composing the myocardium and benefits cardiac function through both vascular-dependent and—independent effects. This study was purposed to investigate the possible adverse effect of NO focusing on the voltage-gated Na+ channel in cardiomyocytes. We carried out patch-clamp experiments on rat neonatal cardiomyocytes demonstrating that NOC-18, an NO donor, significantly reduced Na+ channel current in a dose-dependent manner by a long-term application for 24 h, accompanied by a reduction of Nav1.5-mRNA and the protein, and an increase of a transcription factor forkhead box protein O1 (FOXO1) in the nucleus. The effect of NOC-18 on the Na+ channel was blocked by an inhibitor of thiol oxidation N-ethylmaleimide, a disulfide reducing agent disulfide 1,4-Dithioerythritol, or a FOXO1 activator paclitaxel, suggesting that NO is a negative regulator of the voltage-gated Na+ channel through thiols in regulatory protein(s) for the channel transcription.

Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias

“…However, a very recent study by Wang and co-workers suggested an indirect mechanism by which S-nitrosylation modulates the cardiac sodium channel expression and function. For instance, NO has been demonstrated to down-regulate SCN5A expression and Na v 1.5 function through S-nitrosylation of regulatory transcription factor FOXO1 [188]. These findings increase our current understanding of the role of redox and free radicals in the regulation of Na v 1.5 function (see [100] for further review).…”

The role of nitric oxide on the antiarrhythmic effects of ketamine/xylazine in a rat model of acute cardiac ischemia-reperfusion

“…As a result, myocardial contractility increases. At concentrations, NO causes to produce more amounts of cGMP, by which cardiodepression occurs in response to protein kinase G (PKG) activation with blockade of sarcolemma Ca 2+ channels ( Rastaldo et al, 2007 ; Wang et al, 2021 ). In our study, using L-arginine resulted in increasing NO level so that it exerted a destructive effect and increased arrhythmia in the ketamine/xylazine group.…”

Enhanced BDNF Actions Following Acute Hypoxia Facilitate HIF-1α-Dependent Upregulation of Cav3-T-Type Ca2+ Channels in Rat Cardiomyocytes

“…Images were acquired using a 63× oil objective (Plan-Apochromat 63× [numerical aperture, 1.46] oil immersion objective for differential interference contrast [DIC]; Carl Zeiss, Jena, Germany). All sections were analyzed using a confocal laser microscopy system and software (LSM710, Carl Zeiss, Jena, Germany) that was built around an inverted microscope (Axio Observer Z1, Carl Zeiss, Jena, Germany) as previously described [ 40 ]. The images were saved in TIFF format and analyzed by ImageJ software (Wayne Rasband, National Institutes of Health, Bethesda, MD, USA).…”