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      The functional consequences of sodium channel Na V1.8 in human left ventricular hypertrophy

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          Abstract

          Aims

          In hypertrophy and heart failure, the proarrhythmic persistent Na + current (I NaL) is enhanced. We aimed to investigate the electrophysiological role of neuronal sodium channel Na V1.8 in human hypertrophied myocardium.

          Methods and results

          Myocardial tissue of 24 patients suffering from symptomatic severe aortic stenosis and concomitant significant afterload‐induced hypertrophy with preserved ejection fraction was used and compared with 12 healthy controls. We performed quantitative real‐time PCR and western blot and detected a significant up‐regulation of Na V1.8 mRNA (2.34‐fold) and protein expression (1.96‐fold) in human hypertrophied myocardium compared with healthy hearts. Interestingly, Na V1.5 protein expression was significantly reduced in parallel (0.60‐fold). Using whole‐cell patch‐clamp technique, we found that the prominent I NaL was significantly reduced after addition of novel Na V1.8‐specific blockers either A‐803467 (30 nM) or PF‐01247324 (1 μM) in human hypertrophic cardiomyocytes. This clearly demonstrates the relevant contribution of Na V1.8 to this proarrhythmic current. We observed a significant action potential duration shortening and performed confocal microscopy, demonstrating a 50% decrease in proarrhythmic diastolic sarcoplasmic reticulum (SR)‐Ca 2+ leak and SR‐Ca 2+ spark frequency after exposure to both Na V1.8 inhibitors.

          Conclusions

          We show for the first time that the neuronal sodium channel Na V1.8 is up‐regulated on mRNA and protein level in the human hypertrophied myocardium. Furthermore, inhibition of Na V1.8 reduced augmented I NaL, abbreviated the action potential duration, and decreased the SR‐Ca 2+ leak. The findings of our study suggest that Na V1.8 could be a promising antiarrhythmic therapeutic target and merits further investigation.

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          Most cited references33

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          2016 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure.

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            A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat.

            Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonucleotide studies directed against Na(v)1.8 have shown that this channel contributes to experimental inflammatory and neuropathic pain. We report here the discovery of A-803467, a sodium channel blocker that potently blocks tetrodotoxin-resistant currents (IC(50) = 140 nM) and the generation of spontaneous and electrically evoked action potentials in vitro in rat dorsal root ganglion neurons. In recombinant cell lines, A-803467 potently blocked human Na(v)1.8 (IC(50) = 8 nM) and was >100-fold selective vs. human Na(v)1.2, Na(v)1.3, Na(v)1.5, and Na(v)1.7 (IC(50) values >or=1 microM). A-803467 (20 mg/kg, i.v.) blocked mechanically evoked firing of wide dynamic range neurons in the rat spinal dorsal horn. A-803467 also dose-dependently reduced mechanical allodynia in a variety of rat pain models including: spinal nerve ligation (ED(50) = 47 mg/kg, i.p.), sciatic nerve injury (ED(50) = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED(50) approximately 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection (ED(50) = 41 mg/kg, i.p.). A-803467 was inactive against formalin-induced nociception and acute thermal and postoperative pain. These data demonstrate that acute and selective pharmacological blockade of Na(v)1.8 sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.
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              Aortic Stenosis

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                Author and article information

                Contributors
                samuel.sossalla@ukr.de
                Journal
                ESC Heart Fail
                ESC Heart Fail
                10.1002/(ISSN)2055-5822
                EHF2
                ESC Heart Failure
                John Wiley and Sons Inc. (Hoboken )
                2055-5822
                30 October 2018
                February 2019
                : 6
                : 1 ( doiID: 10.1002/ehf2.v6.1 )
                : 154-163
                Affiliations
                [ 1 ] Department of Internal Medicine II University Medical Center Regensburg Regensburg Germany
                [ 2 ] Department of Cardiology and Pneumology University Hospital, Georg‐August University Goettingen, and DZHK (German Centre for Cardiovascular Research), partner site Goettingen Goettingen Germany
                [ 3 ] Institute of Experimental Cardiovascular Research University Medical Center Hamburg‐Eppendorf Hamburg Germany
                [ 4 ] Department of Thoracic, Cardiac and Vascular Surgery University Hospital, Georg‐August University Goettingen Goettingen Germany
                [ 5 ] Department of Internal Medicine III, Molecular Cardiology and Angiology University Medical Center, Schleswig‐Holstein, Campus Kiel Kiel Germany
                Author notes
                [*] [* ] Correspondence to: Samuel Sossalla, Department of Internal Medicine II, University Medical Center Regensburg, Franz‐Josef‐Strauss‐Allee 11, 93053 Regensburg, Germany. Tel: +49 551 3963648; Fax: +49 551 398941. Email: samuel.sossalla@ 123456ukr.de

                [†]

                The first two and last two authors contributed equally to the study.

                Article
                EHF212378 ESCHF-18-00116
                10.1002/ehf2.12378
                6352890
                30378291
                22bcea36-a609-4b24-a4c9-52fbe4bbdcc9
                © 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 07 June 2018
                : 18 September 2018
                : 10 October 2018
                Page count
                Figures: 5, Tables: 1, Pages: 10, Words: 4370
                Funding
                Funded by: Deutsche Forschungsgemeinschaft
                Award ID: SFB 1002
                Funded by: ReForM‐Programme
                Funded by: Bundesministerium für Bildung und Forschung (BMBF)
                Award ID: 031L0075C
                Funded by: Marga und Walter Boll‐Stiftung
                Award ID: 220‐12.1‐15
                Categories
                Original Research Article
                Original Research Articles
                Custom metadata
                2.0
                ehf212378
                February 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.5.7 mode:remove_FC converted:30.01.2019

                left ventricular hypertrophy,sodium channels,late sodium current,hfpef,arrhythmias,calcium,sr‐ca2+ leak

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