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http://purl.uniprot.org/citations/28430892http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/28430892http://www.w3.org/2000/01/rdf-schema#comment"

Aims

Selective inhibition of cardiac late sodium current (INaL) is an emerging target in the treatment of ventricular arrhythmias. We investigated the electrophysiological effects of GS-458967 (GS967), a potent, selective inhibitor of INaL, in an overlap syndrome model of both gain and loss of sodium channel function, comprising cardiomyocytes derived from both human SCN5A-1795insD+/-induced pluripotent stem cells (hiPSC-CMs) and mice carrying the homologous mutation Scn5a-1798insD+/-.

Methods and results

On patch-clamp analysis, GS967 (300 nmol/l) reduced INaL and action potential (AP) duration in isolated ventricular myocytes from wild type and Scn5a-1798insD+/-mice, as well as in SCN5A-1795insD+/-hiPSC-CMs. GS967 did not affect the amplitude of peak INa, but slowed its recovery, and caused a negative shift in voltage-dependence of INa inactivation. GS967 reduced AP upstroke velocity in Scn5a-1798insD+/-myocytes and SCN5A-1795insD+/-hiPSC-CMs. However, the same concentration of GS967 did not affect conduction velocity in Scn5a-1798insD+/-mouse isolated hearts, as assessed by epicardial mapping. GS967 decreased the amplitude of delayed after depolarizations and prevented triggered activity in mouse Scn5a-1798insD+/-cardiomyocytes.

Conclusion

The INaL inhibitor GS967 decreases repolarization abnormalities and has anti-arrhythmic effects in the absence of deleterious effects on cardiac conduction. Thus, selective inhibition of INaL constitutes a promising pharmacological treatment of cardiac channelopathies associated with enhanced INaL. Our findings furthermore implement hiPSC-CMs as a valuable tool for assessment of novel pharmacological approaches in inherited sodium channelopathies."xsd:string
http://purl.uniprot.org/citations/28430892http://purl.org/dc/terms/identifier"doi:10.1093/cvr/cvx077"xsd:string
http://purl.uniprot.org/citations/28430892http://purl.uniprot.org/core/author"Rajamani S."xsd:string
http://purl.uniprot.org/citations/28430892http://purl.uniprot.org/core/author"Hoekstra M."xsd:string
http://purl.uniprot.org/citations/28430892http://purl.uniprot.org/core/author"Bezzina C.R."xsd:string
http://purl.uniprot.org/citations/28430892http://purl.uniprot.org/core/author"Wilde A.A.M."xsd:string
http://purl.uniprot.org/citations/28430892http://purl.uniprot.org/core/author"Remme C.A."xsd:string
http://purl.uniprot.org/citations/28430892http://purl.uniprot.org/core/author"Verkerk A.O."xsd:string
http://purl.uniprot.org/citations/28430892http://purl.uniprot.org/core/author"Veldkamp M.W."xsd:string
http://purl.uniprot.org/citations/28430892http://purl.uniprot.org/core/author"Casini S."xsd:string
http://purl.uniprot.org/citations/28430892http://purl.uniprot.org/core/author"Belardinelli L."xsd:string
http://purl.uniprot.org/citations/28430892http://purl.uniprot.org/core/author"Mengarelli I."xsd:string
http://purl.uniprot.org/citations/28430892http://purl.uniprot.org/core/author"Portero V."xsd:string
http://purl.uniprot.org/citations/28430892http://purl.uniprot.org/core/date"2017"xsd:gYear
http://purl.uniprot.org/citations/28430892http://purl.uniprot.org/core/name"Cardiovasc Res"xsd:string
http://purl.uniprot.org/citations/28430892http://purl.uniprot.org/core/pages"829-838"xsd:string
http://purl.uniprot.org/citations/28430892http://purl.uniprot.org/core/title"Anti-arrhythmic potential of the late sodium current inhibitor GS-458967 in murine Scn5a-1798insD+/- and human SCN5A-1795insD+/- iPSC-derived cardiomyocytes."xsd:string
http://purl.uniprot.org/citations/28430892http://purl.uniprot.org/core/volume"113"xsd:string
http://purl.uniprot.org/citations/28430892http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/28430892
http://purl.uniprot.org/citations/28430892http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/28430892
http://purl.uniprot.org/uniprot/#_D3YHE8-mappedCitation-28430892http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/28430892
http://purl.uniprot.org/uniprot/#_D3YXW2-mappedCitation-28430892http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/28430892
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