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We investigated the antiarrhythmic actions of two RyR2 inhibitors: dantrolene and VK\u2010II\u201086, a carvedilol analogue lacking antagonist activity at \u03b2\u2010adrenoceptors, in hypokalaemia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Surface ECG and ventricular action potentials (APs) were recorded from whole\u2010heart murine Langendorff preparations. Ventricular arrhythmia incidence was compared in hearts perfused with low [K<jats:sup>+<\/jats:sup>], and those pretreated with dantrolene or VK\u2010II\u201086. Whole\u2010cell patch clamping was used in murine and canine ventricular cardiomyocytes to study effects of dantrolene and VK\u2010II\u201086 on AP parameters in low [K<jats:sup>+<\/jats:sup>] and effects of VK\u2010II\u201086 on the inward rectifier current (I<jats:sub>K1<\/jats:sub>), late sodium current (I<jats:sub>Na_L<\/jats:sub>) and the L\u2010type Ca<jats:sup>2+<\/jats:sup> current (I<jats:sub>Ca<\/jats:sub>). Effects of VK\u2010II\u201086 on I<jats:sub>Kr<\/jats:sub> were investigated in transfected HEK\u2010293 cells. A fluorogenic probe quantified the effects of VK\u2010II\u201086 on oxidative stress in hypokalaemia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Dantrolene reduced the incidence of ventricular arrhythmias induced by low [K<jats:sup>+<\/jats:sup>] in explanted murine hearts by 94%, whereas VK\u2010II\u201086 prevented all arrhythmias. VK\u2010II\u201086 prevented hypokalaemia\u2010induced AP prolongation and depolarization but did not alter AP parameters in normokalaemia. Hypokalaemia was associated with decreased I<jats:sub>K1<\/jats:sub> and I<jats:sub>Kr<\/jats:sub>, and increased I<jats:sub>Na\u2010L<\/jats:sub>, and I<jats:sub>Ca<\/jats:sub>. VK\u2010II\u201086 prevented all hypokalaemia\u2010induced changes in ion channel activity and oxidative stress.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>VK\u2010II\u201086 prevents hypokalaemia\u2010induced arrhythmogenesis by normalizing calcium homeostasis and repolarization reserve. VK\u2010II\u201086 may provide an effective treatment in hypokalaemia and other arrhythmias caused by delayed repolarization or Ca<jats:sup>2+<\/jats:sup> overload.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15775","type":"journal-article","created":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T04:44:19Z","timestamp":1638938659000},"page":"2713-2732","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A carvedilol analogue, VK\u2010II\u201086, prevents hypokalaemia\u2010induced ventricular arrhythmia through novel multi\u2010channel effects"],"prefix":"10.1111","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8343-9286","authenticated-orcid":false,"given":"Victoria M.","family":"Robinson","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health The University of Manchester  Manchester UK"},{"name":"Cardiovascular Sciences Lankenau Institute for Medical Research  Wynnewood Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Izzeddin","family":"Alsalahat","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health The University of Manchester  Manchester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sally","family":"Freeman","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health The University of Manchester  Manchester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles","family":"Antzelevitch","sequence":"additional","affiliation":[{"name":"Cardiovascular Sciences Lankenau Institute for Medical Research  Wynnewood Pennsylvania USA"},{"name":"Sidney Kimmel College of Medicine Thomas Jefferson University  Philadelphia Pennsylvania USA"},{"name":"Lankenau Heart Institute Lankenau Medical Center, Main Line Health  Wynnewood Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H\u00e9ctor","family":"Barajas\u2010Martinez","sequence":"additional","affiliation":[{"name":"Cardiovascular Sciences Lankenau Institute for Medical Research  Wynnewood Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luigi","family":"Venetucci","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health The University of Manchester  Manchester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,2,4]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15538"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15542"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15543"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15539"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2014.279893"},{"issue":"1","key":"e_1_2_12_7_1","first-page":"96","article-title":"Hydrogen peroxide modifies the kinetics of HERG channel expressed in a mammalian cell line","volume":"297","author":"B\u00e9rub\u00e9 J.","year":"2001","journal-title":"The Journal of Pharmacology and Experimental Therapeutics"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.73.2.379"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2003.058248"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14153"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/HJH.0b013e3280127948"},{"key":"e_1_2_12_12_1","first-page":"1395","volume-title":"Europace","author":"Boer T. 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