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The clinical efficacy of flecainide in this context involves complex effects on multiple ion channels that may be influenced by the disease state. A compelling narrative has been constructed around flecainide's nonselective block of sarcoplasmic reticulum (SR) lumen\u2010to\u2010cytoplasm Ca<jats:sup>2+<\/jats:sup> release through intracellular calcium release channels (RyR2). However, ion fluxes across the SR membrane during heart contraction are <jats:italic>bidirectional<\/jats:italic>, and here, we review experimental evidence that flecainide's principal action on RyR2 involves the partial block of ion flow in the cytoplasm\u2010to\u2010lumen direction (i.e., flecainide inhibits RyR2\u2010mediated SR \u2018countercurrent\u2019). Experimental approaches that could advance new knowledge on the mechanism of RyR2 block by flecainide are proposed. Some impediments to progress in this area, that must be overcome to enable the development of superior drugs to treat CPVT, are also considered.<\/jats:p>","DOI":"10.1111\/bph.15718","type":"journal-article","created":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T12:25:17Z","timestamp":1635251117000},"page":"2558-2563","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Moving in the right direction: elucidating the mechanisms of interaction between flecainide and the cardiac ryanodine receptor"],"prefix":"10.1111","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0865-5912","authenticated-orcid":false,"given":"Mark L.","family":"Bannister","sequence":"first","affiliation":[{"name":"Swansea University Medical School Swansea University  Swansea UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0633-1591","authenticated-orcid":false,"given":"Kenneth T.","family":"MacLeod","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute Imperial College, Hammersmith Hospital  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9852-1135","authenticated-orcid":false,"given":"Christopher H.","family":"George","sequence":"additional","affiliation":[{"name":"Swansea University Medical School Swansea University  Swansea UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,12,2]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13521"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.305347"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.318706"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/26.11.1121"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/13543776.2016.1211111"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1529\/biophysj.108.131987"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2009.10.005"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.110.959916"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2017.12.017"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.120.316819"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1987.tb03252.x"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2016.10.078"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.20028723"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.247338"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.159897"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI62834"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.114.094623"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2015.06.021"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/0031-6989(86)90115-3"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13807"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201812035"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvt012"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvt068"},{"key":"e_1_2_10_25_1","first-page":"66","article-title":"K+ channel blocking actions of flecainide compared with those of propafenone and quinidine in adult rat ventricular myocytes","volume":"269","author":"Slawsky M. 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