{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:24:58Z","timestamp":1791473098893,"version":"4.3.4"},"reference-count":61,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,12,14]],"date-time":"2022-12-14T00:00:00Z","timestamp":1670976000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL057832"],"award-info":[{"award-number":["HL057832"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL132871"],"award-info":[{"award-number":["HL132871"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL134781"],"award-info":[{"award-number":["HL134781"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL155762"],"award-info":[{"award-number":["HL155762"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL164453"],"award-info":[{"award-number":["HL164453"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>At the cellular level, cardiac alternans is observed as beat\u2010to\u2010beat alternations in contraction strength, action potential (AP) morphology and Ca<jats:sup>2+<\/jats:sup> transient (CaT) amplitude, and is a risk factor for cardiac arrhythmia. The (patho)physiological roles of small conductance Ca<jats:sup>2+<\/jats:sup>\u2010activated K<jats:sup>+<\/jats:sup> (SK) channels in ventricles are poorly understood. We tested the hypothesis that in single rabbit ventricular myocytes pharmacological modulation of SK channels plays a causative role for the development of pacing\u2010induced CaT and AP duration (APD) alternans. SK channel blockers (apamin, UCL1684) had only a minor effect on AP repolarization. However, SK channel activation by NS309 resulted in significant APD shortening, demonstrating that functional SK channels are well expressed in ventricular myocytes. The effects of NS309 were prevented or reversed by apamin and UCL1684, indicating that NS309 acted on SK channels. SK channel activation abolished or reduced the degree of pacing\u2010induced CaT and APD alternans. Inhibition of K<jats:sub>V<\/jats:sub>7.1 (with HMR1556) and K<jats:sub>V<\/jats:sub>11.1 (with E4031) channels was used to mimic conditions of long QT syndromes type\u20101 and type\u20102, respectively. Both HMR1556 and E4031 enhanced CaT alternans that was prevented by SK channel activation. In AP voltage\u2010clamped cells the SK channel activator had no effect on CaT alternans, confirming that suppression of CaT alternans was caused by APD shortening. APD shortening contributed to protection from alternans by lowering sarcoplasmic reticulum Ca<jats:sup>2+<\/jats:sup> content and curtailing Ca<jats:sup>2+<\/jats:sup> release. The data suggest that SK activation could be a potential intervention to avert development of alternans with important ramifications for arrhythmia prevention and therapy for patients with long QT syndrome.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15371-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>At the cellular level, cardiac alternans is observed as beat\u2010to\u2010beat alternations in contraction strength, action potential (AP) morphology and intracellular Ca<jats:sup>2+<\/jats:sup> release amplitude, and is a risk factor for cardiac arrhythmia.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The (patho)physiological roles of small conductance Ca<jats:sup>2+<\/jats:sup>\u2010activated K<jats:sup>+<\/jats:sup> (SK) channels in ventricles are poorly understood.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We investigated whether pharmacological modulation of SK channels affects the development of cardiac alternans in normal ventricular cells and in cells with drug\u2010induced long QT syndrome (LQTS).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>While SK channel blockers have only a minor effect on AP morphology, their activation leads to AP shortening and abolishes or reduces the degree of pacing\u2010induced Ca<jats:sup>2+<\/jats:sup> and AP alternans. AP shortening contributed to protection against alternans by lowering sarcoplasmic reticulum Ca<jats:sup>2+<\/jats:sup> content and curtailing Ca<jats:sup>2+<\/jats:sup> release.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The data suggest SK activation as a potential intervention to avert the development of alternans with important ramifications for arrhythmia prevention for patients with LQTS.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp283870","type":"journal-article","created":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T08:27:19Z","timestamp":1669364839000},"page":"51-67","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Activation of small conductance Ca<sup>2+<\/sup>\u2010activated K<sup>+<\/sup> channels suppresses Ca<sup>2+<\/sup> transient and action potential alternans in ventricular myocytes"],"prefix":"10.1113","volume":"601","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3593-1182","authenticated-orcid":false,"given":"Giedrius","family":"Kanaporis","sequence":"first","affiliation":[{"name":"Department of Physiology &amp; Biophysics Rush University Medical Center  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3409-8678","authenticated-orcid":false,"given":"Lothar A.","family":"Blatter","sequence":"additional","affiliation":[{"name":"Department of Physiology &amp; Biophysics Rush University Medical Center  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,12,14]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.15420\/ecr.2017:16:1"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2010.04.008"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.114.015125"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2013.07.003"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP275681"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(99)77126-2"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000119923.64774.72"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.00159"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2005.12.020"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2003.12.028"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/jce.13412"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.4103\/apc.APC_112_17"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpcardiol.2008.07.002"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP270818"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP277618"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2014.12.028"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2013.01.033"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2000.00795.x"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00609.2007"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12228"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1540-8167.2004.03550.x"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.305404"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2017.02.004"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP277188"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.114.002214"},{"key":"e_1_2_6_27_1","first-page":"343","article-title":"SK channel enhancers attenuate Ca2+\u2010dependent arrhythmia in hypertrophic hearts by regulating mito\u2010ROS\u2010dependent oxidation and activity of RyR","volume":"113","author":"Kim T. Y.","year":"2017","journal-title":"Cardiovascular Research"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00479.2017"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.104.502831"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.2013.823161"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2009.04.003"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP275492"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00515.2013"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2010.11.019"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2009.07.019"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2010.06.032"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00251.2018"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00302.2012"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1968.25.2.191"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.99.10.1385"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ipej.2017.10.011"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000125629.72053.95"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.108.815654"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.62.5.1027"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.224600"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00079.2012"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.00510"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvu121"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2020.118834"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.115.003206"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.305146"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1529\/biophysj.106.083865"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevE.69.031904"},{"key":"e_1_2_6_54_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00534.2005"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(02)00737-X"},{"key":"e_1_2_6_56_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.114.302505"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.590534"},{"key":"e_1_2_6_58_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.5000711"},{"key":"e_1_2_6_59_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M307508200"},{"key":"e_1_2_6_60_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-021-02535-0"},{"key":"e_1_2_6_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2018.08.004"},{"key":"e_1_2_6_62_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2009.175018"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP283870","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP283870","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP283870","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T18:30:18Z","timestamp":1692469818000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP283870"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,14]]},"references-count":61,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2023,1]]}},"alternative-id":["10.1113\/JP283870"],"URL":"https:\/\/doi.org\/10.1113\/jp283870","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,14]]},"assertion":[{"value":"2022-09-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-11-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-14","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}