{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T08:50:48Z","timestamp":1773737448357,"version":"3.50.1"},"reference-count":38,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2014,10,7]],"date-time":"2014-10-07T00:00:00Z","timestamp":1412640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"crossref","award":["FS\/10\/64\/28532"],"award-info":[{"award-number":["FS\/10\/64\/28532"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"crossref","award":["R01 HL111600"],"award-info":[{"award-number":["R01 HL111600"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["12SDG9010015"],"award-info":[{"award-number":["12SDG9010015"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2015,3,15]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\"><jats:list-item><jats:p>Heart failure leads to dramatic electrophysiological remodelling as a result of numerous cellular and tissue\u2010level changes. Important cellular changes include increased sensitivity of ryanodine receptors (RyRs) to Ca<jats:sup>2+<\/jats:sup>release and down\u2010regulation of the inward rectifying K<jats:sup>+<\/jats:sup>current (<jats:italic>I<\/jats:italic><jats:sub>K1<\/jats:sub>), both of which contribute to triggered action potentials in isolated cells.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>We studied the role of increased RyR sensitivity and decreased<jats:italic>I<\/jats:italic><jats:sub>K1<\/jats:sub>in contributing to focal arrhythmia in the intact non\u2010failing rabbit heart using optical mapping and pharmacological manipulation of RyRs and<jats:italic>I<\/jats:italic><jats:sub>K1<\/jats:sub>.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>Neither increased RyR sensitivity or decreased<jats:italic>I<\/jats:italic><jats:sub>K1<\/jats:sub>alone led to significant increases in arrhythmia following local sympathetic stimulation; however, in combination, these two factors led to a significant increase in premature ventricular complexes and focal ventricular tachycardia.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>These results suggest synergism between increased RyR sensitivity and decreased<jats:italic>I<\/jats:italic><jats:sub>K1<\/jats:sub>in contributing to focal arrhythmia in the intact heart and may provide important insights into novel anti\u2010arrhythmic treatments in heart failure.<\/jats:p><\/jats:list-item><\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Heart failure (HF) results in dramatic electrophysiological remodelling, including increased sensitivity of ryanodine receptors (RyRs) and decreased inward rectifying K<jats:sup>+<\/jats:sup>current (<jats:italic>I<\/jats:italic><jats:sub>K1<\/jats:sub>), which predisposes HF myocytes to delayed afterdepolarizations and triggered activity. Therefore, we sought to determine the role of increased RyR sensitivity and decreased<jats:italic>I<\/jats:italic><jats:sub>K1<\/jats:sub>in contributing to focal arrhythmia in the intact non\u2010failing heart. Optical mapping of transmembrane potential and intracellular Ca<jats:sup>2+<\/jats:sup>was performed in Langendorff\u2010perfused rabbit hearts (<jats:italic>n<\/jats:italic>\u00a0=\u00a015). Local \u03b2\u2010adrenergic receptor stimulation with noradrenaline (norepinephrine; NA, 50\u00a0\u03bcl, 250\u00a0\u03bc<jats:sc>m<\/jats:sc>) was applied to elicit focal activity (premature ventricular complexes (PVCs) or ventricular tachycardia (VT\u00a0\u2265\u00a03\u00a0beats)). NA was administered under control conditions (CTL) and following pretreatment with 50\u00a0\u03bc<jats:sc>m<\/jats:sc>BaCl<jats:sub>2<\/jats:sub>to reduce<jats:italic>I<\/jats:italic><jats:sub>K1<\/jats:sub>, or 200\u00a0\u03bc<jats:sc>m<\/jats:sc>caffeine (Caff) to sensitize RyRs, both alone and in combination. Local NA injection resulted in Ca<jats:sup>2+<\/jats:sup>\u2010driven PVCs arising from the injection site in all hearts studied. No increase in NA\u2010mediated PVCs was observed following pretreatment with either BaCl<jats:sub>2<\/jats:sub>or Caff alone (CTL: 1.1\u00a0\u00b1\u00a00.7, BaCl<jats:sub>2<\/jats:sub>: 1.0\u00a0\u00b1\u00a00.7, Caff: 1.3\u00a0\u00b1\u00a00.8 PVCs\/injection,<jats:italic>P<\/jats:italic>not significant). However, pretreatment with the combination of BaCl<jats:sub>2<\/jats:sub>\u00a0+\u00a0Caff resulted in a significant increase in PVCs (2.3\u00a0\u00b1\u00a02.8 PVCs\/injection,<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05<jats:italic>vs<\/jats:italic>. CTL, BaCl<jats:sub>2<\/jats:sub>, Caff). Additionally, pretreatment with BaCl<jats:sub>2<\/jats:sub>\u00a0+\u00a0Caff led to sustained monomorphic VT arising from the NA application site in all hearts studied, which lasted up to 6\u00a0min following a single NA injection. VT was never observed under any other condition suggesting synergism between increased RyR sensitivity and decreased<jats:italic>I<\/jats:italic><jats:sub>K1<\/jats:sub>in contributing to focal activity. These findings may have important implications for the understanding and prevention of focal arrhythmia in HF.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jphysiol.2014.279638","type":"journal-article","created":{"date-parts":[[2014,9,6]],"date-time":"2014-09-06T03:28:11Z","timestamp":1409974091000},"page":"1479-1493","source":"Crossref","is-referenced-by-count":39,"title":["Decreased inward rectifying K<sup>+<\/sup>current and increased ryanodine receptor sensitivity synergistically contribute to sustained focal arrhythmia in the intact rabbit heart"],"prefix":"10.1113","volume":"593","author":[{"given":"Rachel C.","family":"Myles","sequence":"first","affiliation":[{"name":"Institute of Cardiovascular and Medical Sciences University of Glasgow Glasgow UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lianguo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine University of California Davis CA 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