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We aimed to investigate the antiarrhythmic and molecular mechanisms of ranolazine in <jats:italic>db\/db<\/jats:italic> mouse hearts with acute IR injury. Ranolazine was administered for 1\u00a0week before coronary artery ligation. Diabetic <jats:italic>db\/db<\/jats:italic> and control <jats:italic>db\/<\/jats:italic>+\u2009mice were divided into ranolazine-given and -nongiven groups. IR model was created by 15-min left coronary artery ligation and 10-min reperfusion. In vivo electrophysiological studies showed that the severity of VA inducibility was higher in <jats:italic>db\/db<\/jats:italic> mice than control (<jats:italic>db\/<\/jats:italic>\u2009+) mice. Ranolazine suppressed the VA inducibility and severity. Optical mapping studies in Langendorff-perfused hearts showed that ranolazine significantly shortened action potential duration, Ca<jats:sub>i<\/jats:sub> transient duration, Ca<jats:sub>i<\/jats:sub> decay time, ameliorated conduction inhomogeneity, and suppressed arrhythmogenic alternans induction. Western blotting studies showed that the expression of pThr<jats:sup>17<\/jats:sup>-phospholamban, calsequestrin 2 and voltage-gated sodium channel in the IR zone was significantly downregulated in <jats:italic>db\/db<\/jats:italic> mice, which was ameliorated with ranolazine pretreatment and might play a role in the anti-arrhythmic actions of ranolazine in <jats:italic>db\/db<\/jats:italic> mouse hearts with IR injury.<\/jats:p>","DOI":"10.1038\/s41598-020-77014-0","type":"journal-article","created":{"date-parts":[[2020,11,18]],"date-time":"2020-11-18T11:05:54Z","timestamp":1605697554000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Mechanisms of ranolazine pretreatment in preventing ventricular tachyarrhythmias in diabetic db\/db mice with acute regional ischemia\u2013reperfusion injury"],"prefix":"10.1038","volume":"10","author":[{"given":"Chung-Chuan","family":"Chou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Ling","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwo-Jyh","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hung-Ta","family":"Wo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzung-Hai","family":"Yen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Shien","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao-Tien","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po-Cheng","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,18]]},"reference":[{"key":"77014_CR1","doi-asserted-by":"publisher","first-page":"H763","DOI":"10.1152\/ajpheart.1999.277.2.H763","volume":"277","author":"SP Jones","year":"1999","unstructured":"Jones, S. 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