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I<jats:sub>K1<\/jats:sub> channel agonists have been considered a new type of anti\u2010arrhythmia and cardioprotective agents. We predicted using a drug repurposing strategy that tetramisole (Tet), a known anthelminthic agent, was a new I<jats:sub>K1<\/jats:sub> channel agonist. The present study aimed to experimentally identify the above prediction and further demonstrate that Tet has cardioprotective effects. Results of the whole\u2010cell patch clamp technique showed that Tet at 1\u2013100\u00a0\u03bcmol\/L enhanced I<jats:sub>K1<\/jats:sub> current, hyperpolarized resting potential (RP), and shortened action potential duration (APD) in isolated rat cardiomyocytes, while without effects on other ion channels or transporters. In adult Sprague\u2013Dawley (SD) rats in vivo, Tet showed anti\u2010arrhythmia and anticardiac remodeling effects, respectively, in the coronary ligation\u2010induced myocardial infarction model and isoproterenol (Iso, i.p., 3\u00a0mg\/kg\/day, 10\u2009days) infusion\u2010induced cardiac remodeling model. Tet also showed anticardiomyocyte remodeling effect in Iso (1\u00a0\u03bcmol\/L) infused adult rat ventricular myocytes or cultured H9c2 (2\u20101) cardiomyocytes. Tet at 0.54\u2009mg\/kg in vivo or 30\u2009\u03bcmol\/L in vitro showed promising protections on acute ischemic arrhythmias, myocardial hypertrophy, and fibrosis. Molecular docking was performed and identified the selective binding of Tet with Kir2.1. The cardioprotection of Tet was associated with the facilitation of I<jats:sub>K1<\/jats:sub> channel forward trafficking, deactivation of PKA signaling, and inhibition of intracellular calcium overload. Enhancing I<jats:sub>K1<\/jats:sub> may play dual roles in anti\u2010arrhythmia and antiventricular remodeling mediated by restoration of Ca<jats:sup>2+<\/jats:sup> homeostasis.<\/jats:p>","DOI":"10.1002\/prp2.992","type":"journal-article","created":{"date-parts":[[2022,7,26]],"date-time":"2022-07-26T10:46:48Z","timestamp":1658832408000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Tetramisole is a new I<sub>K1<\/sub> channel agonist and exerts I<sub>K1<\/sub>\u2010dependent cardioprotective effects in rats"],"prefix":"10.1002","volume":"10","author":[{"given":"Qinghua","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pathophysiology Shanxi Medical University  Taiyuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxing","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology Shanxi Medical University  Taiyuan 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