{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T20:10:38Z","timestamp":1791835838319,"version":"4.3.4"},"reference-count":31,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2023,5,9]],"date-time":"2023-05-09T00:00:00Z","timestamp":1683590400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL47678, HL138103, HL152201"],"award-info":[{"award-number":["HL47678, HL138103, HL152201"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001340","name":"W. W. Smith Charitable Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001340","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wistar and Martha Morris Fund."},{"name":"Sharpe Strumia Research Foundation"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Brugada (BrS) and early repolarization syndromes (ERS), the so-called J wave syndromes (JWS), are associated with life-threatening ventricular arrhythmias. Pharmacologic approaches to therapy are currently limited. In this study, we examine the effects of ARumenamide-787 (AR-787) to suppress the electrocardiographic and arrhythmic manifestations of JWS and hypothermia.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>We studied the effects of AR-787 on I<jats:sub>Na<\/jats:sub> and I<jats:sub>Kr<\/jats:sub> in HEK-293 cells stably expressing the \u03b1- and \u03b21-subunits of the cardiac (Na<jats:sub>V<\/jats:sub>1.5) sodium channel and hERG channel, respectively. In addition, we studied its effect on I<jats:sub>to<\/jats:sub>, I<jats:sub>Na<\/jats:sub> and I<jats:sub>Ca<\/jats:sub> in dissociated canine ventricular myocytes along with action potentials and ECG from coronary-perfused right (RV) and left (LV) ventricular wedge preparations. The I<jats:sub>to<\/jats:sub> agonist, NS5806 (5\u201310 \u03bcM), I<jats:sub>Ca<\/jats:sub> blocker, verapamil (2.5 \u03bcM), and I<jats:sub>Na<\/jats:sub> blocker, ajmaline (2.5 \u03bcM), were used to mimic the genetic defects associated with JWS and to induce the electrocardiographic and arrhythmic manifestations of JWS (prominent J waves\/ST segment elevation, phase 2 reentry and polymorphic VT\/VF) in canine ventricular wedge preparations.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>AR-787 (1, 10 and 50 \u03bcM) exerted pleiotropic effects on cardiac ion channels. The predominant effect was inhibition of the transient outward current (I<jats:sub>to<\/jats:sub>) and enhancement of the sodium channel current (I<jats:sub>Na<\/jats:sub>), with lesser effects to inhibit I<jats:sub>Kr<\/jats:sub> and augment calcium channel current (I<jats:sub>Ca<\/jats:sub>). AR-787 diminished the electrocardiographic J wave and prevented and\/or suppressed all arrhythmic activity in canine RV and LV experimental models of BrS, ERS and hypothermia.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Our findings point to AR-787 as promising candidate for the pharmacologic treatment of JWS and hypothermia.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0281977","type":"journal-article","created":{"date-parts":[[2023,5,9]],"date-time":"2023-05-09T23:20:29Z","timestamp":1683674429000},"page":"e0281977","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Mechanisms underlying the antiarrhythmic effect of ARumenamide-787 in experimental models of the J wave syndromes and hypothermia"],"prefix":"10.1371","volume":"18","author":[{"given":"Jos\u00e9 M.","family":"Di 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