{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T13:12:13Z","timestamp":1775826733545,"version":"3.50.1"},"reference-count":50,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2019,3,27]],"date-time":"2019-03-27T00:00:00Z","timestamp":1553644800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"The Research Council of the KU Leuven","award":["GOA\/14\/011"],"award-info":[{"award-number":["GOA\/14\/011"]}]},{"name":"Fund for Scientific Research Flanders","award":["FWO: G.0765.13"],"award-info":[{"award-number":["FWO: G.0765.13"]}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and purpose<\/jats:title><jats:p>The citrus flavanone hesperetin has been proposed for the treatment of several human pathologies, but its cardiovascular actions remain largely unexplored. Here, we evaluated the effect of hesperetin on cardiac electrical and contractile activities, on aortic contraction, on the wild\u2010type voltage\u2010gated Na<jats:sub>V<\/jats:sub>1.5 channel, and on a channel mutant (R1623Q) associated with lethal ventricular arrhythmias in the long QT syndrome type 3 (LQT3).<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental approach<\/jats:title><jats:p>We used cardiac surface ECG and contraction force recordings to evaluate the effects of hesperetin in rat isolated hearts and aortic rings. Whole\u2010cell patch clamp was used to record Na<jats:sub>V<\/jats:sub>1.5 currents (<jats:italic>I<\/jats:italic><jats:sub>Na<\/jats:sub>) in rat ventricular cardiomyocytes and in HEK293T cells expressing hNa<jats:sub>V<\/jats:sub>1.5 wild\u2010type or mutant channels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key results<\/jats:title><jats:p>Hesperetin increased the QRS interval and heart rate and decreased the corrected QT interval and the cardiac and aortic contraction forces at concentrations equal or higher than 30\u00a0\u03bcmol\u00b7L<jats:sup>\u22121<\/jats:sup>. Hesperetin blocked rat and human Na<jats:sub>V<\/jats:sub>1.5 channels with an effective inhibitory concentration of \u2248100\u00a0\u03bcmol\u00b7L<jats:sup>\u22121<\/jats:sup>. This inhibition was enhanced at depolarized holding potentials and higher stimulation frequency and was reduced by the disruption of the binding site for local anaesthetics. Hesperetin increased the rate of inactivation and preferentially inhibited<jats:italic>I<\/jats:italic><jats:sub>Na<\/jats:sub>during the slow inactivation phase, these effects being more pronounced in the R1623Q mutant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and implications<\/jats:title><jats:p>Hesperetin preferentially inhibits the slow inactivation phase of<jats:italic>I<\/jats:italic><jats:sub>Na<\/jats:sub>, more markedly in the mutant R1623Q. Hesperetin could be used as a template to develop drugs against lethal cardiac arrhythmias in LQT3.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14577","type":"journal-article","created":{"date-parts":[[2019,1,16]],"date-time":"2019-01-16T20:59:10Z","timestamp":1547672350000},"page":"1090-1105","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["The citrus flavanone hesperetin preferentially inhibits slow\u2010inactivating currents of a long QT syndrome type 3 syndrome Na<sup>+<\/sup>channel mutation"],"prefix":"10.1111","volume":"176","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5421-4114","authenticated-orcid":false,"given":"Julio","family":"Alvarez\u2010Collazo","sequence":"first","affiliation":[{"name":"Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine VIB\u2010KU Leuven Center for Brain &amp; Disease Research Leuven Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6951-8321","authenticated-orcid":false,"given":"Alejandro","family":"L\u00f3pez\u2010Requena","sequence":"additional","affiliation":[{"name":"Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine VIB\u2010KU Leuven Center for Brain &amp; 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