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This study was aiming to further elucidate the effects of fingolimod on cardiac electrophysiology at three different levels: (i) in vitro, (ii) ex vivo<jats:italic>,<\/jats:italic>and (iii) in vivo. (i) Patch\u2010clamp experiments in whole cell configuration were performed on Ca<jats:sub>v<\/jats:sub>1.2\u2010transfected tsA201 cells exposed to fingolimod\u2010phosphate 100 or 500 nmol\/L (<jats:italic>n<\/jats:italic>= 27 cells, total) to measure drug effect on L\u2010type calcium current (<jats:styled-content style=\"fixed-case\">I<jats:sub>C<\/jats:sub><\/jats:styled-content><jats:sub>aL<\/jats:sub>). (ii) Langendorff perfusion experiments were undertaken on male Hartley guinea\u2010pigs isolated hearts (<jats:italic>n<\/jats:italic>= 4) exposed to fingolimod 10 and 100 nmol\/L to evaluate drug\u2010induced effects on monophasic action potential duration measured at 90% repolarization (<jats:styled-content style=\"fixed-case\">MAPD<\/jats:styled-content><jats:sub>90<\/jats:sub>). (iii) Implanted cardiac telemeters were used to record<jats:styled-content style=\"fixed-case\">ECG<\/jats:styled-content>s in guinea\u2010pigs (<jats:italic>n<\/jats:italic>= 7) treated with a single dose of fingolimod 0.0625 mg\/kg suspension, administered as an oral gavage. (i) In vitro cellular experiments showed that fingolimod\u2010phosphate causes a concentration\u2010dependent reduction in<jats:styled-content style=\"fixed-case\">I<jats:sub>C<\/jats:sub><\/jats:styled-content><jats:sub>aL<\/jats:sub>. (ii) Ex vivo Langendorff experiments revealed that fingolimod had no significant effect on<jats:styled-content style=\"fixed-case\">MAPD<\/jats:styled-content><jats:sub>90<\/jats:sub>. (iii) Fingolimod caused significant prolongations of the<jats:styled-content style=\"fixed-case\">RR<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\">PR<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\">QT<\/jats:styled-content>, and<jats:styled-content style=\"fixed-case\">QT<\/jats:styled-content>c<jats:sub>F<\/jats:sub>intervals in vivo. Reversible<jats:styled-content style=\"fixed-case\">AV<\/jats:styled-content>blocks were also observed in 7\/7 animals. Fingolimod possesses<jats:styled-content style=\"fixed-case\">I<jats:sub>C<\/jats:sub><\/jats:styled-content><jats:sub>aL<\/jats:sub>\u2010blocking properties, further contributing to its<jats:styled-content style=\"fixed-case\">AV<\/jats:styled-content>conduction\u2010slowing effects. These properties are also consistent with its mitigated effect on the<jats:styled-content style=\"fixed-case\">QT<\/jats:styled-content>interval in humans, despite previously shown<jats:styled-content style=\"fixed-case\">HERG<\/jats:styled-content>\u2010blocking effect.<\/jats:p>","DOI":"10.1111\/fcp.12284","type":"journal-article","created":{"date-parts":[[2017,3,16]],"date-time":"2017-03-16T07:42:52Z","timestamp":1489650172000},"page":"392-402","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Fingolimod (Gilenya<sup>\u00ae<\/sup>) in multiple sclerosis: bradycardia, atrioventricular blocks, and mild effect on the<scp>QT<\/scp>c interval. 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