Modulation of the heart's electrical properties by the anticonvulsant drug retigabine.
Retigabine, currently used as antiepileptic drug, has a wide range of potential medical uses. Administration of the drug in patients can lead to QT interval prolongation in the electrocardiogram and to cardiac arrhythmias in rare cases. This suggests that the drug may perturb the electrical properties of the heart, and the underlying mechanisms were investigated here. Effects of retigabine on currents through human cardiac ion channels, heterologously expressed in tsA-201 cells, were studied in whole-cell patch-clamp experiments. In addition, the drug's impact on the cardiac action potential was tested. This was done using ventricular cardiomyocytes isolated from Langendorff-perfused guinea pig hearts and cardiomyocytes derived from human induced pluripotent stem cells. Further, to unravel potential indirect effects of retigabine on the heart which might involve the autonomic nervous system, membrane potential and noradrenaline release from sympathetic ganglionic neurons were measured in the absence and presence of the drug. Retigabine significantly inhibited currents through hKv11.1 potassium, hNav1.5 sodium, as well as hCav1.2 calcium channels, but only in supra-therapeutic concentrations. In a similar concentration range, the drug shortened the action potential in both guinea pig and human cardiomyocytes. Therapeutic concentrations of retigabine, on the other hand, were sufficient to inhibit the activity of sympathetic ganglionic neurons. We conclude that retigabine- induced QT interval prolongation, and the reported cases of cardiac arrhythmias after application of the drug in a typical daily dose range, cannot be explained by a direct modulatory effect on cardiac ion channels. They are rather mediated by indirect actions at the level of the autonomic nervous system.
['Rubi|Lena|L|', 'Kovar|Michael|M|', 'Zebedin-Brandl|Eva|E|', 'Koenig|Xaver|X|', 'Dominguez-Rodriguez|Manuel|M|', 'Todt|Hannes|H|', 'Kubista|Helmut|H|', 'Boehm|Stefan|S|', 'Hilber|Karlheinz|K|']
D000200:Action Potentials D000818:Animals D000927:Anticonvulsants D001145:Arrhythmias, Cardiac D002121:Calcium Channel Blockers D020746:Calcium Channels, L-Type D002219:Carbamates D002460:Cell Line D004305:Dose-Response Relationship, Drug D000072237:ERG1 Potassium Channel D005728:Ganglia, Sympathetic D005730:Ganglionic Blockers D006168:Guinea Pigs D006329:Heart Conduction System D006339:Heart Rate D006801:Humans D057026:Induced Pluripotent Stem Cells D007473:Ion Channels D000067268:Isolated Heart Preparation D032383:Myocytes, Cardiac D062554:NAV1.5 Voltage-Gated Sodium Channel D009638:Norepinephrine D010655:Phenylenediamines D026902:Potassium Channel Blockers D017207:Rats, Sprague-Dawley D018570:Risk Assessment D013997:Time Factors D014162:Transfection D061567:Voltage-Gated Sodium Channel Blockers
Retigabine QT interval Cardiac arrhythmia Ion channels Cardiomyocytes Sympathetic ganglionic neurons