Proceedings of The Physiological Society
University of Oxford (2011) Proc Physiol Soc 23, PC271
Studies on IKr Channel Blockade in Human Cardiomyocytes as a Cause of Arrhythmias
H. N. Rubaiy1,2, E. Wärdell2, I. Nylander1, C. Sylvén2
1. Division of Pharmaceutical Pharmacology, Uppsala University, Uppsala, Sweden. 2. Department of Medicine, Division of Cardiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
According to guidelines from the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) all new drugs both from the point of teratogenicity and the adult risk of sudden death should be tested regarding proarrhythmic (Torsades de Pointes, TdP) potentially life threatening arrhythmias caused by blockage of the rapid delayed rectifier potassium channel (IKr) that is expressed by the HERG genes. The drugs associated with TdP include antiarrhythmics, antihistamines, antibiotics, antipsychotics and others. Effects on IKr have been studied in rodents and cardiomyocytes derived from rodents. It is therefore of considerable toxicological value to develop a human fetal cardiomycyte model where the expression of IKr can be characterized on cells derived from fetuses of age 5-12 weeks. Electrophysiological recordings (ECG) were done with Multichannel Electrical Assay (MEA) on cardiospheres derived from donated human first trimester myocardium. Dose-response (0-20 µM) curves were established for isoproterenol (β-adrenergic agonist). The R-R interval increased with increasing dose as expected. Dose-response (0-100 µM) curves were established for dofetilide, a class III antiarrhythmic agent. With increasing dose the amplitude of the ECG complex diminished until it was eliminated and QT interval was prolonged. The rate corrected repolarization duration was prolonged and self-determined short arrhythmias were triggered by early after depolarizations (EADs). In conclusion, in human cardiomyocytes, dofetilide as an IKr blocker causes a prolongation of rate-corrected QT interval and at the tail of a prolonged action potential induce EADs, which provoke TdP.
Where applicable, experiments conform with Society ethical requirements