Drug Block of I Kr : Model Systems and Relevance to Human Arrhythmias

The long QT-related arrhythmia torsades de pointes (TdP) can arise with mutations in HERG and during treatment with drugs that block cardiac I Kr, the current encoded by HERG. Multiple test systems have been used to assess drug block of I Kr. This study evaluated the I Kr blocking potency of a series of antiarrhythmics associated with a range of clinical risks of TdP in two such systems: mouse AT-1 cells (in which I Kr is the major repolarizing current) and Ltk cells transiently transfected with HERG (n = 4-10 cells per drug). For each compound, the concentration required to produce 50% block of I Kr or HERG tail currents (IC 50 ) was determined. There was an excellent correlation ( r = 0.98, p 50 microM ). Conversely, verapamil and amiodarone, drugs not associated with TdP, were also blockers (IC 50 < or = 1 microM ). We conclude that I Kr blocking potency can be readily assessed in either AT-1 cells or systems in which HERG is heterologously expressed. However, not all drugs causing TdP are potent I Kr blockers, and I Kr block is not necessarily associated with TdP. Other properties of these drugs, therefore, contribute to their propensity to cause TdP.