Estimation of potency of HERG channel blockers: Impact of voltage protocol and temperature

Yao, Jianan; Du, Xian; Lu, Daniel C.; Baker, Robert L.; Daharsh, Eric D.; Atterson, Philip

doi:10.1016/j.vascn.2005.04.008

Cited by 80 publications

(96 citation statements)

References 22 publications

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“…Remarkably, EADs were not seen at temperatures lower than 33°C. Although this study did not investigate whether HERG channel block by E-4031 was more potent at higher temperatures, other studies did not find a temperature-dependent change in the potency of E-4031 block of HERG channels (34,35). These data illustrate that the functional implications of I Kr reduction are greater during hyperthermia and support our postulate that failure of mutant HERG current to adequately increase at higher temperatures delays cardiac repolarization.…”

Section: Discussionsupporting

confidence: 61%

Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome

Amin¹,

Herfst²,

Delisle³

et al. 2008

J. Clin. Invest.

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Type 2 congenital long QT syndrome (LQT-2) is linked to mutations in the human ether a-go-go-related gene (HERG) and is characterized by rate-corrected QT interval (QTc) prolongation, ventricular arrhythmias, syncope, and sudden death. Recognized triggers of these cardiac events include emotional and acoustic stimuli. Here we investigated the repeated occurrence of fever-induced polymorphic ventricular tachycardia and ventricular fibrillation in 2 LQT-2 patients with A558P missense mutation in HERG. ECG analysis showed increased QTc with fever in both patients. WT, A558P, and WT+A558P HERG were expressed heterologously in HEK293 cells and were studied using biochemical and electrophysiological techniques. A558P proteins showed a trafficking-deficient phenotype. WT+A558P coexpression caused a dominant-negative effect, selectively accelerated the rate of channel inactivation, and reduced the temperature-dependent increase in the WT current. Thus, the WT+A558P current did not increase to the same extent as the WT current, leading to larger current density differences at higher temperatures. A similar temperature-dependent phenotype was seen for coexpression of the trafficking-deficient LQT-2 F640V mutation. We postulate that the weak increase in the HERG current density in WT-mutant coassembled channels contributes to the development of QTc prolongation and arrhythmias at febrile temperatures and suggest that fever is a potential trigger of life-threatening arrhythmias in LQT-2 patients.

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Section: Discussionsupporting

confidence: 61%

Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome

Amin¹,

Herfst²,

Delisle³

et al. 2008

J. Clin. Invest.

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“…• C elicited a statistically significant decreased blocking potency for 2 drugs, increased potency for 4 drugs, and had no effect on 9 additional drugs evaluated using a 2-second step pulse clamp protocol; for the same change in temperature, Yao and colleagues also reported an increased potency for hERG block with 1 drug, decreased potency for a second drug, and no changes in 2 additional drugs (Yao et al, 2005).…”

Section: General Limitations Of Evaluations Of Herg Channel Blockmentioning

confidence: 92%

Utility of hERG Assays as Surrogate Markers of Delayed Cardiac Repolarization and QT Safety

Gintant

Martin

et al. 2006

Toxicol Pathol

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HERG (human-ether-a-go-go-related gene) encodes for a cardiac potassium channel that plays a critical role in defining ventricular repolarization. Noncardiovascular drugs associated with a rare but potentially lethal ventricular arrhythmia (Torsades de Pointes) have been linked to delayed cardiac repolarization and block of hERG current. This brief overview will discuss the role of hERG current in cardiac electrophysiology, its involvement in drug-induced delayed repolarization, and approaches used to define drug effects on hERG current. In addition, examples of hERG blocking drugs acting differently (i.e., overt and covert hERG blockade due to multichannel block) together with the utility and limitations of hERG assays as tools to predict the risk of delayed repolarization and proarrhythmia are discussed.

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“…The potency of some hERG blockers shows marked sensitivity to stimulus protocol and/or measurement temperature. [30][31][32] The extent to which measurement conditions/protocol influence half-maximal inhibitory effect concentration (IC 50 ) may vary significantly between drugs: one comparative analysis of cisapride and dofetilide using manual patch reported variability of I hERG IC 50 for dofetilide between 4 and 46 nM and for cisapride between 7 and 240 nM in published literature derived from mammalian cell lines. 32 This further correlated with greater variability for cisapride than for dofetilide IC 50 (7-72 nM versus 4-15 nM) in experiments at a single temperature in a single study, between step, step-ramp, and AP voltage commands.…”

Section: Drawbacks Of the Existing Approach And Predominant Focus On mentioning

confidence: 99%

A New Perspective in the Field of Cardiac Safety Testing through the Comprehensive In Vitro Proarrhythmia Assay Paradigm

et al. 2016

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For the past decade, cardiac safety screening to evaluate the propensity of drugs to produce QT interval prolongation and Torsades de Pointes (TdP) arrhythmia has been conducted according to ICH S7B and ICH E14 guidelines. Central to the existing approach are hERG channel assays and in vivo QT measurements. Although effective, the present paradigm carries a risk of unnecessary compound attrition and high cost, especially when considering costly thorough QT (TQT) studies conducted later in drug development. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative is a publicprivate collaboration with the aim of updating the existing cardiac safety testing paradigm to better evaluate arrhythmia risk and remove the need for TQT studies. It is hoped that CiPA will produce a standardized ion channel assay approach, incorporating defined tests against major cardiac ion channels, the results of which then inform evaluation of proarrhythmic actions in silico, using human ventricular action potential reconstructions. Results are then to be confirmed using human (stem cell-derived) cardiomyocytes. This perspective article reviews the rationale, progress of, and challenges for the CiPA initiative, if this new paradigm is to replace existing practice and, in time, lead to improved and widely accepted cardiac safety testing guidelines.

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Estimation of potency of HERG channel blockers: Impact of voltage protocol and temperature

Cited by 80 publications

References 22 publications

Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome

Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome

Utility of hERG Assays as Surrogate Markers of Delayed Cardiac Repolarization and QT Safety

A New Perspective in the Field of Cardiac Safety Testing through the Comprehensive In Vitro Proarrhythmia Assay Paradigm

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