Novel Potent Human <i>Ether-à-Go-Go</i>-Related Gene (<i>hERG</i>) Potassium Channel Enhancers and Their in Vitro Antiarrhythmic Activity

Zhou, Jun; Augelli‐Szafran, Corinne E.; Bradley, Jenifer A.; Chen, Xian; Koci, Bryan; Volberg, Walter A.; Sun, Zhuoqian; Cordes, Jason

doi:10.1124/mol.105.014035

Cited by 133 publications

(157 citation statements)

References 24 publications

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“…PD-118057 has been shown to be effective in reversing the long QT intervals and suppressing early afterdepolarization activity induced by I Kr blockers. 13 The present study highlights the proarrhythmic potential of I Kr agonists and provides additional support for the arrhythmogenic potential QT abbreviation. Our data also extend the proarrhythmic potential of reversing the direction of activation of the ventricular wall to include the short QT syndrome.…”

Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 89%

“…13 The drug showed no major effect on I Na , I Ca-L , I K1 , or I Ks . 13 The increase in net repolarizing current during phases 2 and 3 abbreviates action potential duration and hence QT interval. PD-118057 induces preferential abbreviation of epicardial APD as compared to M cell and endocardial APD, leading to increase in T peak -T end interval and TDR.…”

Section: Discussionmentioning

confidence: 89%

“…12 The present study involves the development and characterization of a specific model of SQT1 made possible by the recent availability of a selective I Kr agonist, PD-118057. 13 Available data indicate that PD-118057 binds to the I Kr channel directly and increases its open channel probability without affecting the voltage-dependence and kinetics of gating parameters.…”

Section: Introductionmentioning

confidence: 99%

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Cellular basis for arrhythmogenesis in an experimental model of the SQT1 form of the short QT syndrome

Patel

Antzelevitch

2008

Heart Rhythm

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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Cellular basis for arrhythmogenesis in an experimental model of the SQT1 form of the short QT syndrome

Patel

Antzelevitch

2008

Heart Rhythm

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“…The first drug in this class, RPR260243, was shown to reverse dofetilide-induced APD prolongation in guinea pig myocytes (Kang et al, 2005). More potent than the first agent, PD-118057 was found to reduce the APD of endocardial and epicardial cells and abbreviate the QT interval when infused alone in rabbit left ventricular wedge (Zhou et al, 2005). PD-118057 at 3 μmol/ l concentration prevented the dofetilide induced APD and QT prolongation and abolished EADs (Zhou et al, 2005).…”

Section: Sodium Channel Blocker-lqt3mentioning

confidence: 99%

Pharmacological approach to the treatment of long and short QT syndromes

Patel

Antzelevitch

2008

Pharmacology & Therapeutics

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Inherited channelopathies have received increasing attention in recent years. The past decade has witnessed impressive progress in our understanding of the molecular and cellular basis of arrhythmogenesis associated with inherited channelopathies. An imbalance in ionic forces induced by these channelopathies affects the duration of ventricular repolarization and amplifies the intrinsic electrical heterogeneity of the myocardium, creating an arrhythmogenic milieu. Today, many of the channelopathies have been linked to mutations in specific genes encoding either components of ion channels or membrane or regulatory proteins. Many of the channelopathies are genetically heterogeneous with a variable degree of expression of the disease. Defining the molecular basis of channelopathies can have a profound impact on patient management, particularly in cases in which genotype-specific pharmacotherapy is available.The long QT syndrome (LQTS) is one of the first identified and most studied channelopathies where abnormal prolongation of ventricular repolarization predisposes an individual to life threatening ventricular arrhythmia called Torsade de Pointes. On the other hand of the spectrum, molecular defects favoring premature repolarization lead to Short QT syndrome (SQTS), a recently described inherited channelopathy. Both of these channelopathies are associated with a high risk of sudden cardiac death due to malignant ventricular arrhythmia. Whereas pharmacological therapy is first line treatment for LQTS, defibrillators are considered as primary treatment for SQTS. This review provides a comprehensive review of the molecular genetics, clinical features, genotype-phenotype correlations and genotype-specific approach to pharmacotherapy of these two mirror-image channelopathies, SQTS and LQTS.

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