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Allosteric Modulation of K(v)11.1 (hERG) Channels Protects Against Drug-Induced Ventricular Arrhythmias
- Source :
- Circulation: Arrhythmia and Electrophysiology, 9(4)
- Publication Year :
- 2016
-
Abstract
- Background— Ventricular arrhythmias as a result of unintentional blockade of the K v 11.1 (hERG [human ether-à-go-go–related gene]) channel are a major safety concern in drug development. In past years, several highly prescribed drugs have been withdrawn for their ability to cause such proarrhythmia. Here, we investigated whether the proarrhythmic risk of existing drugs could be reduced by K v 11.1 allosteric modulators. Methods and Results— Using [ 3 H]dofetilide-binding assays with membranes of human K v 11.1-expressing human embryonic kidney 293 cells, 2 existing compounds (VU0405601 and ML-T531) and a newly synthesized compound (LUF7244) were found to be negative allosteric modulators of dofetilide binding to the K v 11.1 channel, with LUF7244 showing the strongest effect at 10 μmol/L. The K v 11.1 affinities of typical blockers (ie, dofetilide, astemizole, sertindole, and cisapride) were significantly decreased by LUF7244. Treatment of confluent neonatal rat ventricular myocyte (NRVM) monolayers with astemizole or sertindole caused heterogeneous prolongation of action potential duration and a high incidence of early afterdepolarizations on 1-Hz electric point stimulation, occasionally leading to unstable, self-terminating tachyarrhythmias. Pretreatment of NRVMs with LUF7244 prevented these proarrhythmic effects. NRVM monolayers treated with LUF7244 alone displayed electrophysiological properties indistinguishable from those of untreated NRVM cultures. Prolonged exposure of NRVMs to LUF7244 or LUF7244 plus astemizole did not affect their viability, excitability, and contractility as assessed by molecular, immunological, and electrophysiological assays. Conclusions— Allosteric modulation of the K v 11.1 channel efficiently suppresses drug-induced ventricular arrhythmias in vitro by preventing potentially arrhythmogenic changes in action potential characteristics, raising the possibility to resume the clinical use of unintended K v 11.1 blockers via pharmacological combination therapy.
- Subjects :
- 0301 basic medicine
ERG1 Potassium Channel
cell culture techniques
cardiac
hERG
Allosteric regulation
cardiotoxicity
subfamily H
Dofetilide
030204 cardiovascular system & hematology
Pharmacology
member 2
Afterdepolarization
Contractility
radioligand assay
03 medical and health sciences
0302 clinical medicine
Sertindole
Allosteric Regulation
Physiology (medical)
medicine
Animals
Humans
Myocytes, Cardiac
Cells, Cultured
potassium voltage-gated channel
Proarrhythmia
biology
business.industry
Reverse Transcriptase Polymerase Chain Reaction
voltage-sensitive dye imaging
Gene Expression Regulation, Developmental
myocytes
medicine.disease
Immunohistochemistry
Ether-A-Go-Go Potassium Channels
Rats
Disease Models, Animal
030104 developmental biology
Astemizole
Animals, Newborn
biology.protein
Tachycardia, Ventricular
RNA
Cardiology and Cardiovascular Medicine
business
Anti-Arrhythmia Agents
arrhythmias
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Circulation: Arrhythmia and Electrophysiology, 9(4)
- Accession number :
- edsair.doi.dedup.....5074b4ccec0ff52981699a66623bb4f5