Block of HERG-carried K+ currents by the new repolarization delaying agent H 345/52.
BACKGROUND
The aim of this study was to analyze the block of HERG-carried membrane currents caused by H 345/52, a new antiarrhythmic compound with low proarrhythmic activity, in transfected mouse fibroblasts.


RESULTS
Using the whole-cell configuration of the voltage patch clamp technique, it was demonstrated that H 345/52 concentration-dependently blocked HERG-carried currents with an IC50 of 230 nM. H 345/52 preferentially bound to the open channel with unusually rapid kinetics and was trapped by channel closure. Voltage-independent behavior of H 345/52 was observed during both square-pulse and action potential clamp protocols. In contrast, the Class III agents dofetilide (10 nM) and almokalant (250 nM) demonstrated significant membrane potential-dependent effects during square-pulse clamp protocols. When using action potential clamp protocols, voltage dependence was seen with dofetilide but not with almokalant. Mathematical simulations of human ventricular action potentials predicted that the different voltage-dependent behaviors would not produce marked variations in action potential duration prolongation patterns.


CONCLUSIONS
We propose that block of IKr is the principal mechanism by which H 345/52 delays repolarization in human myocardium. The voltage independence of HERG/IKr block is unlikely to underlie the low proarrhythmic potential, and ancillary effects on other membrane currents must be considered.
Amos
Gregory J
GJ
AstraZeneca Research & Development Mölndal, Integrative Pharmacology, Mölndal, Sweden.
Jacobson
Ingemar
I
Duker
Göran
G
Carlsson
Leif
L
D000200:Action Potentials / Q000187:drug effects; D000473:Alkanes / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D027682:Cation Transport Proteins; D002460:Cell Line; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D006321:Heart / Q000502:physiology; D006801:Humans; D020128:Inhibitory Concentration 50; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D023421:Models, Animal; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D024642:Potassium Channels, Voltage-Gated; D011237:Predictive Value of Tests; D011412:Propanolamines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
C423187:3,7-diazabicyclo(3.3.1)nonane-3-carboxylic acid, 7-((2S)3-(4-cyanophenoxy)-2-hydroxypropyl)-1,1-dimethylethyl ester; D000473:Alkanes; D000889:Anti-Arrhythmia Agents; D001643:Bridged Bicyclo Compounds; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011412:Propanolamines; D013449:Sulfonamides; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C074334:almokalant; C063533:dofetilide