Pharmacological activation of IKr impairs conduction in guinea pig hearts.
BACKGROUND
The hERG (Kv11.1) potassium channel underlies cardiac I(Kr) and is important for cardiac repolarization. Recently, hERG agonists have emerged as potential antiarrhythmic drugs. As modulation of outward potassium currents has been suggested to modulate cardiac conduction, we tested the hypothesis that pharmacological activation of I(Kr) results in impaired cardiac conduction.


RESULTS
Cardiac conduction was assessed in Langendorff-perfused guinea pig hearts. Application of the hERG agonist NS3623 (10 microM) prolonged the QRS rate dependently. A significant prolongation (16 +/- 6%) was observed at short basic cycle length (BCL 90 ms) but not at longer cycle lengths (BCL 250 ms). The effect could be reversed by the I(Kr) blocker E4031 (1 microM). While partial I(Na) inhibition with flecainide (1 microM) alone prolonged the QRS (34 +/- 3%, BCL 250 ms), the QRS was further prolonged by 19 +/- 2% when NS3623 was added in the presence of flecainide. These data suggest that the effect of NS3623 was dependent on sodium channel availability. Surprisingly, in the presence of the voltage sensitive dye di-4-ANEPPS a similar potentiation of the effect of NS3623 was observed. With di-4-ANEPPS, NS3623 prolonged the QRS significantly (26 +/- 4%, BCL 250 ms) compared to control with a corresponding decrease in conduction velocity.


CONCLUSIONS
Pharmacological activation of I(Kr) by the hERG agonist NS3623 impairs cardiac conduction. The effect is dependent on sodium channel availability. These findings suggest a role for I(Kr) in modulating cardiac conduction and may have implications for the use of hERG agonists as antiarrhythmic drugs.
Larsen
Anders Peter
AP
Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Olesen
Søren-Peter
SP
Grunnet
Morten
M
Poelzing
Steven
S
D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002304:Cardiac Pacing, Artificial; D051638:Ether-A-Go-Go Potassium Channels / Q000819:agonists* / Q000378:metabolism; D005424:Flecainide / Q000494:pharmacology; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D010477:Perfusion; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013777:Tetrazoles / Q000009:adverse effects / Q000494:pharmacology*; D013997:Time Factors; D056969:Voltage-Sensitive Dye Imaging
D000889:Anti-Arrhythmia Agents; D051638:Ether-A-Go-Go Potassium Channels; C423868:NS 3623; D010671:Phenylurea Compounds; D010880:Piperidines; D026902:Potassium Channel Blockers; D011725:Pyridines; D026941:Sodium Channel Blockers; D013777:Tetrazoles; C063968:E 4031; D005424:Flecainide; D011188:Potassium