Pharmacological Activation of Rapid Delayed Rectifier Potassium Current Suppresses Bradycardia-Induced Triggered Activity in the Isolated Guinea Pig Heart
- NeuroSearch A/S, Ballerup, Denmark (R.S.H., M.G.); and Danish National Research Foundation Centre for Cardiac Arrhythmia, Panum Institute, University of Copenhagen, Copenhagen, Denmark (R.S.H., S.-P.O., M.G.R.)
- Address correspondence to:
Morten Grunnet, NeuroSearch A/S, Pederstrupvej 93, 2750 Ballerup, Denmark. E-mail: mgr{at}neurosearch.dk
Abstract
Recently, attention has been drawn to compounds that activate the human ether-a-go-go channel potassium channel (hERG), which is responsible for the repolarizing rapid delayed rectifier potassium current (IKr) in the mammalian myocardium. The compound NS3623 [N-(4-bromo-2-(1H-tetrazol-5-yl)-phenyl)-N′-(3′-trifluoromethylphenyl) urea] increases the macroscopic current conducted by the hERG channels by increasing the time constant for channel inactivation, which we have reported earlier. In vitro studies suggest that pharmacological activation is an attractive approach for the treatment of some arrhythmias. We present here data that support that NS3623 affects native IKr and report the effects that activating this potassium current have in the intact guinea pig heart. In Langendorff-perfused hearts, the compound showed a concentration-dependent shortening of action potential duration, which was also detected as concentration-dependent shorter QT intervals. There was no sign of action potential triangulation or reverse use dependence. NS3623 decreased QT variability and distinctly decreased the occurrence of extrasystoles in the acutely bradypaced hearts. Taken together, the present data strongly support the concept of using hERG activators as a treatment for certain kinds of arrhythmias and suggest further investigation of this new approach.
Footnotes
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The work was supported by The Danish National Research Foundation.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.118448.
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ABBREVIATIONS: IKr, rapid delayed rectifier potassium current; IKs, slow delayed rectifier potassium current; hERG, human ether a-go-go potassium channel; E-4031, N-(4-{1-[2-(6-methyl-pyridin-2-yl)-ethyl]-piperidine-4-carbonyl}-phenyl)-methane-sulfonamide; MK-499, (+)-N-[1′-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro(2H-1-benzopyran-2,4′-piperidin)-6-yl]methanesulfonamide] monohydrochloride; ECG, electrocardiogram; NS3623, N-(4-bromo-2-(1H-tetrazol-5-yl)-phenyl)-N′-(3′-trifluoromethylphenyl) urea; MAP, monophasic action potential; AV, atrioventricular; PVC, premature ventricular contraction; APD, action potential duration; MAPD, monophasic action potential duration; PD118057, 2-{4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid.
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- Received December 11, 2006.
- Accepted February 22, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
