Small-conductance calcium-activated potassium (SK) channels contribute to action potential repolarization in human atria.

Lasse Skibsbye, Claire Poulet, Jonas Goldin Diness, Bo Hjorth Bentzen, Lei Yuan, Utz Kappert, Klaus Matschke, Erich Wettwer, Ursula Ravens, Morten Grunnet, Torsten Christ, Thomas Jespersen

Journal: Cardiovascular research 2015;103(1):156-67

PMID: 24817686

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Abstract

AIMS

Small-conductance calcium-activated potassium (SK) channels are expressed in the heart of various species, including humans. The aim of the present study was to address whether SK channels play a functional role in human atria.

METHODS AND RESULTS

Quantitative real-time PCR analyses showed higher transcript levels of SK2 and SK3 than that of the SK1 subtype in human atrial tissue. SK2 and SK3 were reduced in chronic atrial fibrillation (AF) compared with sinus rhythm (SR) patients. Immunohistochemistry using confocal microscopy revealed widespread expression of SK2 in atrial myocytes. Two SK channel inhibitors (NS8593 and ICAGEN) were tested in heterologous expression systems revealing ICAGEN as being highly selective for SK channels, while NS8593 showed less selectivity for these channels. In isolated atrial myocytes from SR patients, both inhibitors decreased inwardly rectifying K(+) currents by ∼15% and prolonged action potential duration (APD), but no effect was observed in myocytes from AF patients. In trabeculae muscle strips from right atrial appendages of SR patients, both compounds increased APD and effective refractory period, and depolarized the resting membrane potential, while only NS8593 induced these effects in tissue from AF patients. SK channel inhibition did not alter any electrophysiological parameter in human interventricular septum tissue.

CONCLUSIONS

SK channels are present in human atria where they participate in repolarization. SK2 and SK3 were down-regulated and had reduced functional importance in chronic AF. As SK current was not found to contribute substantially to the ventricular AP, pharmacological inhibition of SK channels may be a putative atrial-selective target for future antiarrhythmic drug therapy.

Address: Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.; Department of Pharmacology and Toxicology, Medical Faculty, Technical University Dresden, Dresden, Germany.; Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark Acesion Pharma ApS, Ole Maaløes Vej 3, Copenhagen DK-2200, Denmark.; Clinic for Cardiac Surgery, Heart Center Dresden, Medical Faculty, Dresden University of Technology, Dresden, Germany.; Acesion Pharma ApS, Ole Maaløes Vej 3, Copenhagen DK-2200, Denmark [email protected].; Department of Pharmacology and Toxicology, Medical Faculty, Technical University Dresden, Dresden, Germany Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

DOI: 10.1093/cvr/cvu121

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MeSH Terms: 1-Naphthylamine, Action Potentials, Atrial Fibrillation, Heart Atria, Heart Ventricles, Humans, Membrane Potentials, Myocardium, Myocytes, Cardiac, Pyridines, RNA, Messenger, Small-Conductance Calcium-Activated Potassium Channels, Thiazoles