n-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine and Atrial-Fibrillation

Dose is an important parameter in terms of both efficacy and adverse effects in pharmacological treatment of atrial fibrillation (AF). Both of the class III antiarrhythmics dofetilide and amiodarone have documented anti-AF effects. While dofetilide has dose-related ventricular side effects, amiodarone primarily has adverse non-cardiac effects. Pharmacological inhibition of small conductance Ca

Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Drug Synergism; Guinea Pigs; Heart; Heart Rate; Isolated Heart Preparation; Phenethylamines; Potassium Channel Blockers; Pyridines; Small-Conductance Calcium-Activated Potassium Channels; Sulfonamides; Thiazoles

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.. 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.. 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.

Topics: 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