ns-1643 and Arrhythmias--Cardiac

Impaired ventricular repolarization can lead to long QT syndrome (LQT), a proarrhythmic disease with high risk of developing lethal ventricular tachyarrhythmias. The compound ICA-105574 is a recently developed hERG activator and it enhances IKr current with very high potency by removing the channel inactivation. The present study was designed to investigate antiarrhythmic properties of ICA-105574. For comparison, the effects of another compound NS1643 was in-parallel assessed, which also acts primarily to attenuate channel inactivation with moderate potency. We found that both ICA-105574 and NS1643 concentration-dependently shortened action potential duration (APD) in ventricular myocytes, and QT/QTc intervals in isolated guinea-pig hearts. ICA-105574, but not NS1643, completely prevented ventricular arrhythmias in intact guinea-pig hearts caused by IKr and IKs inhibitors, although both ICA-105574 and NS1643 could reverse the drug-induced prolongation of APD in ventricular myocytes. Reversing prolongation of QT/QTc intervals and antagonizing the increases in transmural dispersion of repolarization and instability of the QT interval induced by IKr and IKs inhibitors contributed to antiarrhythmic effect of ICA-105574. Meanwhile, ICA-105574 at higher concentrations showed a potential proarrhythmic risk in normal hearts. Our results suggest that ICA-105574 has more efficient antiarrhythmic activity than NS1643. However, its potential proarrhythmic risk implies that benefits and risks should be seriously taken into consideration for further developing this type of hERG activators.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Benzamides; Cresols; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Guinea Pigs; HEK293 Cells; Humans; Male; Myocardium; Perfusion; Phenylurea Compounds

We explored the anti-arrhythmic efficacy of K(+) channel activation in the hypokalaemic murine heart using NS1643 and nicorandil, compounds which augment I(Kr) and I(KATP) respectively.. Left ventricular epicardial and endocardial monophasic action potentials were compared in normokalaemic and hypokalaemic preparations in the absence and presence of NS1643 (30 microM) and nicorandil (20 microM).. Spontaneously beating hypokalaemic hearts (3 mM K(+)) all elicited early afterdepolarizations (EADs) and episodes of ventricular tachycardia (VT). Perfusion with NS1643 and nicorandil suppressed EADs and VT in 7 of 13 and five of six hypokalaemic hearts. Provoked arrhythmia studies using programmed electrical stimulation induced VT in all hypokalaemic hearts, but failed to do so in 7 of 13 and five of six hearts perfused with NS1643 and nicorandil respectively. These anti-arrhythmic effects were accompanied by reductions in action potential duration at 90% repolarization (APD(90)) and changes in the transmural gradient of repolarization, reflected in DeltaAPD(90). NS1643 and nicorandil reduced epicardial APD(90) from 68.3 +/- 1.1 to 56.5 +/- 4.1 and 51.5 +/- 1.5 ms, respectively, but preserved endocardial APD(90) in hypokalaemic hearts. NS1643 and nicorandil thus restored DeltaAPD(90) from -9.6 +/- 4.3 ms under baseline hypokalaemic conditions to 3.9 +/- 4.1 and 9.9 +/- 2.1 ms, respectively, close to normokalaemic values.. These findings demonstrate, for the first time, the anti-arrhythmic efficacy of K(+) channel activation in the setting of hypokalaemia. NS1643 and nicorandil are anti-arrhythmic through the suppression of EADs, reductions in APD(90) and restorations of DeltaAPD(90).

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cresols; Electric Stimulation; Female; Heart; Hypokalemia; Ion Channel Gating; Male; Mice; Nicorandil; Organ Culture Techniques; Phenylurea Compounds; Potassium Channels

Dysfunction or pharmacologic inhibition of repolarizing cardiac ionic currents can lead to fatal arrhythmias. The hERG potassium channel underlies the repolarizing current I(Kr), and mutations therein can produce both long and short QT syndromes (LQT2 and SQT1). We previously reported on the diphenylurea compound NS1643, which acts on hERG channels in two distinct ways: by increasing overall conductance and by shifting the inactivation curve in the depolarized direction.. The purpose of this study was to determine which of the two components contributes more to the antiarrhythmic effects of NS1643 under normokalemic and hypokalemic conditions.. The study consisted of mathematical simulation of action potentials in a human ventricular ionic cell model in single cell and string of 100 cells.. Regardless of external potassium concentration or diastolic interval used, NS1643 decreases action potential duration and triangulation. For single cells, NS1643 increases the postrepolarization refractory time but shortens the absolute refractory period. In one dimensional simulations, NS1643 increases the vulnerable window for unidirectional block but suppresses the emergence of premature action potentials and unidirectional blocks around APD(90). During normokalemia, shifting the inactivation curve has greater impact than increasing conductance, whereas the opposite occurs during hypokalemia.. Increased hERG conductance and the depolarizing shift of the inactivation curve both contribute to the antiarrhythmic actions of NS1643, with relative effects dependent on external K(+) concentration.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cresols; Ether-A-Go-Go Potassium Channels; Humans; Hyperkalemia; Models, Theoretical; Phenylurea Compounds; Potassium