Mutational analysis of block and facilitation of HERG current by a class III anti-arrhythmic agent, nifekalant.

Chemicals and toxins are useful tools to elucidate the structure-function relationship of various proteins including ion channels. The HERG channel is blocked by many compounds and this may cause life-threatening cardiac arrhythmia. Besides block, some chemicals such as the class III anti-arrhythmic agent nifekalant stimulate HERG at low potentials by shifting its activation curve towards hyperpolarizing voltages.

In silico risk assessment for drug-induction of cardiac arrhythmia.

The main components of repolarization reserve for the ventricular action potential (AP) are the rapid (I(Kr)) and slow (I(Ks)) delayed outward K(+) currents. While many drugs block I(Kr) and cause life-threatening arrhythmias including torsades de pointes, the frequency of arrhythmias varies between different I(Kr)-blockers. Different types of block of I(Kr) cause distinct phenotypes of prolongation of action potential duration (APD), increase in transmural dispersion of repolarization (TDR) and, accordingly, occurrence of torsades de pointes.

In silico study on the effects of IKur block kinetics on prolongation of human action potential after atrial fibrillation-induced electrical remodeling.

Pharmacological treatment with various antiarrhythmic agents for the termination or prevention of atrial fibrillation (AF) is not yet satisfactory. This is in part because the drugs may not be sufficiently selective for the atrium, and they often cause ventricular arrhythmias. The ultrarapid-delayed rectifying potassium current (I(Kur)) is found in the atrium but not in the ventricle, and it has been recognized as a potentially promising target for anti-AF drugs that would be without ventricular proarrhythmia.

Frequency-dependent effects of various IKr blockers on cardiac action potential duration in a human atrial model.

Rapidly activating K(+) current (I(Kr)) blockers prolong action potential (AP) duration (APD) in a reverse-frequency-dependent manner and may induce arrhythmias, including torsade de pointes in the ventricle. The I(Kr) blocker dofetilide has been approved for treatment of atrial arrhythmias, including fibrillation. There are, however, a limited number of studies on the action of I(Kr) blockers on atrial AP.

Comparison of kinetic properties of quinidine and dofetilide block of HERG channels.

Many drugs inhibit human ether-a-go-go related gene (HERG) current and prolong cardiac action potential duration. We examined the kinetic properties of quinidine block of HERG channels expressed in Xenopus oocytes in comparison with those of the block by a class III antiarrhythmic dofetilide. Both of the drugs inhibited HERG currents in a use-dependent and frequency-independent manner.