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This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/H793    most recent 01229.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Tsujimae, K. Articles by Kurachi, Y. PubMed PubMed Citation Articles by Tsujimae, K. Articles by Kurachi, Y.

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

¹Division of Molecular and Cellular Pharmacology, Department of Pharmacology, Graduate School of Medicine, and ²The Center for Advanced Medical Engineering and Informatics, Osaka University, Osaka, Japan

Submitted 23 October 2007 ; accepted in final form 30 November 2007

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. Several new agents that specifically block I_Kur have been developed. They block I_Kur in a voltage- and time-dependent manner. Here we use mathematical models of normal and electrically remodeled human atrial action potentials to examine the effects of the blockade kinetics of I_Kur on atrial action potential duration (APD). It was found that after AF remodeling, an I_Kur blocker with fast onset can effectively prolong APD at any stimulus frequency, whereas a blocker with slow onset prolongs APD in a frequency-dependent manner only when the recovery is slow. The results suggest that the voltage and time dependence of I_Kur blockade should be taken into account in the testing of anti-AF drugs. This modeling study suggests that a simple voltage-clamp protocol with a short pulse of 10 ms at 1 Hz may be useful to identify the effective anti-AF drugs among various I_Kur blockers.

ultrarapid-delayed rectifying potassium current; atrial action potential; computer simulation