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. When we tested a mathematical model of the human atrial AP (M Courtemanche, RJ Ramirez, S Nattel. Am J Physiol Heart Circ Physiol 275: H301-H321, 1998) to examine the effects of dofetilide-type I-Kr blockade, this model could not reproduce the reverse-frequency-dependent nature of I-Kr blockade on atrial APD. We modified the model by introducing a slowly activating K+ current activation parameter. As the slow time constant was increased, dofetilide-type blockade induced more prominent reverse-frequency-dependent APD prolongation. Using the modified model, we also examined the effects of two more types of I-Kr blockade similar to those of quinidine and vesnarinone. Voltage-and time-dependent block of I-Kr through the onset of inhibition by quinidine is much faster than by vesnarinone. When we incorporated the kinetics of the effects of these drugs on I-Kr into the model, we found that quinidine-type blockade caused a reverse-frequency-dependent prolongation of APD that was similar to the effect of dofetilide-type blockade, whereas vesnarinone-type blockade did not. This finding coincides with experimental observations. The lack of the reverse frequency dependence in vesnarinone-type blockade was accounted for by the slow development of I-Kr blockade at depolarized potentials. These results suggest that the voltage-and time-dependent nature of I-Kr blockade by drugs may be critical for the phenotype of the drug effect on atrial AP.