I_Kr-blockers prolong the action potential duration (APD) in a reverse frequency-dependent manner and may induce arrhythmias including torsades des pointes in the ventricle. Meanwhile, the I_Kr-blocker dofetilide has been authorized for treating atrial arrhythmias including fibrillation. There are, however, a limited number of studies on the action of I_Kr-blockers on atrial action potential. When we tested a mathematical model of the human atrial action potential (Courtemanche et al. 1998) to examine the effects of dofetilide-type I_Kr-blockade, this model could not reproduce the reverse-frequent nature of I_Kr-blockade on atrial APD. Accordingly, we modified the model by introducing a slow I_Ks activation parameter. In this case, as the slow time constant was increased dofetilide-type blockade induced more prominent reverse frequency-dependent APD elongation. Using the modified model, we also examined the effects of two more types of I_Kr-blockade similar to those of quinidine and vesnarinone. Both drugs show voltage- and time-dependent block of I_Kr though the onset of inhibition by quinidine is much faster than that of 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 elongation of APD which was similar to the effect of dofetilide-type, while vesnarinone-type did not. This 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 voltage- and time-dependence of I_Kr-blockade by drugs may be critical for the phenotype of drug-effect on atrial action potential.