title: Frequency-dependent effects of various IKr blockers on cardiac action potential duration in a human atrial model.
abstract: 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.
authors.affiliation: Division of Molecular and Cellular Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tsujimae
authors.forename: Shingo
authors.initials: S
authors.lastname: Suzuki
authors.forename: Shingo
authors.initials: S
authors.lastname: Murakami
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kurachi
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D016275:Atrial Function / Q000187:drug effects / Q000502:physiology*; D003198:Computer Simulation; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008955:Models, Cardiovascular; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000008:administration & dosage*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*
chemical_list: D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011188:Potassium