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(Circulation. 2001;104:951.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Density and Kinetics of I_Kr and I_Ks in Guinea Pig and Rabbit Ventricular Myocytes Explain Different Efficacy of I_Ks Blockade at High Heart Rate in Guinea Pig and Rabbit

Implications for Arrhythmogenesis in Humans

Zhibo Lu, MD; Kaichiro Kamiya, MD; Tobias Opthof, PhD; Kenji Yasui, MD; Itsuo Kodama, MD

From the Department of Circulation, Division of Regulation of Organ Function, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan (Z.L., K.K., K.Y., I.K.), and the Department of Medical Physiology, University Medical Center Utrecht, Utrecht, Netherlands (T.O.).

Correspondence to Kaichiro Kamiya, Department of Circulation, Division of Regulation of Organ Function, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan. E-mail kamiya{at}riem.nagoya-u.ac.jp

Background—— Class III antiarrhythmic agents commonly exhibit reverse frequency-dependent prolongation of the action potential duration (APD). This is undesirable because of the danger of bradycardia-related arrhythmias and the limited protection against ventricular tachyarrhythmias. The effects of blockade of separate components of delayed rectifier K⁺ current (I_K) may help to develop agents effective at high heart rate.

Methods and Results—— We assessed the density and kinetics of the 2 components of the delayed rectifier K⁺ current, I_Kr and I_Ks, in rabbit and guinea pig ventricular myocytes. The effects of their specific blockers (chromanol 293B for I_Ks and E-4031 for I_Kr) on the action potential was studied at different heart rates by use of whole-cell patch-clamp techniques. In guinea pig ventricular myocytes only, blockade of I_Ks causes APD prolongation in a frequency-independent manner, whereas blockade of I_Ks in rabbit ventricular myocytes shows reverse frequency dependence, as does blockade of I_Kr in both species. This result can be explained primarily by the higher density of I_Ks in guinea pig ventricle and by its slow deactivation kinetics, which allows I_Ks to accumulate at high heart rate because little time is available for complete deactivation of it during diastole.

Conclusions—— Density and kinetics of components of I_K explain why blockade of I_Ks is more effective at high heart rate in the guinea pig ventricle than in the rabbit ventricle, without adverse effects at low heart rate.

Key Words: potassium • ion channels • antiarrhythmia agents • action potentials

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