Density and Kinetics of IKr and IKs in Guinea Pig and Rabbit Ventricular Myocytes Explain Different Efficacy of IKs Blockade at High Heart Rate in Guinea Pig and Rabbit: Implications for Arrhythmogenesis in Humans

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 (IK) 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, IKr and IKs, in rabbit and guinea pig ventricular myocytes. The effects of their specific blockers (chromanol 293B for IKs and E-4031 for IKr) 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 IKs causes APD prolongation in a frequency-independent manner, whereas blockade of IKs in rabbit ventricular myocytes shows reverse frequency dependence, as does blockade of IKr in both species. This result can be explained primarily by the higher density of IKs in guinea pig ventricle and by its slow deactivation kinetics, which allows IKs 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 IK explain why blockade of IKs is more effective at high heart rate in the guinea pig ventricle than in the rabbit ventricle, without adverse effects at low heart rate.

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