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

Abstract

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.