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 (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 IKs 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.