Density and kinetics of I-Kr and I-Ks in guinea pig and rabbit ventricularmyocytes explain different efficacy of I-Ks blockade at high heart rate inguinea pig and rabbit - Implications for arrhythmogenesis in humans

Background-Class III antiarrhythmic agents commonly exhibit reverse frequen cy-dependent prolongation of the action potential duration (APD). This is u ndesirable because of the danger of bradycardia-related arrhythmias and the limited protection against ventricular tachyarrhythmias. The effects of bl ockade of separate components of delayed rectifier K+ current (I-K) may hel p to develop agents effective at high heart rate. Methods and Results-We assessed the density and kinetics of the 2 component s of the delayed rectifier K+ current, I-Kr and I-Ks in rabbit and guinea p ig 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 d ifferent 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 ventricu lar myocytes shows reverse frequency dependence, as does blockade of I-Kr i n both species. This result can be explained primarily by the higher densit y of I-Ks in guinea pig ventricle and by its slow deactivation kinetics, wh ich allows I-Ks to accumulate at high heart rate because little time is ava ilable 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 th an in the rabbit ventricle, without adverse effects at low heart rate.