Blockade of I_Ks causes frequency-independent APD prolongation in guinea pig ventricular myocytes, whereas it shows reverse frequency dependence in rabbit myocytes.
Does blockade of I_Ks or I_Kr affect action potential duration differently at high heart rates in guinea pig versus rabbit ventricular myocytes?
The density and kinetics of delayed rectifier K+ current components explain why I_Ks blockade is more effective at high heart rates in guinea pig ventricles compared to rabbits, providing mechanistic insights for developing antiarrhythmic agents.
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.
Lu et al. (Tue,) reported a other. Blockade of I_Ks (chromanol 293B) and I_Kr (E-4031) was evaluated on Action potential duration (APD) prolongation at different heart rates. Blockade of I_Ks causes frequency-independent APD prolongation in guinea pig ventricular myocytes, whereas it shows reverse frequency dependence in rabbit myocytes.