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 ϩ 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 ϩ 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.

Mechanosensitivity of GIRK Channels Is Mediated by Protein Kinase C-dependent Channel-Phosphatidylinositol 4,5-Bisphosphate Interaction

“…Single atrial myocytes were isolated enzymatically as described previously (15). Whole cell currents were recorded in modified Tyrode solution using standard techniques.…”

Computational biology in the study of cardiac ion channels and cell electrophysiology

“…8a) (Silva & Rudy, 2005). We added a cooperative, voltage-independent transition before opening, to reproduce steady-state activation measurements (Lu et al 2001). Application of phosphatidylinositol-4,5-bisphosphate (PIP 2 ) to excised patches containing I Ks channels strongly affects their open probability, but does not change the voltage-dependent properties of the channel (Loussouarn et al 2003) indicating that PIP 2 interaction is with this voltage-independent transition [observed in Shaker K + channels as well (Koren et al 1990)].…”

Modelling conduction through the Purkinje ventricular junction and the short-QT syndrome associated with HERG mutation in the rabbit ventricles

“…The LabHEART model [12] of the rabbit ventricular AP was modified to incorporate newly available experimental data on the membrane ionic currents and transmural heterogeneity of the rabbit ventricles [13][14][15][16][17][18][19][20][21]. Densities and activation/inactivation kinetics of all the ionic currents were modified to account for the respective experimental data: fast sodium, I Na [13], L-type calcium, I CaL [14,15], transient outward, I to , and outward rectifier, I K1 [15,16], slow delayed rectifier, I Ks , and rapid delayed rectifier, I Kr [15,17,18] and calcium activated chloride current, I Cl(Ca) [19,20].…”

“…Densities and activation/inactivation kinetics of all the ionic currents were modified to account for the respective experimental data: fast sodium, I Na [13], L-type calcium, I CaL [14,15], transient outward, I to , and outward rectifier, I K1 [15,16], slow delayed rectifier, I Ks , and rapid delayed rectifier, I Kr [15,17,18] and calcium activated chloride current, I Cl(Ca) [19,20]. Transmural differences between the epi, M, and endo cells were introduced based on the experimentally reported differences in the current densities of I to , I K1 [16,21], I Ks [17] and I Cl(Ca) [20] in these three cell-types.…”