Slow Delayed Rectifier Potassium Research Articles

Sensitivity of the Slow Component of the Delayed Rectifier Potassium Current (IKs) to Potassium Channel Blockers: Implications for Clinical Reverse Use-Dependent Effects

The slow delayed rectifier potassium current (I_Ks) is unique in its slow activation and deactivation kinetics. It is important during cardiac repolarization, especially when the heart rate is fast. We compared the effects of quinidine, procainamide, sotalol, and amiodarone on I_Ks and correlated the findings with the clinical reverse use-dependent effects of potassium channel blockers. Human minK RNA was obtained by reverse transcription-polymerase chain reaction using explanted human heart. The RNA was injected into Xenopus oocytes for heterologous expression of I_Ks. A two-electrode voltage clamp technique was performed to investigate the I_Ks. We demonstrated that quinidine, sotalol and procainamide had no effects on I_Ks up to a concentration of 300 μM while amiodarone inhibited I_Ks in a concentration-dependent manner starting from 10 μM. The inhibition by amiodarone was state-dependent with gradual unblocking after depolarization. The degree of inhibition was 53% immediately after depolarization and 19% at the end of a 5-second depolarization. I_Ks is 30 times more sensitive to amiodarone than to quinidine, sotalol, and procainamide. Quinidine, sotalol and procainamide have reverse use-dependent effects while amiodarone does not. This is compatible with the hypothesis that no inhibition of I_Ks at clinical concentrations contributes to the clinical reverse use-dependent effects.

Sensitivity of the slow component of the delayed rectifier potassium current (IKs) to potassium channel blockers: implications for clinical reverse use-dependent effects.

The slow delayed rectifier potassium current (I(Ks)) is unique in its slow activation and deactivation kinetics. It is important during cardiac repolarization, especially when the heart rate is fast. We compared the effects of quinidine, procainamide, sotalol, and amiodarone on I(Ks) and correlated the findings with the clinical reverse use-dependent effects of potassium channel blockers. Human minK RNA was obtained by reverse transcription-polymerase chain reaction using explanted human heart. The RNA was injected into Xenopus oocytes for heterologous expression of I(Ks). A two-electrode voltage clamp technique was performed to investigate the I(Ks). We demonstrated that quinidine, sotalol and procainamide had no effects on I(Ks) up to a concentration of 300 microM while amiodarone inhibited I(Ks) in a concentration-dependent manner starting from 10 microM. The inhibition by amiodarone was state-dependent with gradual unblocking after depolarization. The degree of inhibition was 53% immediately after depolarization and 19% at the end of a 5-second depolarization. I(Ks) is 30 times more sensitive to amiodarone than to quinidine, sotalol, and procainamide. Quinidine, sotalol and procainamide have reverse use-dependent effects while amiodarone does not. This is compatible with the hypothesis that no inhibition of I(Ks) at clinical concentrations contributes to the clinical reverse use-dependent effects.

Role of multiple calcium and calcium-dependent conductances in regulation of hippocampal dentate granule cell excitability.

We have constructed a detailed model of a hippocampal dentate granule (DG) cell that includes nine different channel types. Channel densities and distributions were chosen to reproduce reported physiological responses observed in normal solution and when blockers were applied. The model was used to explore the contribution of each channel type to spiking behavior with particular emphasis on the mechanisms underlying postspike events. T-type calcium current in more distal dendrites contributed prominently to the appearance of the depolarizing after-potential, and its effect was controlled by activation of BK-type calcium-dependent potassium channels. Coactivation and interaction of N-, and/or L-type calcium and AHP currents present in somatic and proximal dendritic regions contributed to the adaptive properties of the model DG cell in response to long-lasting current injection. The model was used to predict changes in channel densities that could lead to epileptogenic burst discharges and to predict the effect of altered buffering capacity on firing behavior. We conclude that the clustered spatial distributions of calcium related channels, the presence of slow delayed rectifier potassium currents in dendrites, and calcium buffering properties, together, might explain the resistance of DG cells to the development of epileptogenic burst discharges.