Effects of Ranolazine on Cloned Cardiac Kv4.3 Potassium Channels

Abstract

The effects of ranolazine, an antianginal drug, on potassium channel Kv4.3 were examined by using the whole-cell patchclamp technique. Ranolazine inhibited the peak amplitude of Kv4.3 in a reversible, concentration-dependent manner with an IC 50 of 128.31 M. The activation kinetics were not significantly affected by ranolazine at concentrations up to 100 M. Applications of 10 and 30 M ranolazine had no effect on the fast and slow inactivation of Kv4.3. However, at concentrations of 100 and 300 M ranolazine caused a significant decrease in the rate of fast inactivation, and at a concentration of 300 M it caused a significant decrease in the rate of slow inactivation, resulting in a crossover of the current traces during depolarization. The Kv4.3 inhibition by ranolazine increased steeply between Ϫ20 and ϩ20 mV. In the full activation voltage range, however, no voltage-dependent inhibition was found. Ranolazine shifted the voltage dependence of the steady-state inactivation of Kv4.3 in the hyperpolarizing direction in a concentration-dependent manner. The apparent dissociation constant (K i ) for ranolazine for interacting with the inactivated state of Kv4.3 was calculated to be 0.32 M. Ranolazine produced little use-dependent inhibition at frequencies of 1 and 2 Hz. Ranolazine did not affect the time course of recovery from the inactivation of Kv4.3. The results indicated that ranolazine inhibited Kv4.3 and exhibited a low affinity for Kv4.3 channels in the closed state but a much higher affinity for Kv4.3 channels in the inactivated state.

Auxiliary KChIP4a Suppresses A-type K+ Current through Endoplasmic Reticulum (ER) Retention and Promoting Closed-state Inactivation of Kv4 Channels

“…8, D and G). Recent pharmacological studies showed that some compounds can inhibit Kv4.3 function by accelerating channel CSI, suggesting that Kv4 inhibition might result from an increased number of unavailable channels that are in closed inactivated states (41)(42)(43)(44)(45). To test the gating effect of KChIP4a, we co-expressed Kv4.3 with the KChIP4a core (KChIP4a⌬2-34) and found that preferential CSI was reduced (Fig.…”

Multitargeting in cardioprotection: An example of biaromatic compounds

“…It is possible that the cardioprotective effects of the drug are linked to its ability to inhibit Kv4.3 in the inactivated state, especially in pathologic conditions such as cardiac ischemia, where membrane potentials of myocytes are depolarized and the fraction of Kv4.3 channels in the inactivated state is abnormally high. [261] Ratel et al discovered that ranolazine acts as a suppression agent for TASK-1 potassium channels, reducing TASK-1 currents with an IC 50 of 30.6 µM when tested on mammalian cells and 198.4 µM when tested on Xenopus laevis oocytes. They determined that the inhibition of TASK-1 by ranolazine is not reliant on frequency, but is impacted by voltage, displaying a higher level of inhibition at more depolarized membrane potentials.…”

“…It is possible that the cardioprotective effects of the drug are linked to its ability to inhibit Kv4.3 in the inactivated state, especially in pathologic conditions such as cardiac ischemia, where membrane potentials of myocytes are depolarized and the fraction of Kv4.3 channels in the inactivated state is abnormally high. [ 261 ]…”