Inhibition of voltage-gated Na+ currents by eleclazine in rat atrial and ventricular myocytes

Abstract

Background Atrial-ventricular differences in voltage-gated Na + currents might be exploited for atrial-selective antiarrhythmic drug action for the suppression of atrial fibrillation without risk of ventricular tachyarrhythmia. Eleclazine (GS-6615) is a putative antiarrhythmic drug with properties similar to the prototypical atrial-selective Na + channel blocker ranolazine that has been shown to be safe and well tolerated in patients. Objective The present study investigated atrial-ventricular differences in the biophysical properties and inhibition by eleclazine of voltage-gated Na + currents. Methods The fast and late components of whole-cell voltage-gated Na + currents (respectively, I Na and I NaL ) were recorded at room temperature (∼22°C) from rat isolated atrial and ventricular myocytes. Results Atrial I Na activated at command potentials ∼5.5 mV more negative and inactivated at conditioning potentials ∼7 mV more negative than ventricular I Na . There was no difference between atrial and ventricular myocytes in the eleclazine inhibition of I NaL activated by 3 nM ATX-II (IC 50 s ∼200 nM). Eleclazine (10 μM) inhibited I Na in atrial and ventricular myocytes in a use-dependent manner consistent with preferential activated state block. Eleclazine produced voltage-dependent instantaneous inhibition in atrial and ventricular myocytes; it caused a negative shift in voltage of half-maximal inactivation and slowed the recovery of I Na from inactivation in both cell types. Conclusions Differences exist between rat atrial and ventricular myocytes in the biophysical properties of I Na . The more negative voltage dependence of I Na activation/inactivation in atrial myocytes underlies differences between the 2 cell types in the voltage dependence of instantaneous inhibition by eleclazine. Eleclazine warrants further investigation as an atrial-selective antiarrhythmic drug.

Delayed Ventricular Repolarization and Sodium Channel Current Modification in a Mouse Model of Rett Syndrome

“…A previous study included limited data on fast I Na amplitude at a single test voltage, under recording conditions that were optimised for I Na,Late , but not for fast I Na [ 18 ] and saw no difference in current amplitude. In contrast, our experiments, performed under conditions that facilitate accurate recording of fast I Na [ 32 , 33 , 34 ], revealed significant reductions in I Na amplitude over the voltage range that encompassed maximal I Na magnitude, without any significant alteration to voltage dependent activation V 0.5 and with only a modest effect on the slope of voltage-dependent inactivation ( Figure 4 and Figure 5 ). The reduction in I Na amplitude may help explain QRS complex widening in the Mecp2 Null/Y mouse ECG.…”

“…McCauley et al suggested there is little difference in I Na between the strains, but that was based on measurements from the fast current component under conditions optimised for I Na,Late [ 18 ]. The speed and amplitude of I Na make accurate voltage clamp of the current difficult with high [Na + ] o and cardiac I Na measurement is facilitated by a combination of the use of low [Na + ] o to reduce I Na amplitude and experimentation at room temperature (e.g., [ 32 , 33 , 34 ]). Accordingly, measurements of I Na were made at room temperature with pipette and external solutions giving rise to symmetrical 5 mM [Na + ] (see Methods).…”

“…Recovery from inactivation time-course was quantified through biexponential fitting (Equation (7), Methods). Figure 5 D shows mean recovery time-course data, plotted on a logarithmic time-scale (data from eight cells from four mice for each of WT and Mecp2 Null/Y conditions are plotted) [ 34 ]. The fast time constant of recovery from inactivation (τ fast ) was 11.0 ± 0.7 ms for WT I Na and 8.6 ± 0.2 ms for Mecp2 Null/Y I Na ( p < 0.05), whilst the slow time constant of recovery from inactivation (τ Slow ) was 362.0 ± 53.4 ms for WT I Na and 311.5 ± 50.2 ms for Mecp2 Null/Y I Na (no significant difference).…”

The Antidepressant Paroxetine Reduces the Cardiac Sodium Current

“…The concentration of 3 µM was chosen because it gave rise to a considerable amount of changes in NaV1.5 current in voltage clamp experiments on HEK-293 cells (Figures 1-3) without too extreme effects that might prevent excitability of cardiomyocytes completely. Figure 4a shows typical AP recordings Many NaV1.5 current inhibitors-including, for example, methylflavonolamine and lidocaine [36], hesperetin [37], eleclazine [38], carbamazepine [39], mexiletine [40], and aripiprazole [41]-generate a shift in steady-state inactivation to more negative potentials (as shown for paroxetine in Figure 2c,d) that is accompanied by a slowing of recovery from inactivation. Under close-to-physiological conditions, i.e., at a potential of −85 mV and 37 °C [35], recovery from inactivation of the sodium current in cardiomyocytes is not fully complete within 1 s, which explains why the maximum AP upstroke velocity at a pacing frequency of 3 Hz is smaller than at 1 Hz under control conditions (Figure 5a, gray lines; Figure 5b, gray bars).…”