Dataset Information

The novel late Na⁺ current inhibitor, GS-6615 (eleclazine) and its anti-arrhythmic effects in rabbit isolated heart preparations.

ABSTRACT:

Background and purpose

Enhanced late Na⁺ current (late I_Na ) in the myocardium is pro-arrhythmic. Inhibition of this current is a promising strategy to stabilize ventricular repolarization and suppress arrhythmias. Here, we describe GS-6615, a selective inhibitor of late I_Na , already in clinical development for the treatment of long QT syndrome 3 (LQT3).

Experimental approach

The effects of GS-6615 to inhibit late I_Na , versus other ion currents to shorten the ventricular action potential duration (APD), monophasic APD (MAPD) and QT interval, and decrease to the incidence of ventricular arrhythmias was determined in rabbit cardiac preparations. To mimic the electrical phenotype of LQT3, late I_Na was increased using the sea anemone toxin (ATX-II).

Key results

GS-6615 inhibited ATX-II enhanced late I_Na in ventricular myocytes (IC₅₀ = 0.7 ?M), shortened the ATX-II induced prolongation of APD, MAPD, QT interval, and decreased spatiotemporal dispersion of repolarization and ventricular arrhythmias. Inhibition by GS-6615 of ATX-II enhanced late I_Na was strongly correlated with shortening of myocyte APD and isolated heart MAPD (R² = 0.94 and 0.98 respectively). In contrast to flecainide, GS-6615 had the minimal effects on peak I_Na . GS-6615 did not decrease the maximal upstroke velocity of the action potential (Vmax) nor widen QRS intervals.

Conclusions and implications

GS-6615 was a selective inhibitor of late I_Na , stabilizes the ventricular repolarization and suppresses arrhythmias in a model of LQT3. The concentrations at which the electrophysiological effects of GS-6615 were observed are comparable to plasma levels associated with QTc shortening in patients with LQT3, indicating that these effects are clinically relevant.

SUBMITTER: Rajamani S

PROVIDER: S-EPMC5056228 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Publications

The novel late Na<sup>+</sup> current inhibitor, GS-6615 (eleclazine) and its anti-arrhythmic effects in rabbit isolated heart preparations.

Rajamani Sridharan S Liu Gongxin G El-Bizri Nesrine N Guo Donglin D Li Cindy C Chen Xiao-Liang XL Kahlig Kristopher M KM Mollova Nevena N Elzein Elfatih E Zablocki Jeff J Belardinelli Luiz L

British journal of pharmacology 20160914 21

<h4>Background and purpose</h4>Enhanced late Na<sup>+</sup> current (late I<sub>Na</sub> ) in the myocardium is pro-arrhythmic. Inhibition of this current is a promising strategy to stabilize ventricular repolarization and suppress arrhythmias. Here, we describe GS-6615, a selective inhibitor of late I<sub>Na</sub> , already in clinical development for the treatment of long QT syndrome 3 (LQT3).<h4>Experimental approach</h4>The effects of GS-6615 to inhibit late I<sub>Na</sub> , versus other ion ...[more]

PMID: 27449698

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