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The physiological role of cardiac late Na + current ( I Na ) has not been well described. In this study, we tested the hypothesis that selective inhibition of physiological late I Na abbreviates the normal action potential (AP) duration (APD) and counteracts the prolongation of APD and arrhythmic activities caused by inhibition of the delayed rectifier K + current ( I Kr ). The effects of GS-458967 (GS967) on the physiological late I Na and APs in rabbit isolated ventricular myocytes and on the monophasic APs and arrhythmias in rabbit isolated perfused hearts were determined. In ventricular myocytes, GS967 and, for comparison, tetrodotoxin concentration dependently decreased the physiological late I Na with IC 50 values of 0.5 and 1.9 µM, respectively, and significantly shortened the APD measured at 90% repolarization (APD 90 ). A strong correlation between inhibition of the physiological late I Na and shortening of APD by GS967 or tetrodotoxin ( R 2 of 0.96 and 0.97, respectively) was observed. Pretreatment of isolated myocytes or hearts with GS967 (1 µM) significantly shortened APD 90 and monophasic APD 90 and prevented the prolongation and associated arrhythmias caused by the I Kr inhibitor E4031 (1 µM). In conclusion, selective inhibition of physiological late I Na shortens the APD, stabilizes ventricular repolarization, and decreases the proarrhythmic potential of pharmacological agents that slow ventricular repolarization. Thus, selective inhibition of late I Na may constitute a generalizable approach to stabilize ventricular repolarization and suppress arrhythmogenicity associated with conditions whereby AP or QT intervals are prolonged. NEW & NOTEWORTHY The contribution of physiological late Na + current in action potential duration (APD) of rabbit cardiac myocytes was estimated. The inhibition of this current prevented the prolongation of APD in rabbit cardiac myocytes, the prolongation of monophasic APD, and generation of arrhythmias in rabbit isolated hearts caused by delayed rectifier K + current inhibition.

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 (IC 50  = 0.7 μM), 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 (R 2  = 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., (© 2016 The British Pharmacological Society.)

The treatment of heart failure (HF) is challenging and morbidity and mortality are high. The goal of this study was to determine if inhibition of the late Na(+) current with ranolazine during early hypertensive heart disease might slow or stop disease progression. Spontaneously hypertensive rats (aged 7 mo) were subjected to echocardiographic study and then fed either control chow (CON) or chow containing 0.5% ranolazine (RAN) for 3 mo. Animals were then restudied, and each heart was removed for measurements of t-tubule organization and Ca(2+) transients using confocal microscopy of the intact heart. RAN halted left ventricular hypertrophy as determined from both echocardiographic and cell dimension (length but not width) measurements. RAN reduced the number of myocytes with t-tubule disruption and the proportion of myocytes with defects in intracellular Ca(2+) cycling. RAN also prevented the slowing of the rate of restitution of Ca(2+) release and the increased vulnerability to rate-induced Ca(2+) alternans. Differences between CON- and RAN-treated animals were not a result of different expression levels of voltage-dependent Ca(2+) channel 1.2, sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a, ryanodine receptor type 2, Na(+)/Ca(2+) exchanger-1, or voltage-gated Na(+) channel 1.5. Furthermore, myocytes with defective Ca(2+) transients in CON rats showed improved Ca(2+) cycling immediately upon acute exposure to RAN. Increased late Na(+) current likely plays a role in the progression of cardiac hypertrophy, a key pathological step in the development of HF. Early, chronic inhibition of this current slows both hypertrophy and development of ultrastructural and physiological defects associated with the progression to HF.

Inhibition of cardiac late sodium current (late I(Na)) is a strategy to suppress arrhythmias and sodium-dependent calcium overload associated with myocardial ischemia and heart failure. Current inhibitors of late I(Na) are unselective and can be proarrhythmic. This study introduces GS967 (6-[4-(trifluoromethoxy)phenyl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine), a potent and selective inhibitor of late I(Na), and demonstrates its effectiveness to suppress ventricular arrhythmias. The effects of GS967 on rabbit ventricular myocyte ion channel currents and action potentials were determined. Anti-arrhythmic actions of GS967 were characterized in ex vivo and in vivo rabbit models of reduced repolarization reserve and ischemia. GS967 inhibited Anemonia sulcata toxin II (ATX-II)-induced late I(Na) in ventricular myocytes and isolated hearts with IC(50) values of 0.13 and 0.21 µM, respectively. Reduction of peak I(Na) by GS967 was minimal at a holding potential of -120 mV but increased at -80 mV. GS967 did not prolong action potential duration or the QRS interval. GS967 prevented and reversed proarrhythmic effects (afterdepolarizations and torsades de pointes) of the late I(Na) enhancer ATX-II and the I(Kr) inhibitor E-4031 in isolated ventricular myocytes and hearts. GS967 significantly attenuated the proarrhythmic effects of methoxamine+clofilium and suppressed ischemia-induced arrhythmias. GS967 was more potent and effective to reduce late I(Na) and arrhythmias than either flecainide or ranolazine. Results of all studies and assays of binding and activity of GS967 at numerous receptors, transporters, and enzymes indicated that GS967 selectively inhibited late I(Na). In summary, GS967 selectively suppressed late I(Na) and prevented and/or reduced the incidence of experimentally induced arrhythmias in rabbit myocytes and hearts.

Ranolazine, an anti-anginal drug, reduces neuropathic and inflammatory-induced allodynia in rats. However, the mechanism of ranolazin's anti-allodynic effect is not known. We hypothesized that ranolazine would reduce dorsal root ganglion (DRG) Na(+) current (I(Na)) and neuronal firing by stabilizing Na(+) channels in inactivated states to cause voltage- and frequency-dependent block. Therefore, we investigated the effects of ranolazine on tetrodotoxin-sensitive (TTXs) and tetrodotoxin-resistant (TTXr) I(Na) and action potential parameters of small diameter DRG neurons from embryonic rats. Ranolazine (10 and 30 μM) significantly reduced the firing frequency of evoked action potentials in DRG neurons from 19.2 ± 1.4 to 9.8 ± 2.7 (10 μM) and 5.7 ± 1.3 (30 μM) Hz at a resting membrane potential of -40 mV. Ranolazine blocked TTXs and TTXr in a voltage- and frequency-dependent manner. Furthermore, ranolazine (10 μM) blocked hNa(v)1.3 (expressed in HEK293 cells) and caused a hyperpolarizing shift in the voltage dependence of steady-state intermediate and slow inactivation Na(v)1.3 current. Taken together, the results suggest that ranolazine suppresses the hyperexcitability of DRG neurons by interacting with the inactivated states of Na(+) channels and these actions may contribute to its anti-allodynic effect in animal models of neuropathic pain., (Copyright © 2012 Elsevier Ltd. All rights reserved.)