Role Of Late Sodium Current Research Articles

Late Sodium Current of the Heart: Where Do We Stand and Where Are We Going?

Late sodium current has long been linked to dysrhythmia and contractile malfunction in the heart. Despite the increasing body of accumulating information on the subject, our understanding of its role in normal or pathologic states is not complete. Even though the role of late sodium current in shaping action potential under physiologic circumstances is debated, it’s unquestioned role in arrhythmogenesis keeps it in the focus of research. Transgenic mouse models and isoform-specific pharmacological tools have proved useful in understanding the mechanism of late sodium current in health and disease. This review will outline the mechanism and function of cardiac late sodium current with special focus on the recent advances of the area.

GW26-e4594 Late sodium current plays a role in proarrhythmic and antiarrhythmic effects of QT prolonging drugs of multichannel blocking properties

Proarrhythmic and antiarrhythmic effects of QT prolonging drugs vary significantly. The purpose of this study was to examine the role of late sodium current as a modulator of proarrhythmic and antiarrhythmic effects of multichannel blocking drugs. New-Zealand White rabbit hearts were isolated and

Abstract 14727: Late Sodium Current Plays a Role in Ventricular Arrhythmias Associated With Increased Intracellular Calcium Concentration

Objective: An increase in intracellular calcium concentration is associated with the prolongation of action potential duration (APD) and polymorphic ventricular tachycardia (PVT). Recent studies indicated that late sodium current inhibitor is effective in preventing ventricular arrhythmias in patients with long QT syndrome 8. The objective of the study was to determine the role of late sodium current in calcium related ventricular arrhythmias. Methods: Hearts from New Zealand female rabbits were perfused in a Langendorff mode. The atrioventricular nodal area was thermally ablated to produce complete atrioventricular block, and then heart was paced at stated frequency. Multiple channel monophasic action potentials (MAP) and pseudo 12-lead electrocardiograms (ECGs) were recorded. Calcium transient and myocyte contraction were determined in rabbit ventricular myocytes. Results: Bay-K 8644 (10-300 nM) increased both epi- and endo- cardial MAPD90 of left ventricle in concentration dependent manners, from (176±6) to (222±13) ms, and (201±6) to (246±10) ms (n=15, p<0.05 vs control), respectively. In the presence of 1 nM ATX-II, Bay-K 8644 caused a greater prolongation of epi-MAPD90 which was increased from (182±6) to (342±21) ms (n=9, p<0.05 vs control). The prolongation of MAPD90 caused by Bay-K 8644 were reversed by 1 μM TTX in both absence and presence of ATX-II. Additionally, the incidence of PVT evoked by Bay-K 8644 was also greater in the presence compared to the absence of ATX-II. 200 nM Bay-K 8644 caused few arrhythmias in absence of ATX-II. In contrast, PVT occurred in 7/9 (77.78%) of hearts treated with 200 nM Bay-K 8644 in the presence of ATX-II. These arrhythmias could be abolished by 1 μM TTX in the continued presence of Bay-K 8644. TTX (1 μM) attenuated the increase by 200 nM Bay-K 8644 of intracellular calcium transient and myocyte contraction amplitude by 10.8% and 14.6%, respectively (n=6, p<0.05). Conclusion: Both endogenous and enhanced late sodium current contributes to the ventricular arrhythmias with increased intracellular calcium concentration. Inhibition of late sodium current may be effective in preventing or treating calcium overload-related ventricular arrhythmias and dysfunction of myocardial contraction.

GW25-e3563 Role of late sodium current in ventricular arrhythmias caused by increased intracellular calcium concentration

GW25-e3563 Role of late sodium current in ventricular arrhythmias caused by increased intracellular calcium concentration

Role of late sodium current as a potential arrhythmogenic mechanism in the progression of pressure-induced heart disease

The aim of the study was to determine the characteristics of the late Na current (INaL) and its arrhythmogenic potential in the progression of pressure-induced heart disease. Transverse aortic constriction (TAC) was used to induce pressure overload in mice. After one week the hearts developed isolated hypertrophy with preserved systolic contractility. In patch-clamp experiments both, INaL and the action potential duration (APD90) were unchanged. In contrast, after five weeks animals developed heart failure with prolonged APDs and slowed INaL decay time which could be normalized by addition of the INaL inhibitor ranolazine (Ran) or by the Ca/calmodulin-dependent protein kinase II (CaMKII) inhibitor AIP. Accordingly the APD90 could be significantly abbreviated by Ran, tetrodotoxin and the CaMKII inhibitor AIP. Isoproterenol increased the number of delayed afterdepolarizations (DAD) in myocytes from failing but not sham hearts. Application of either Ran or AIP prevented the occurrence of DADs. Moreover, the incidence of triggered activity was significantly increased in TAC myocytes and was largely prevented by Ran and AIP. Western blot analyses indicate that increased CaMKII activity and a hyperphosphorylation of the Nav1.5 at the CaMKII phosphorylation site (Ser571) paralleled our functional observations five weeks after TAC surgery. In pressure overload-induced heart failure a CaMKII-dependent augmentation of INaL plays a crucial role in the AP prolongation and generation of cellular arrhythmogenic triggers, which cannot be found in early and still compensated hypertrophy. Inhibition of INaL and CaMKII exerts potent antiarrhythmic effects and might therefore be of potential therapeutic interest. This article is part of a Special Issue entitled “Na+ Regulation in Cardiac Myocytes”.

Role of late sodium current in modulating the proarrhythmic and antiarrhythmic effects of quinidine

Quinidine is used to treat atrial fibrillation and ventricular arrhythmias. However, at low concentrations, it can induce torsade de pointes (TdP). The purpose of this study was to examine the role of late sodium current (I(Na)) as a modulator of the arrhythmogenicity of quinidine in female rabbit isolated hearts and cardiomyocytes. Epicardial and endocardial monophasic action potentials (MAPs), ECG signals, and ion channel currents were measured. The sea anemone toxin ATX-II was used to increase late I(Na). Quinidine had concentration-dependent and often biphasic effects on measures of arrhythmogenicity. Quinidine increased the duration of epicardial MAP (MAPD(90)), QT interval, transmural dispersion of repolarization (TDR), and ventricular effective refractory period. Beat-to-beat variability of MAPD(90) (BVR), the interval from peak to end of the T wave (Tpeak-Tend) and index of Tpeak-Tend/QT interval were greater at 0.1 to 3 micromol/L than at 10-30 micromol/L quinidine. In the presence of 1 nmol/L ATX-II, quinidine caused significantly greater concentration-dependent and biphasic changes of Tpeak-Tend, TDR, BVR, and index of Tpeak-Tend/QT interval. Quinidine (1 micromol/L) induced TdP in 2 and 13 of 14 hearts in the absence and presence of ATX-II, respectively. Increases of BVR, index of Tpeak-Tend/QT interval, and Tpeak-Tend were associated with quinidine-induced TdP. Quinidine inhibited I(Kr), peak I(Na), and late I(Na) with IC(50)s of 4.5 +/- 0.3 micromol/L, 11.0 +/- 0.7 micromol/L, and 12.0 +/- 0.7 micromol/L. Quinidine had biphasic proarrhythmic effects in the presence of ATX-II, suggesting that late I(Na) is a modulator of the arrhythmogenicity of quinidine. Enhancement of late I(Na) increased proarrhythmia caused by low but not high concentrations of quinidine.

Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts — Role of late sodium current and intracellular ion accumulation

The goal of this study was to test the hypothesis that the novel anti-ischemic drug ranolazine, which is known to inhibit late I Na, could reduce intracellular [Na +] i and diastolic [Ca 2+] i overload and improve diastolic function. Contractile dysfunction in human heart failure (HF) is associated with increased [Na +] i and elevated diastolic [Ca 2+] i. Increased Na + influx through voltage-gated Na + channels (late I Na) has been suggested to contribute to elevated [Na +] i in HF. In isometrically contracting ventricular muscle strips from end-stage failing human hearts, ranolazine (10 µmol/L) did not exert negative inotropic effects on twitch force amplitude. However, ranolazine significantly reduced frequency-dependent increase in diastolic tension (i.e., diastolic dysfunction) by ~ 30% without significantly affecting sarcoplasmic reticulum (SR) Ca 2+ loading. To investigate the mechanism of action of this beneficial effect of ranolazine on diastolic tension, Anemonia sulcata toxin II (ATX-II, 40 nmol/L) was used to increase intracellular Na + loading in ventricular rabbit myocytes. ATX-II caused a significant rise in [Na +] i typically seen in heart failure via increased late I Na. In parallel, ATX-II significantly increased diastolic [Ca 2+] i. In the presence of ranolazine the increases in late I Na, as well as [Na +] i and diastolic [Ca 2+] i were significantly blunted at all stimulation rates without significantly decreasing Ca 2+ transient amplitudes or SR Ca 2+ content. In summary, ranolazine reduced the frequency-dependent increase in diastolic tension without having negative inotropic effects on contractility of muscles from end-stage failing human hearts. Moreover, in rabbit myocytes the increases in late I Na, [Na +] i and [Ca 2+] i caused by ATX-II, were significantly blunted by ranolazine. These results suggest that ranolazine may be of therapeutic benefit in conditions of diastolic dysfunction due to elevated [Na +] i and diastolic [Ca 2+] i.

Can Novel Therapies for Arrhythmias Caused by Spontaneous Sarcoplasmic Reticulum Ca 2+ Release be Developed Using Mouse Models?

See related article, pages e77–e82 Ventricular arrhythmias are a significant cause of premature death in Western society and occur both in the absence and presence of heart disease. For example, in heart failure close to 50% of patients die of lethal forms of ventricular arrhythmias. In spite of a large amount of basic and clinical investigations, current pharmacotherapy for ventricular arrhythmias is inadequate, demonstrating the need for novel therapeutic approaches. Abnormal automaticity is responsible for induction and maintenance of different types of ventricular tachycardias. The form of abnormal automaticity that results from abnormal release of Ca2+ from a Ca2+ overloaded sarcoplasmic reticulum (SR), referred to as a “triggered arrhythmia”, is the topic of this editorial. In vitro studies have shown that increasing the SR Ca2+ load beyond a critical level causes spontaneous opening of the SR Ca2+ release channel (ryanodine receptor; RYR) and results in spontaneous SR Ca2+ release.1 The subsequent increase in cytosolic [Ca] activates an inward current through the sarcolemmal Na+/ Ca2+ exchanger which causes membrane depolarization.1,2 Spontaneous SR Ca2+ release during the diastolic interval causes depolarization (delayed after depolarizations; DADs) which has been shown to result in action potentials in single cells and in the intact heart when the aberrant release is adequately synchronized within and among cardiac myocytes.3,4 Factors that lead to DADs include increased heart rate and catecholamine stress, which both induce triggered arrhythmias by increasing SR Ca2+ loading.3 Whereas many molecules are involved in SR Ca2+ overload (DAD) related arrhythmias, abnormal opening …