Late Sodium Current is a Novel Target for Amiodarone: Studies in Failing Human Myocardium

Maltsev, Victor A.; Sabbah, Hani N.; Undrovinas, A. I.

doi:10.1006/jmcc.2001.1355

Cited by 91 publications

(93 citation statements)

References 26 publications

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“…The model AP morphology ( Figure 2A) and APD ( Figure 2B) agree with canine epicardial recordings 26 over a CL range from 8000 to 300 ms. Most important for canine APD rate adaptation is I Ca(L) , supported by the fact that eliminating I Ca(L) from the model reduced adaptation (CL range of 8000 to 300 ms) from 99 to 30 ms (71% decrease, Figure 2B).…”

Section: Apd Rate Dependence (Adaptation)supporting

confidence: 65%

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Rate Dependence and Regulation of Action Potential and Calcium Transient in a Canine Cardiac Ventricular Cell Model

2004

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Background-Computational biology is a powerful tool for elucidating arrhythmogenic mechanisms at the cellular level, where complex interactions between ionic processes determine behavior. A novel theoretical model of the canine ventricular epicardial action potential and calcium cycling was developed and used to investigate ionic mechanisms underlying Ca 2ϩ transient (CaT) and action potential duration (APD) rate dependence. Methods and Results-The Ca 2ϩ /calmodulin-dependent protein kinase (CaMKII) regulatory pathway was integrated into the model, which included a novel Ca 2ϩ -release formulation, Ca 2ϩ subspace, dynamic chloride handling, and formulations for major ion currents based on canine ventricular data. Decreasing pacing cycle length from 8000 to 300 ms shortened APD primarily because of I Ca(L) reduction, with additional contributions from I to1 , I NaK , and late I Na . CaT amplitude increased as cycle length decreased from 8000 to 500 ms. This positive rate-dependent property depended on CaMKII activity. Key Words: electrophysiology Ⅲ action potentials Ⅲ calcium Ⅲ ion channels T he dependence of action potential duration (APD) and the Ca 2ϩ transient (CaT) on pacing rate is a fundamental property of cardiac myocytes that, when altered, may promote life-threatening cardiac arrhythmias. We have developed a detailed and physiologically based mathematical canine ventricular cell model (Hund-Rudy dynamic [HRd] cell model) that simulates rate-dependent phenomena associated with ion-channel kinetics, AP properties, and Ca handling. The dog is commonly used to investigate cardiac electrophysiology, making it a logical choice for modeling. An epicardial myocyte was chosen rather than endocardial or midmyocardial myocytes because epicardial cells contain the highest density of I to1 (transient outward K ϩ current), producing a unique and complex AP morphology. Conclusions-CaMKII MethodsComplete HRd equations, definitions, and detailed comments appear in the online-only Data Supplement. Important model properties (schematic in Figure 1A) are summarized here. Figure 1B) is introduced through a multiplicative factor dependent on the I Ca(L) driving force. Though controversial (online-only Data Supplement section J), CaMKII phosphorylation is thought to promote RyR channel opening. 5,14,20 Accordingly, the I rel inactivation time constant ( ri ) depends on CaMKII activity. A 10-ms maximal CaMKII-dependent increase in ri yields a steady-state CaT amplitude (CaT amp ) 95% 20 greater for control than with CaMKII suppressed at rapid pacing (CLϭ300 ms). Variable 1-second prepulse (V pre ) was followed by 10-ms holding interval at Ϫ50 mV and ϩ80 mV test pulse. Right, I Ca(L) recovery from voltage-dependent inactivation compared with canine ventricular data. 52 Prepulse of 350 ms to ϩ20 mV was followed by varying interpulse interval at Ϫ40 mV and ϩ20 mV test pulse. Model Ca 2ϩ -dependent inactivation gates were held constant to isolate voltage-dependent inactivation. E, Peak I Ks and I Kr tail currents on repolariz...

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Section: Apd Rate Dependence (Adaptation)supporting

confidence: 65%

“…The 4AP-sensitive transient outward K ϩ current, I to1 , incorporates the activation and inactivation kinetics of Dumaine et al 25 We add a second inactivation gate with a slower time constant 26 than in Dumaine's formulation. The model I to1 I-V curve agrees with experimental data 27 ( Figure 1F).…”

Section: Transient Outward K ؉ Currentmentioning

confidence: 99%

Rate Dependence and Regulation of Action Potential and Calcium Transient in a Canine Cardiac Ventricular Cell Model

2004

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“…The underlying mechanisms for elevated [Na + ] i are incompletely understood, but may involve a decrease in Na + /K + -ATPase activity [58,156,169,172,175,206], enhanced Na + /H + -exchanger (NHE) activity [2,6,40,142], or an increase in a tetrodotoxin-sensitive persistent (late) I Na [58,121,[203][204][205]. During the AP, increased [Na + ] i facilitates repolarization and pronounced cytosolic Ca 2+ -influx via reverse-mode I NCX , which partly compensates the impaired SR Ca 2+ -release and contractility in failing myocytes [3,58,153,210,212].…”

Section: Pathophysiological Aspects Defects In Ec Coupling In Chronicmentioning

confidence: 99%

“…These defects, potentially aggravated by L-type Ca 2+ channel dysfunction [41,71,81,86,113,131,146,184] or t-tubular derangement [32,86,115,145,184] [17,81,113,115,146,184]. Decreased SR Ca 2+ -ATPase activity is partly compensated by increased expression and activity of the NCX [16,65,93,146,178,190] The underlying mechanisms for elevated [Na + ] i are incompletely understood, but may involve a decrease in Na + /K + -ATPase activity [58,156,169,172,175,206], enhanced Na + /H + -exchanger (NHE) activity [2,6,40,142], or an increase in a tetrodotoxin-sensitive persistent (late) I Na [58,121,[203][204][205]. During the AP, increased [Na + ] i facilitates repolarization and pronounced cytosolic Ca 2+ -influx via reverse-mode I NCX , which partly compensates the impaired SR Ca 2+ -release and contractility in failing myocytes [3,58,153,…”

mentioning

confidence: 99%

Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

218

183

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Cardiac excitation-contraction (EC) coupling consumes vast amounts of cellular energy, most of which is produced in mitochondria by oxidative phosphorylation. In order to adapt the constantly varying workload of the heart to energy supply, tight coupling mechanisms are essential to maintain cellular pools of ATP, phosphocreatine and NADH. To our current knowledge, the most important regulators of oxidative phosphorylation are ADP, P i , and Ca 2+ . However, the kinetics of mitochondrial Ca 2+ -uptake during EC coupling are currently a matter of intense debate. Recent experimental findings suggest the existence of a mitochondrial Ca 2+ microdomain in cardiac myocytes, justified by the close proximity of mitochondria to the sites of cellular Ca 2+ release, i. e., the ryanodine receptors of the sarcoplasmic reticulum. Such a Ca 2+ microdomain could explain seemingly controversial results on mitochondrial Ca 2+ uptake kinetics in isolated mitochondria versus whole cardiac myocytes. Another important consideration is that rapid mitochondrial Ca 2+ uptake facilitated by microdomains may shape cytosolic Ca 2+ signals in cardiac myocytes and have an impact on energy supply and demand matching. Defects in EC coupling in chronic heart failure may adversely affect mitochondrial Ca 2+ uptake and energetics, initiating a vicious cycle of contractile dysfunction and energy depletion. Future therapeutic approaches in the treatment of heart failure could be aimed at interrupting this vicious cycle. Keywords calcium; sodium; microdomain; heart failure; adenosine triphosphate; adenosine diphosphate; respiration; tricarboxylic acid cycle Physiological aspectsThe most important function of the heart is to pump blood to supply the body with oxygen and substrates. In order to adapt cardiac output to the constantly changing demand of blood supply, the heart utilizes three major mechanisms to increase cardiac output: the force-frequency relationship (the Bowditch effect or Treppe; [22]), the Frank-Starling mechanism (sarcomere length-dependent activation of contractile force) [66,149,164], and sympathetic activation [28]. All of these mechanisms increase and accelerate myocardial force generation, and at the same time increase cellular energy demand. By these mechanisms, cardiac output during exertion can be increased more than five-fold compared to resting conditions. © Steinkopff Verlag 2007Correspondence to: Christoph Maack. NIH Public Access Excitation-contraction couplingOf fundamental importance for cardiac contraction and relaxation are the processes of excitation-contraction (EC) coupling (Fig. 1). During the action potential (AP), voltage-gated Na + -channels are activated, and the inward Na + -current (I Na ) induces a rapid depolarization of the cell membrane, facilitating voltage-dependent opening of L-type Ca 2+ -channels (I Ca,L ). The Ca 2+ influx triggers the opening of the ryanodine receptor (RyR2 subtype), inducing the release of even greater amounts of Ca 2+ from the sarcoplasmic reticulum (SR), a process te...

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“…The late sodium current recorded in acutely isolated atrial and ventricular myocytes was also inhibited with similar potency, an approximately 50% block at 10 μM AZD7009. Inhibition of the late sodium current has been described for several agents such as lidocaine Orth et al, 2006), flecainide Nagatomo et al, 2000), RSD1235 Orth et al, 2006), ranolazine (Antzelevitch et al, 2004;Belardinelli et al, 2006) and amiodarone (Maltsev et al, 2001). The reported amounts of inhibition of the late sodium current relative to the peak sodium current are different for the various drugs.…”

Section: Characteristics Of Ion Channel Blockade By Azd7009mentioning

confidence: 99%

Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

Persson

Andersson

Duker

et al. 2007

European Journal of Pharmacology

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Atrial fibrillation (AF) is the most common tachyarrhythmia in the adult population and is a major cause of morbidity and mortality. AF can be terminated and sinus rhythm restored by prolonging the action potential duration (APD) and the refractory period. Unfortunately, antiarrhythmic agents that prolong the APD and increase the refractory period via selective inhibition of the rapid delayed rectifier potassium current (IK r ), i.e. class III antiarrhythmic drugs, are associated with an increased risk of the ventricular tachycardia Torsades de Pointes. AZD7009 is an antiarrhythmic agent with predominant actions on atrial electrophysiology that shows high antiarrhythmic efficacy and low proarrhythmic potential in animals and man. The aim of the current studies was to characterize the effect of AZD7009 on cardiac ion currents and APD in order to provide a mechanistic explanation for its predominant atrial effects and low proarrhythmic potential.The human cardiac ion channels hERG (IK r ), Kv1.5 (IK ur ), Kv4.3/KChIP2.2 (I to ), KvLQT1/minK (IK s ), Kir3.1/Kir3.4 (IK ACh ) and Nav1.5 (INa) were expressed in mammalian cells. Whole-cell currents were inhibited by AZD7009 with the following IC 50 values: hERG 0.6 μM, Nav1.5 8 μM, Kv4.3/KChIP2.2 24 μM, Kv1.5 27 μM, Kir3.1/Kir3.4 166 μM and KvLQT1/minK 193 μM. Whole-cell sodium and calcium currents were recorded in isolated rabbit atrial and ventricular myocytes using amphotericin B perforated patch. The late sodium current in rabbit atrial and ventricular myocytes was inhibited by AZD7009 in a concentration dependent way, with approximately 50% inhibition at 10 μM AZD7009. The L-type Ca 2+ current (ICa L ) in rabbit ventricular myocytes was inhibited with an IC 50 of 90 μM. Transmembrane action potentials were recorded in tissue pieces from rabbit atrium, ventricle and Purkinje fibre in control, during exposure to the selective IK r blocker E-4031 and to E-4031 in combination with AZD7009. In Purkinje fibres, but not in ventricular tissue, AZD7009 attenuated the E-4031-induced APD prolongation. In contrast, in atrial cells, AZD7009 further prolonged the APD. In addition, AZD7009 was able to suppress early afterdepolarisations (EADs) induced by E-4031 in Purkinje fibre preparations.In conclusion, AZD7009 delays repolarisation and increases refractoriness in atrial tissue through synergistic inhibition of IK r , I to , IK ur and INa, a mixed ion channel blockade that may underlie its high antiarrhythmic efficacy. Inhibition of the late sodium current, counteracting excessive APD prolongation and EADs in susceptible cells (midmyocardial and Purkinje cells), may explain the low proarrhythmic potential of AZD7009.

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Late Sodium Current is a Novel Target for Amiodarone: Studies in Failing Human Myocardium

Cited by 91 publications

References 26 publications

Rate Dependence and Regulation of Action Potential and Calcium Transient in a Canine Cardiac Ventricular Cell Model

Rate Dependence and Regulation of Action Potential and Calcium Transient in a Canine Cardiac Ventricular Cell Model

Excitation-contraction coupling and mitochondrial energetics

Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

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