Increased Na+ concentration and altered Na/K pump activity in hypertrophied canine ventricular cells

Verdonck, Fons; Volders, Paul G.A.; Vos, Marc A.; Sipido, Karin R.

doi:10.1016/s0008-6363(02)00734-4

Cited by 83 publications

(70 citation statements)

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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,…”

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confidence: 99%

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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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Section: Pathophysiological Aspects Defects In Ec Coupling In Chronicmentioning

confidence: 99%

mentioning

confidence: 99%

Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

218

183

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“…In fact, impairment of Na/K pump activity has been shown to take place in a number of diseased conditions, including atrial fibrillation [74], ischemia [16,17], heart failure [3,45,60,69], hypertension [14,40,43], hypo/hyper-thyroidism [40,43] and diabetes [23,64]. Na/K pump inhibition has also been used for therapeutic action in a number of conditions, like the treatment of atrial fibrillation and heart failure by cardiac glycosides [28,71].…”

Section: Introductionmentioning

confidence: 99%

“…However, ion pumps operate through the entire course of the action potential to slowly, actively transport ions thermodynamically uphill, resulting in a current as small as~20 aA for a single Na/K molecule [20]. Hence, although it is possible to measure the total current generated by the millions of Na/K pumps located in the entire cell membrane [19,25,46,61,69,78], the associated experimental difficulties may have limited the study of the impact of the Na/K pump on cardiac repolarization compared to other ion channel currents. Understanding the therapeutical and pathophysiological consequences of Na/K pump alterations from the cellular to the whole organ function therefore requires of further investigations.…”

Section: Introductionmentioning

confidence: 99%

Na/K pump regulation of cardiac repolarization: insights from a systems biology approach

Bueno‐Orovio

Sánchez

Pueyo

et al. 2013

Pflugers Arch - Eur J Physiol

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The sodium-potassium pump is widely recognized as the principal mechanism for active ion transport across the cellular membrane of cardiac tissue, being responsible for the creation and maintenance of the transarcolemmal sodium and potassium gradients, crucial for cardiac cell electrophysiology. Importantly, sodium-potassium pump activity is impaired in a number of major diseased conditions, including ischemia and heart failure. However, its subtle ways of action on cardiac electrophysiology, both directly through its electrogenic nature and indirectly via the regulation of cell homeostasis, make it hard to predict the electrophysiological consequences of reduced sodium-potassium pump activity in cardiac repolarization. In this review, we discuss how recent studies adopting the Systems Biology approach, through the integration of experimental and modeling methodologies, have identified the sodium-potassium pump as one of the most important ionic mechanisms in regulating key properties of cardiac repolarization and its rate-dependence, from subcellular to whole organ levels. These include the role of the pump in the biphasic modulation of cellular repolarization and refractoriness, the rate control of intracellular sodium and calcium dynamics and therefore of the adaptation of repolarization to changes in heart rate, as well as its importance in regulating pro-arrhythmic substrates through modulation of dispersion of repolarization and restitution. Theoretical findings are consistent across a variety of cell types and species including human, and widely in agreement with experimental findings. The novel insights and hypotheses on the role of the pump in cardiac electrophysiology obtained through this integrative approach could eventually lead to novel therapeutic and diagnostic strategies.

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“…At the cellular level, K + currents I Ks and I Kr are reduced [1], whereas sarcoplasmic reticulum Ca 2+ release and I NaCaX are enhanced, especially at slow heart rates [7]. An increase in subsarcolemmal Na + concentration underlies the altered Ca 2+ handling [8]. Previous work has shown that the reduction of I Ks in chronic AVB can be due to a downregulation of KCNQ1-and KCNE1-gene transcription in the basal and midlateral parts of the left-(LV) and right-ventricular wall [9].…”

Section: Introductionmentioning

confidence: 99%

Temporal patterns of electrical remodeling in canine ventricular hypertrophy: Focus on IKs downregulation and blunted β-adrenergic activation

Štengl

Ramakers

Donker

et al. 2006

Cardiovascular Research

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Objectives: Electrical remodeling in cardiac hypertrophy often involves the downregulation of K + currents, including β-adrenergic (β-A)-sensitive I Ks . Temporal patterns of ion-channel downregulation are poorly resolved. In dogs with complete atrioventricular block (AVB), we examined (1) the time course of molecular alterations underlying I Ks downregulation from acute to chronic hypertrophy; and (2) concomitant changing responses of repolarization to β-adrenergic receptor (β-AR) stimulation. Methods and Results: Serial left-ventricular (LV) biopsies were collected from anesthetized dogs during sinus rhythm (SR; control) and at 3, 7 and 30 days of AVB. KCNQ1 mRNA and protein decreased within 3 days (protein expression 58 ± 10% of control), remaining low thereafter. β1-AR mRNA and protein decreased more gradually to 53 ± 8% at 7 days. In chronic-AVB LV myocytes, I Ks -tail density was reduced: 1.4 ± 0.3 pA/pF versus 2.6 ± 0.4 pA/pF in controls. β-A enhancement of I Ks was reduced. Isoproterenol shortened action-potential duration in control cells, while causing heterogeneous repolarization responses in chronic AVB. β-A early afterdepolarizations were induced in 4 of 13 chronic-AVB cells, but not in controls. In intact conscious dogs, isoproterenol shortened QT c at SR (by −8 ± 3% from 295 ms), left it unaltered at 3 days AVB (+1 ± 3% from 325 ms) and prolonged QT c at 30 days (+ 6 ± 3% from 365 ms). Conclusions: Profound decrease of KCNQ1 occurs within days after AVB induction and is followed by a more gradual decrease of β1-AR expression. Downregulation and blunted β-A activation of I Ks contribute to the loss of β-A-induced shortening of ventricular repolarization, favoring proarrhythmia. Provocation testing with isoproterenol identifies repolarization instability based on acquired channelopathy.

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Increased Na+ concentration and altered Na/K pump activity in hypertrophied canine ventricular cells

Cited by 83 publications

References 53 publications

Excitation-contraction coupling and mitochondrial energetics

Excitation-contraction coupling and mitochondrial energetics

Na/K pump regulation of cardiac repolarization: insights from a systems biology approach

Temporal patterns of electrical remodeling in canine ventricular hypertrophy: Focus on IKs downregulation and blunted β-adrenergic activation

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