The Molecular Physiology of the Cardiac Transient Outward Potassium Current (Ito) in Normal and Diseased Myocardium

Oudit, Gavin Y.; Kassiri, Zamaneh; Sah, Rajan; Ramírez, Rafael J.; Zobel, Carsten; Backx, Peter H.

doi:10.1006/jmcc.2001.1376

Cited by 175 publications

(176 citation statements)

References 219 publications

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“…The time course of APD restitution is thought to play an important role in the stability of ventricular arrhythmias (22). Our results suggest that experimentally observed heterogeneity in I to1 density and recovery kinetics (30,32) may play a role in the stability of arrhythmias in different species, regions of tissue, or pathophysiological states. Canine experiments have shown transmural heterogeneity in I NaK (61), I to1 (25), I Ks (24), and I NaCa (62).…”

Section: Discussionmentioning

confidence: 66%

Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium

Decker¹,

Heijman²,

Silva³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

117

121

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Decker KF, Heijman J, Silva JR, Hund TJ, Rudy Y. Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium. Am J Physiol Heart Circ Physiol 296: H1017-H1026, 2009. First published January 23, 2009 doi:10.1152/ajpheart.01216.2008.-Computational models of cardiac myocytes are important tools for understanding ionic mechanisms of arrhythmia. This work presents a new model of the canine epicardial myocyte that reproduces a wide range of experimentally observed rate-dependent behaviors in cardiac cell and tissue, including action potential (AP) duration (APD) adaptation, restitution, and accommodation. Model behavior depends on updated formulations for the 4-aminopyridine-sensitive transient outward current (Ito1), the slow component of the delayed rectifier K ϩ current (IKs), the L-type Ca 2ϩ channel current (ICa,L), and the Na ϩ -K ϩ pump current (INaK) fit to data from canine ventricular myocytes. We found that Ito1 plays a limited role in potentiating peak ICa,L and sarcoplasmic reticulum Ca 2ϩ release for propagated APs but modulates the time course of APD restitution. IKs plays an important role in APD shortening at short diastolic intervals, despite a limited role in AP repolarization at longer cycle lengths. In addition, we found that ICa,L plays a critical role in APD accommodation and rate dependence of APD restitution. Ca 2ϩ entry via ICa,L at fast rate drives increased Na ϩ -Ca 2ϩ exchanger Ca 2ϩ extrusion and Na ϩ entry, which in turn increases Na ϩ extrusion via outward INaK. APD accommodation results from this increased outward INaK. Our simulation results provide valuable insight into the mechanistic basis of rate-dependent phenomena important for determining the heart's response to rapid and irregular pacing rates (e.g., arrhythmia). Accurate simulation of rate-dependent phenomena and increased understanding of their mechanistic basis will lead to more realistic multicellular simulations of arrhythmia and identification of molecular therapeutic targets. arrhythmia; cardiac electrophysiology; mathematical modeling; ion channels CARDIAC ARRHYTHMIAS and sudden death involve complex myocardial activation patterns, including unidirectional block, reentry, and fibrillation. To understand the relations and transitions between these patterns, the ionic determinants of the response of healthy and diseased cardiac myocytes to complex patterns of excitation must be understood. The single-cell response to such excitation patterns depends on the complex interaction between ionic currents, intracellular ion concentrations, and membrane voltage. Computational cell models provide critical tools for exploring these interactions, allowing the development and testing of hypotheses about underlying ionic mechanisms based on careful integration of available experimental data (37). The dog is a common animal model for studying cell electrophysiology in a range of disease states. Our group and others have developed detailed mathematical models of the canine action ...

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Section: Discussionmentioning

confidence: 66%

Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium

Decker¹,

Heijman²,

Silva³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

117

121

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“…The transient outward potassium current (I to , also called I to1 and I tof ) has fast activation and inactivation kinetics and contributes to the early repolarisation (phase 1) of the action potential in atrial and ventricular myocytes (Oudit et al, 2001). The channel protein underlying I to differs among different mammalian species (see the discussion on species differencies below).…”

Section: Cardiac Ion Currents and Ion Channelsmentioning

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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“…For example, downregulation of K V 4.3-encoding I to and increased ␤-MHC͞␣-MHC ratio, both of which are prevented in D2-overexpressing mice subjected to pressure overload, have been suggested to contribute to depressed cardiac function in heart disease (39,40,43). On the other hand, although defective Ca 2ϩ handling in heart disease has also been linked to elevated NCX expression͞activity leading to SR Ca 2ϩ depletion and negative force-frequency relationships (35), no NCX expression changes were observed in mice after pressure overload, as reported previously (36,37).…”

Section: Effects Of D2 Expression On Cardiac Function and Ca 2؉ Cyclingmentioning

confidence: 99%

Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

Trivieri

Oudit

Sah

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Thyroid hormone (TH) is critical for cardiac development and heart function. In heart disease, TH metabolism is abnormal, and many biochemical and functional alterations mirror hypothyroidism. Although TH therapy has been advocated for treating heart disease, a clear benefit of TH has yet to be established, possibly because of peripheral actions of TH. To assess the potential efficacy of TH in treating heart disease, type 2 deiodinase (D2), which converts the prohormone thyroxine to active triiodothyronine (T3), was expressed transiently in mouse hearts by using the tetracycline transactivator system. Increased cardiac D2 activity led to elevated cardiac T3 levels and to enhanced myocardial contractility, accompanied by increased Ca 2؉ transients and sarcoplasmic reticulum (SR) Ca 2؉ uptake. These phenotypic changes were associated with up-regulation of sarco(endo)plasmic reticulum calcium ATPase (SERCA) 2a expression as well as decreased Na ؉ ͞Ca 2؉ exchanger, ␤-myosin heavy chain, and sarcolipin (SLN) expression. In pressure overload, targeted increases in D2 activity could not block hypertrophy but could completely prevent impaired contractility and SR Ca 2؉ cycling as well as altered expression patterns of SERCA2a, SLN, and other markers of pathological hypertrophy. Our results establish that elevated D2 activity in the heart increases T3 levels and enhances cardiac contractile function while preventing deterioration of cardiac function and altered gene expression after pressure overload.calcium ͉ cardiac hypertrophy ͉ sarcoplasmic reticulum ͉ deiodinase ͉ transgenic mice T hyroid hormone (TH) is essential for normal development in vertebrates (1), with TH levels rising postnatally and peaking in the third week of life (2). This surge is critical for fetal-to-adult switch in the cardiac gene program and is responsible for changes in Ca 2ϩ homeostasis, myosin isozyme content [␣-myosin heavy chain (MHC)-to-␤-MHC switch], and action potential profile (3, 4). Intriguingly, the genetic and functional changes associated with heart failure, such as reduced Ca 2ϩ transients and ␣-MHC-to-␤-MHC shifts, which recapitulate the fetal gene program, are also observed in hypothyroidism (5, 6). In addition, TH metabolism and signaling are abnormal in heart failure (5, 7, 8). For example, circulating and cardiac triiodothyronine (T3) levels (i.e., active TH) are reduced in advanced heart disease, after acute myocardial infarction, and in patients with cardiopulmonary bypass. These T3 changes occur in association with decreased peripheral conversion of thyroxine (T4) into T3 (5, 8) and elevated cardiac deiodinase type 3 (D3) activity (9). TH receptor expression is also altered in pathological hypertrophy (10), and myocardial contractility is impaired in mice lacking TH receptors (11). Not surprisingly, TH and its analogue 3,5-diiodothyropropionic acid (DITPA) have been advocated for treating heart failure (12, 13) and for reversing cardiac dysfunction in patients with hypothyroidism (5), although TH use has been limited by car...

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The Molecular Physiology of the Cardiac Transient Outward Potassium Current (Ito) in Normal and Diseased Myocardium

Cited by 175 publications

References 219 publications

Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium

Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium

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

Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

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