Heterogeneous expression of repolarizing, voltage‐gated K<sup>+</sup> currents in adult mouse ventricles

Brunet, Sylvain; Aimond, Franck; Li, Huilin; Guo, Weinong; Eldstrom, Jodene; Fedida, David; Yamada, Kathryn A.; Nerbonne, Jeanne M.

doi:10.1113/jphysiol.2004.063347

Cited by 185 publications

(307 citation statements)

References 44 publications

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“…8 -11 Subsequent experiments focused, there- fore, on investigating the effects of LVH on repolarizing K ϩ currents in cells isolated from the EPI and ENDO surfaces of the LV wall. As previously reported in wild-type cells, 15 meanϮSEM I peak ( Figure 4A and 4C), I to,f ( Figure 4D), and I K,slow ( Figure 4E) densities were significantly (PϽ0.001) higher in sham EPI, than ENDO, LV myocytes (Table). Regional differences in current densities 15 have been suggested to contribute to the native transmural repolarization gradient.…”

Section: Regional Differences In the Effects Of Tac-induced Lvh On K supporting

confidence: 86%

“…As previously reported in wild-type cells, 15 meanϮSEM I peak ( Figure 4A and 4C), I to,f ( Figure 4D), and I K,slow ( Figure 4E) densities were significantly (PϽ0.001) higher in sham EPI, than ENDO, LV myocytes (Table). Regional differences in current densities 15 have been suggested to contribute to the native transmural repolarization gradient. 21 There were also marked regional differences in the cellular effects of LVH.…”

Section: Regional Differences In the Effects Of Tac-induced Lvh On K supporting

confidence: 86%

“…The decay phases of the Kv currents in adult wild-type mouse ventricular myocytes are best described by the sum of 2 exponentials, reflecting the inactivating currents I to,f and I K,slow and a noninactivating current, I ss . 15 Kinetic analyses of the currents revealed that meanϮSEM I to,f ( Figure 2D), I K,slow ( Figure 2E), and I ss ( Figure 2F) densities were significantly (PϽ0.001) lower in TAC, than in sham, LV myocytes (Table). MeanϮSEM I to,f and I K1 amplitudes in TAC and sham LV myocytes, however, were indistinguishable ( Figure 2I), suggesting that the reductions in I to,f and I K1 densities ( Figure 2J) reflect only the increase in C m ( Figure 2H).…”

Section: K ؉ Current Remodeling In Tac LV Myocytesmentioning

confidence: 90%

“…14 Myocytes were isolated from the LV (and RV), as well as from the epicardial (EPI) and endocardial (ENDO) LV surfaces, of sham and TAC hearts by enzymatic dissociation and mechanical dispersion using described methods. 15 Whole-cell membrane currents and action potentials were measured as previously described. 15 …”

Section: Electrophysiological Recordingsmentioning

confidence: 99%

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Left Ventricular Hypertrophy

Ebert¹

2005

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Abstract-Left ventricular hypertrophy (LVH) is associated with electric remodeling and increased arrhythmia risk, although the underlying mechanisms are poorly understood. In the experiments here, functional voltage-gated (Kv) and inwardly rectifying (Kir) K ϩ channel remodeling was examined in a mouse model of pressure overload-induced LVH, produced by transverse aortic constriction (TAC). Action potential durations (APDs) at 90% repolarization in TAC LV myocytes and QT c intervals in TAC mice were prolonged. Mean whole-cell membrane capacitance (C m ) was higher, and Key Words: hypertrophy Ⅲ arrhythmia Ⅲ heart failure L eft ventricular hypertrophy (LVH) is an adaptive response of the myocardium to an increase in load. 1 LVH is seen in various disease states including hypertension and myocardial infarction, as well as in valvular and congenital heart diseases. 1 LVH is also observed in physiological states following rigorous, prolonged exercise. 2 Although physiological LVH does not confer increased morbidity and mortality, pathological LVH is consistently associated with prolongation of ventricular action potentials and alterations in the dispersion of repolarization, both of which result in electric instability and increase the propensity to develop lifethreatening arrhythmias. 3 Several lines of evidence suggest that these electric changes reflect, at least in part, alterations in the functioning of the K ϩ channels that underlie ventricular action potential repolarization. 3,4 Various experimental models of LVH, 5-7 including pressure overload-induced LVH, 8,9 have been developed to explore the mechanisms underlying K ϩ current remodeling.Although several studies have examined regional differences in remodeling, 8 -11 few have probed the underlying molecular and cellular mechanisms. In the studies here, a mouse model of pressure overload-induced LVH, produced by transverse aortic constriction (TAC), was exploited to quantify the effects of LVH on repolarizing K ϩ currents in LV myocytes and to delineate the mechanisms underlying K ϩ current remodeling. These experiments revealed that APDs were prolonged in TAC LV myocytes and that QT c intervals were increased in TAC mice. Mean whole-cell membrane capacitance (C m ) was increased significantly, and the densities of voltage-gated K ϩ (Kv) and inwardly rectifying K ϩ (Kir) currents were reduced in TAC LV myocytes. Further electrophysiological, molecular, and biochemical analyses revealed marked regional differences in the effects of LVH and that distinct cellular and molecular mechanisms contribute to the functional remodeling of repolarizing Kv and Kir currents.

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Section: Regional Differences In the Effects Of Tac-induced Lvh On K supporting

confidence: 86%

Section: Regional Differences In the Effects Of Tac-induced Lvh On K supporting

confidence: 86%

Section: K ؉ Current Remodeling In Tac LV Myocytesmentioning

confidence: 90%

Section: Electrophysiological Recordingsmentioning

confidence: 99%

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Left Ventricular Hypertrophy

Ebert¹

2005

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“…6). The variations in the APD -18mV and in the I to amplitudes may indicate the regional heterogeneity of repolarizing K + current reported in mouse heart cells [37,38].…”

Section: Properties Of the Isolated Heart Cellsmentioning

confidence: 99%

A Simple Technique for Isolating Healthy Heart Cells from Mouse Models

Shioya

2007

J. Physiol. Sci

126

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Single heart cells of mouse models provide powerful tools for heart research. However, their isolation is not easy, and it imposes a significant bottleneck on their use in cellular studies of the heart. Aiming to overcome this problem, this report introduces a novel technique that reproducibly isolates healthy heart cells from mouse models. Using simple devices that ensure easy handling and the rapid aortic cannulation of a small mouse heart, cell isolation was done under physiological conditions without using the "KB" medium or 2,3-butanedione monoxime (BDM). The isolated cells consistently had a healthy appearance and a high viability of 75 ± 5% (mean ± SD) in Tyrode solution containing 1.8 mM Ca 2+ . After 8 h of storage at 37°C, they still had a viability of 45 ± 12%. The cells showed normal contraction properties when field-stimulated, and they generated normal action potentials and membrane currents under the whole-cell clamp condition. The β-adrenergic signal transduction of the cells was also normal when it was examined with the isoproterenol enhancement of the L-type Ca 2+ current.Key words: mouse, cardiac myocyte, contraction, action potential, ionic current.Single heart cells of mouse models provide powerful tools for heart research. In these cells, one can take advantage of the versatility of recent genetic engineering technology [1] and also of the accuracy of single-cell measurement techniques such as patch-clamp and Ca 2+ imaging. So far, molecular mechanisms of fundamental heart functions, such as excitation-contraction coupling, action potential shaping, and β-adrenergic signaling, have been successfully unveiled by using single heart cells of mouse models [2][3][4][5][6][7]. Moreover, these cells also provide a convenient platform for analyzing pathogenic mechanisms and the pathophysiology of hereditary heart diseases in molecular detail [8,9].For such single-cell studies, healthy heart cells are absolutely necessary; however, their isolation from mouse models is not easy. Surgery and aortic cannulation of a small mouse heart are hard to do and require a long time, and during that time, the heart suffers from complete ischemia. Consequently, the cells isolated from these hearts show various signs of ischemic damages, such as bizarre appearance, low viability levels, and abnormalities in their excitation and contraction properties. Cells of these kinds are hard to use for the experiment, and the data they provide are often difficult to interpret. This issue imposes a significant bottleneck on the use of mouse heart cells and is especially problematic in genetically engineered mouse models that are usually available only in limited amounts.To solve this problem, two major work-arounds have been devised and used for heart cell isolation from mouse models. One is to incubate the cells in high-K + , Ca 2+ -free "KB" medium at 4°C [10,11], and the other is to administer 10-20 mM 2,3-butanedione monoxime (BDM) in the media for cell isolation and storage [12,13]. Both workarounds proved to be...

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I_Kur, Ultra‐Rapid Delayed Rectifier Potassium Current: A Therapeutic Target for Atrial Arrhythmias

Sridhar

Carnes

2009

Novel Therapeutic Targets for Antiarrhythmic Drugs

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Heterogeneous expression of repolarizing, voltage‐gated K⁺ currents in adult mouse ventricles

Cited by 185 publications

References 44 publications

Left Ventricular Hypertrophy

Left Ventricular Hypertrophy

A Simple Technique for Isolating Healthy Heart Cells from Mouse Models

I_Kur, Ultra‐Rapid Delayed Rectifier Potassium Current: A Therapeutic Target for Atrial Arrhythmias

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Heterogeneous expression of repolarizing, voltage‐gated K+ currents in adult mouse ventricles

Cited by 185 publications

References 44 publications

Left Ventricular Hypertrophy

Left Ventricular Hypertrophy

A Simple Technique for Isolating Healthy Heart Cells from Mouse Models

IKur, Ultra‐Rapid Delayed Rectifier Potassium Current: A Therapeutic Target for Atrial Arrhythmias

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Product

Resources

About

Heterogeneous expression of repolarizing, voltage‐gated K⁺ currents in adult mouse ventricles

I_Kur, Ultra‐Rapid Delayed Rectifier Potassium Current: A Therapeutic Target for Atrial Arrhythmias