Inhibitory effect of 2,3‐butanedione monoxime (BDM) on Na<sup>+</sup>/Ca<sup>2+</sup>exchange current in guinea‐pig cardiac ventricular myocytes

Watanabe, Yasuhide; Iwamoto, Takahiro; Matsuoka, Isao; Ohkubo, Satoko; Ono, Tomoyuki; Watano, Tomokazu; Shigekawa, Munekazu; Kimura, Junko

doi:10.1038/sj.bjp.0703926

Cited by 59 publications

(52 citation statements)

References 40 publications

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“…However, the inhibitory effect of BDM on I NCX is not affected by okadaic acid. In addition, BDM inhibits both I NCX from CCL39 cells expressing NCX1 and its mutant in which three major phosphorylatable serine residues are replaced with alanine (55). We conclude that the mechanism of inhibition of BDM is not by dephosphory- lation of NCX as a chemical phosphatase.…”

Section: Other Antiarrhythmic Drugs (Dronedarone Cibenzoline and Azmentioning

confidence: 76%

“…We conclude that the mechanism of inhibition of BDM is not by dephosphory- lation of NCX as a chemical phosphatase. The inhibitory mechanism of BDM on I NCX is unclear, but intracellular trypsin treatment almost completely abolishes the inhibitory effect of BDM (55), suggesting that BDM affects NCX at an intracellular site.…”

Section: Other Antiarrhythmic Drugs (Dronedarone Cibenzoline and Azmentioning

confidence: 99%

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Topics on the Na+/Ca2+ Exchanger: Pharmacological Characterization of Na+/Ca2+ Exchanger Inhibitors

2006

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Abstract. Using the whole-cell voltage clamp, we examined acute effects of various agents on Na + / Ca 2+ exchange current (I NCX ) in guinea-pig cardiac ventricular cells and transfected cells. Among the antiarrhythmic drugs, amiodarone, bepridil, dronedarone, cibenzoline, azimilide, and aprindine inhibited I NCX in a concentration-dependent manner. We also investigated the effects on NCX of 2,3-buanedione monoxim (BDM) and selective NCX inhibitors such as KB-R7943, SEA0400, and SN-6. The presence of trypsin in the pipette solution attenuated the inhibitory effects on NCX of amiodarone, bepridil, and BDM, suggesting that these drugs inhibit NCX from the cytosolic side. In contrast, the trypsin-insensitive NCX inhibitors were aprindine, azimilide, dronedarone, cibenzoline, KB-R7943, SEA0400, and SN-6. KB-R7943, SEA0400, and SN-6 suppressed the uni-directional outward I NCX more potently than the uni-directional inward I NCX . The mechanism of this mode-dependency is unknown, but is suggested to be related to intracellular Na + concentration.

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Section: Other Antiarrhythmic Drugs (Dronedarone Cibenzoline and Azmentioning

confidence: 76%

Section: Other Antiarrhythmic Drugs (Dronedarone Cibenzoline and Azmentioning

confidence: 99%

Topics on the Na+/Ca2+ Exchanger: Pharmacological Characterization of Na+/Ca2+ Exchanger Inhibitors

2006

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“…To abolish the motion artifact from recorded data, the optical mapping techniques require the use of excitation-contraction uncouplers. In the present study, we utilized BDM, which is known to change several membrane conductances (6,56) and thereby causes some electrophysiological effects (14,37,40), including flattening the APD restitution curve (3). To examine the potential effect of BDM on the dynamics of cardiac response, we conducted two additional experiments using a new excitation-contraction uncoupling agent, blebbistatin, which is considered to have no effects on the AP morphology in rabbit cardiac tissue (22).…”

Section: Discussionmentioning

confidence: 99%

Regional increase of extracellular potassium leads to electrical instability and reentry occurrence through the spatial heterogeneity of APD restitution

Sidorov¹,

Uzelac

Wikswo

2011

American Journal of Physiology-Heart and Circulatory Physiology

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Sidorov VY, Uzelac I, Wikswo JP. Regional increase of extracellular potassium leads to electrical instability and reentry occurrence through the spatial heterogeneity of APD restitution. Am J Physiol Heart Circ Physiol 301: H209 -H220, 2011. First published May 2, 2011; doi:10.1152/ajpheart.01141.2010.-The heterogeneities of electrophysiological properties of cardiac tissue are the main factors that control both arrhythmia induction and maintenance. Although the local increase of extracellular potassium ([K ϩ ]o) due to coronary occlusion is a well-established metabolic response to acute ischemia, the role of local [K ϩ ]o heterogeneity in phase 1a arrhythmias has yet to be determined. In this work, we created local [K ϩ ]o heterogeneity and investigated its role in fast pacing response and arrhythmia induction. The left marginal vein of a Langendorff-perfused rabbit heart was cannulated and perfused separately with solutions containing 4, 6, 8, 10, and 12 mM of K ϩ . The fluorescence dye was utilized to map the voltage distribution. We tested stimulation rates, starting from 400 ms down to 120 ms, with steps of 5-50 ms. We found that local [K ϩ ]o heterogeneity causes action potential (AP) alternans, 2:1 conduction block, and wave breaks. The effect of [K ϩ ]o heterogeneity on electrical stability and vulnerability to arrhythmia induction was largest during regional perfusion with 10 mM of K ϩ . We detected three concurrent dynamics: normally propagating activation when excitation waves spread over tissue perfused with normal K ϩ , alternating 2:2 rhythm near the border of [K ϩ ]o heterogeneity, and 2:1 aperiodicity when propagation was within the high [K ϩ ]o area. [K ϩ ]o elevation changed the AP duration (APD) restitution and shifted the restitution curve toward longer diastolic intervals and shorter APD. We conclude that spatial heterogeneity of the APD restitution, created with regional elevation of [K ϩ ]o, can lead to AP instability, 2:1 block, and reentry induction. restitution heterogeneity; regional perfusion; optical mapping THE STATIONARY AND DYNAMIC heterogeneities of electrophysiological properties of cardiac tissue play a key role in the induction and maintenance of cardiac arrhythmias (1,10,16,59). Cardiac tissue heterogeneities increase drastically when acute regional ischemia occurs. The early stage of acute ischemia is characterized by abrupt metabolic and electrophysiological changes in the affected area (11). Among them, the more prominent are increased extracellular potassium ([K ϩ ] o ) (25, 26), decreased creatine phosphate (43, 63), elevated intracellular inorganic phosphate (63), acidosis (27, 46), catecholamine release (39), and partial depolarization of transmembrane potential (V m ) (28,36).Since an early change in V m closely relates to [K ϩ ] o accumulation (34, 60), the K ϩ imbalance is considered to be the major factor affecting excitability and is responsible for slow impulse propagation and induction of reentry (51) Although numerous studies have been devoted to investigation ...

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“…Alternatively, the administration of 10-20 mM BDM in the media for cell isolation is also widely used for reducing cell damage [12,30]. However, reports have shown that BDM affects the electrophysiological and contraction properties of heart cells, as well as their Ca 2+ signaling, via direct action, protein phosphorylation, and/or altered gene expression [16,17,[31][32][33].…”

Section: Comparison With Other Heart Cell Isolation Techniquesmentioning

confidence: 99%

A Simple Technique for Isolating Healthy Heart Cells from Mouse Models

Shioya

2007

J. Physiol. Sci

128

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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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Inhibitory effect of 2,3‐butanedione monoxime (BDM) on Na⁺/Ca²⁺exchange current in guinea‐pig cardiac ventricular myocytes

Cited by 59 publications

References 40 publications

Topics on the Na+/Ca2+ Exchanger: Pharmacological Characterization of Na+/Ca2+ Exchanger Inhibitors

Topics on the Na+/Ca2+ Exchanger: Pharmacological Characterization of Na+/Ca2+ Exchanger Inhibitors

Regional increase of extracellular potassium leads to electrical instability and reentry occurrence through the spatial heterogeneity of APD restitution

A Simple Technique for Isolating Healthy Heart Cells from Mouse Models

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Inhibitory effect of 2,3‐butanedione monoxime (BDM) on Na+/Ca2+exchange current in guinea‐pig cardiac ventricular myocytes

Cited by 59 publications

References 40 publications

Topics on the Na+/Ca2+ Exchanger: Pharmacological Characterization of Na+/Ca2+ Exchanger Inhibitors

Topics on the Na+/Ca2+ Exchanger: Pharmacological Characterization of Na+/Ca2+ Exchanger Inhibitors

Regional increase of extracellular potassium leads to electrical instability and reentry occurrence through the spatial heterogeneity of APD restitution

A Simple Technique for Isolating Healthy Heart Cells from Mouse Models

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Inhibitory effect of 2,3‐butanedione monoxime (BDM) on Na⁺/Ca²⁺exchange current in guinea‐pig cardiac ventricular myocytes