2-APB Induces Instability in Rat Left Atrial Mechanical Activity

Wolkowicz, Paul E.; Wu, Hsien Chin; Urthaler, Ferdinand; Ku, David D.

doi:10.1097/fjc.0b013e3180408d8d

Cited by 8 publications

(7 citation statements)

References 30 publications

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“…On the other hand, 2-APB has been reported to induce Ca 2+ store release [11,20]. Previous studies evidenced that 2-APB induced sporadic spontaneous mechanical activity in rat left atria [13]. In the present study, we found that 2-APB induced ectopic activity in rat atria and 2-APB-induced ectopic activity was inhibited by Na [24,29,30].…”

Section: Discussionsupporting

confidence: 69%

“…Base on this understanding and the present results, the schematic illustration of 2-APBinduced atria ectopic activity was described as following ( Previous studies explored the mechanism of 2-APBinduced mechanical activity in isolated rat left atria. Wolkowicz et al reported that 2-APB-induced mechanical activity depended on the concentration of superfusate sodium, chloride, and potassium, and was sensitive to anion transport inhibitor, hyperpolarization-activated current (If) inhibitors [13,14]. These results indicated that the mechanism of 2-APB-induced mechanical activity in atria was complicated.…”

Section: Discussionmentioning

confidence: 86%

“…However, it has been suggested that 2-APB has multiple targets and can potentiate Ca 2+ responses in some situations [11,12]. Recently, Wolkowicz et al reported that 2-APB provoked sporadic mechanical activity in isolated rat left atria [13,14] and suggested that hyperpolarization-activated current (If), chloride channel and sodium-calcium exchanger might underlie this activity. The aim of the present study is to characterize 2-APBinduced ectopic activity in rat atria and test the efficacy of the putative anti-arrhythmic drugs in this model.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of 2-Aminoethoxydiphenyl Borate-induced Rat Atrial Ectopic Activity by Anti-arrhythmic Drugs

Hu¹,

Li²,

Lu³

et al. 2010

Cell Physiol Biochem

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Background/Aims: 2-aminoethoxydiphenyl borate (2-APB) provokes spontaneous mechanical activity in isolated rat left atria. The present study is to characterize 2-APB-induced ectopic activity in rat atria and to investigate the inhibition of 2-APB-induced ectopic activity by anti-arrhythmic drugs. Methods: 2-APB-induced ectopic activity was measured through an isometric force transducer connected to a multichannel acquisition and analysis system. Intracellular [Ca²⁺]_i was measured with fluorescence laser scanning confocal microscopy. Voltage-dependent L- type Ca²⁺ currents were recorded by using patch-clamp technique. Results: 2-APB dose-dependently increased the ectopic activity of left atria at 1, 5, 10, 20, 50 µM. Anti-arrhythmic drugs, quinidine (10µM), lidocaine (10µM), verapamil (5µM), and amiodarone (50µM,100µM) inhibited 2-APB-induced ectopic activity. 2-APB-induced ectopic activity was inhibited by Ca²⁺-free bath, Na⁺/Ca²⁺ exchanger blockers, 3′,4′-dichlorobenzamil hydrochloride (DHC) and Ni²⁺, not by non-selective cation channel blocker Gd³⁺. 2-APB also induced ectopic contractions in ventricular tissue straps and the ectopic contractions were inhibited by quinidine, verapamil and DHC. Lidocaine, verapamil and DHC inhibited 2-APB-induced increase of intracellular Ca²⁺ concentration in cardiomyocytes. Low molecular weight heparin inhibited phenylephrine (PE)-induced but not 2-APB -induced atria ectopic activity, and the pattern of 2-APB-induced ectopic activity was continuous, distinct from the discontinuous activity induced by PE. Conclusion: 2-APB-induced atria ectopic activity was inhibited by classic anti-arrhythmic drugs quinidine, lidocaine, verapamil, amiodarone, and Na⁺/Ca²⁺ exchanger blockers. It can be used for testing agents able to affect any of Na⁺, Ca²⁺ channel, Na⁺/Ca²⁺ exchanger without selectivity.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

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Inhibition of 2-Aminoethoxydiphenyl Borate-induced Rat Atrial Ectopic Activity by Anti-arrhythmic Drugs

Hu¹,

Li²,

Lu³

et al. 2010

Cell Physiol Biochem

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“…We found that 2APB provokes a novel type of arrhythmic activity [103][104][105][106] which appears to satisfy the demands of the focal source hypothesis of Engelmann and Scherf. In particular,…”

Section: Is Voltage-independent Calcium Signaling a Focal Source Of Asupporting

confidence: 57%

Voltage-Independent Calcium Channels, Molecular Sources of Supraventricular Arrhythmia

Wolkowicz¹,

Umeda²,

Urthaler³

et al. 2013

Atrial Fibrillation - Mechanisms and Treatment

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Since its identification over one hundred years ago, atrial fibrillation has been shown to occur frequently in the general population and is now recognized as an important medical problem in developed societies. Three major hypotheses to explain cardiac rhythm disorders like atrial fibrillation have been proposed during this time and one of these three, impulse reentry has become predominate. The two other explanations, designated as focal source hypotheses, have been relegated to a secondary role in understanding arrhythmia. Despite widespread acceptance of the reentry hypothesis, however, current noninvasive anti-arrhythmic drugs based on this mechanism poorly prevent or reverse atrial fibrillation or other types of arrhythmia. One interpretation of this paradoxical clinical result is that mechanisms other than reentry initiate arrhythmias like atrial fibrillation in real-life settings. As a consequence, current non-invasive therapeutics may neither target nor effectively suppress important but unrecognized non-reentrant mechanisms that provoke clinical arrhythmia. We have found that challenging isolated non-automatic left atrial muscle, left ventricular papillary muscle, and perfused heart in sinus rhythm with an activator of the voltage-independent Orai calcium channels provokes high frequent tachycardia and fibrillation. Thus the Orais and related voltage-independent calcium channels may be unexpected sources of arrhythmia. This manuscript provides a a synopsis of the identification of atrial fibrillation as a clinical entity, b an overview of the development of the three current hypotheses for arrhythmia, and c our hypothesis that dysregulated voltage-independent calcium channels may be a fourth means to provoke electrical instability in heart muscle.

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“…29,30 This discrepancy can be explained by the different dosages of 2-APB used in these studies as 2-APB suppresses IP 3 R-linked calcium signaling at low concentrations, while at higher concentrations it induces leakage from cell calcium stores. 29,30 A potential limitation is that it is still unknown whether changes of cytosolic Ca 2þ interfere with measurements of cytosolic Mg 2þ in HL-1 cells. But it is reported that cytoplasmic free Ca 2þ does not contribute significantly to Mg 2þ -Fura-2 intensity unless the concentration exceeds 1 mmol/L.…”

Section: Discussionmentioning

confidence: 94%

2-Aminoethoxydiphenyl borate, a inositol 1,4,5-triphosphate receptor inhibitor, prevents atrial fibrillation

Xiao

Liang

Zhao

et al. 2010

Exp Biol Med (Maywood)

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The expression of the inositol 1,4,5-triphosphate receptor (IP3R) is upregulated and the function of IP3R also increases during atrial fibrillation (AF). 2-Aminoethoxydiphenyl borate (2-APB) is a membrane-permeable inhibitor of IP3R. However, the effect of 2-APB on AF is unknown. The aim of the present study is to explore the effects of 2-APB on AF. In vitro rabbit heart models of ischemia-, stretch- and cholinergic agitation-induced AF were developed. Fura-2-acetoxymethyl (Fura-2-AM) and Mg2+-Fura-2-AM were used to monitor alterations of intracellular Ca2+ and ATP, respectively, in HL-1 cells, an atrial muscle cell line, under chemical ischemia or cholinergic agitation. The results showed that inhibition of IP3R significantly reduced the incidence and its probability of being sustained in all three types of AF. IP3R inhibition ameliorated the cytoplasmic Ca2+ overload and energy compromise resulting from chemical ischemia or cholinergic agitation. Thus, IP3R inhibition may be a novel target for AF treatment, and IP3R may be an important molecule in the context of different kinds of AF.

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2-APB Induces Instability in Rat Left Atrial Mechanical Activity

Cited by 8 publications

References 30 publications

Inhibition of 2-Aminoethoxydiphenyl Borate-induced Rat Atrial Ectopic Activity by Anti-arrhythmic Drugs

Inhibition of 2-Aminoethoxydiphenyl Borate-induced Rat Atrial Ectopic Activity by Anti-arrhythmic Drugs

Voltage-Independent Calcium Channels, Molecular Sources of Supraventricular Arrhythmia

2-Aminoethoxydiphenyl borate, a inositol 1,4,5-triphosphate receptor inhibitor, prevents atrial fibrillation

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