Role of the Alternans of Action Potential Duration and Aconitine-Induced Arrhythmias in Isolated Rabbit Hearts

Jung, Byung Chun; Lee, Sangeun; Cho, Yong Keun; Park, Hyoung Seob; Kim, Yoon Nyun; Lee, Young Soo; Shin, Dong Gu

doi:10.3346/jkms.2011.26.12.1576

Cited by 10 publications

(7 citation statements)

References 19 publications

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“…As with APD-RT, the potentiation of alternans appears to be a function of the duration of the action potential rather than a property related to any individual ion channel. In support of this we can observe that alternans are potentiated by interventions that prolong APD by increasing inward Na + current 70,71 or decreasing outward K + currents. 65 Moreover, data from Fujimoto et al demonstrates that the increase in alternan amplitude with disopyramide mediated APD prolongation can be reversed by nicorandil, an activator of the ATP sensitive potassium current.…”

Section: Electrical Alternanssupporting

confidence: 71%

“…These factors include bradycardia, 46 experimental heart failure, 47 excitation-contraction uncoupling agents 48,49 and the action of drugs that prolong APD by reducing outward K + current [50][51][52] or increasing inward Na + current. 53 By comparison, factors that shorten APD act to flatten the APD-RT curve (see Figure 5). 50,[54][55][56] to increase the magnitude of APD-RT.…”

Section: Action Potential Duration Restitutionmentioning

confidence: 99%

“…50,[54][55][56] to increase the magnitude of APD-RT. 46,[50][51][52][53] Additionally, it is difficult to understand why interventions that would be predicted to flatten the APD-RT curve (e.g. a decrease in K + conductance) actually have the opposite effect.…”

Section: Action Potential Duration Restitutionmentioning

confidence: 99%

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Geometrical considerations in cardiac electrophysiology and arrhythmogenesis

Winter¹,

Shattock²

2015

Europace

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The rate of repolarization (RRepol) and so the duration of the cardiac action potential are determined by the balance of inward and outward currents across the cardiac membrane (net ionic current). Plotting action potential duration (APD) as a function of the RRepol reveals an inverse non-linear relationship, arising from the geometric association between these two factors. From the RRepol-APD relationship, it can be observed that a longer action potential will exhibit a greater propensity to shorten, or prolong, for a given change in the RRepol (i.e. net ionic current), when compared with one that is initially shorter. This observation has recently been used to explain why so many interventions that prolong the action potential exert a greater effect at slow rates (reverse rate-dependence). In this article, we will discuss the broader implications of this simple principle and examine how common experimental observations on the electrical behaviour of the myocardium may be explained in terms of the RRepol-APD relationship. An argument is made, with supporting published evidence, that the non-linear relationship between the RRepol and APD is a fundamental, and largely overlooked, property of the myocardium. The RRepol-APD relationship appears to explain why interventions and disease with seemingly disparate mechanisms of action have similar electrophysiological consequences. Furthermore, the RRepol-APD relationship predicts that prolongation of the action potential, by slowing repolarization, will promote conditions of dynamic electrical instability, exacerbating several electrophysiological phenomena associated with arrhythmogenesis, namely, the rate dependence of dispersion of repolarization, APD restitution, and electrical alternans.

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Section: Electrical Alternanssupporting

confidence: 71%

Section: Action Potential Duration Restitutionmentioning

confidence: 99%

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Geometrical considerations in cardiac electrophysiology and arrhythmogenesis

Winter¹,

Shattock²

2015

Europace

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“…These effects of aconitine and GS967 on APD and APD restitution are consistent with previous reports. 2,25 GS967 had no proarrhythmic effects either during sinus rhythm or during rapid ventricular pacing (Supplemental Figure 1). …”

Section: Resultsmentioning

confidence: 94%

Selective inhibition of late sodium current suppresses ventricular tachycardia and fibrillation in intact rat hearts

Pezhouman¹,

Madahian²,

Stepanyan³

et al. 2014

Heart Rhythm

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Background Enhanced late inward Na current (INa-L) modulates action potential duration (APD) and plays a key role in the genesis of early and delayed afterdepolarizations (EADs & DADs) and triggered activity. Objectives To define the influence of selective block of the INa-L on EAD- & DAD-mediated triggered ventricular tachycardia and fibrillation (VT & VF) in intact hearts using (GS967), a selective and potent (IC50=0.13±0.01 μM) blocker of the INa-L. Methods VT/VF were induced either by local aconitine injection (50 μg) in the LV muscle of adult (3–4 months) male rats (N=21) or by arterial perfusion of 0.1 mM H2O2 in aged male rats (24–26 months, N=16). The LV epicardial surface of the isolated-perfused hearts was optically mapped using fluorescent voltage-sensitive dye, and microelectrode recordings of APs were made adjacent to the aconitine injection site. The suppressive and preventive effects of GS967 (1 μM) against EAD/DAD-mediated VT/VF were then determined. Results Aconitine induced VT in all 13 hearts studied. Activation map (N=6) showed that the VT was initiated by a focal activity arising from the aconitine injection site (CLs of 84±12) that degenerated to VF (CL=52±8 ms) within a few seconds. VF was maintained by multifocal activity with occasional incomplete reentrant wavefronts. Administration of GS967 suppressed the VT/VF in 10 out of 13 hearts (P<0.001). Pre-exposure to GS967 for 15 min prior to aconitine injection prevented the initiation of VT/VF in 5 of 8 additional hearts (P<0.02). The VF reoccurred within 10 min upon washout of GS967. Microelectrode recordings (N=7) showed that the VT/VF was initiated by EAD- and DAD-mediated triggered activity at CL of 86±14ms (NS from VT CL) that preceded the VF. GS967 shortened the AP duration (APD), flattened the slope of the dynamic APD restitution curve and reduced APD dispersion from 42±12 ms to 8±3 ms (P<0.01). H2O2 perfusion in 8 fibrotic aged hearts promoted EAD-mediated focal VT/VF, which was suppressed by GS967 in 5 hearts (P<0.02). Conclusions The selective INa-L blocker GS967 effectively suppresses and prevents aconitine and oxidative stress-induced EADs, DADs and focal VT/VF. The suppression of EADs, DADs and reduction of APD dispersion make GS967 a potentially useful antiarrhythmic drug in conditions of enhanced INa-L.

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“…The toxic components of Chuan-wu include AC and mesaconitine. AC can stimulate the vagus nerve, and inhibit the sinoatrial node and conduction system, resulting in a slowed heart rate and conduction block ( 24 , 25 ). In addition, AC can act directly on myocardial cells, promoting the opening of Na + channels, accelerating the ion influx, inducing cell membrane depolarization and improving the automaticity of fast response cells, including atrioventricular bundles and Purkinje fibers, thereby causing one-source or multifocal ectopic rhythms ( 26 , 27 ).…”

Section: Discussionmentioning

confidence: 99%

Protective effect of berberine on aconite‑induced myocardial injury and the associated mechanisms

Chen

Guo

et al. 2018

Mol Med Report

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Aconitum plants, which have analgesic, diuretic and anti-inflammatory effects, have been widely used to treat various types of disease. However, the apparent toxicity of Aconitum-derived agents, particularly in the cardiovascular system, has largely limited their clinical use. Thus, the present study investigated whether berberine (Ber), an isoquinoline alkaloid, may reduce myocardial injury induced by aconitine (AC) in rats and the underlying mechanisms. Rats (n=40) were randomly divided into four groups: Control, Chuan-wu and Chuan-wu + Ber (8 and 16 mg/kg doses). Electrocardiograms (ECG) of the rats were recorded and serum biomarkers of cardiac function [lactate dehydrogenase (LDH), creatine kinase (CK) and CK-MB] were assayed. Histopathological changes were assessed using myocardial tissue sectioning and hematoxylin and eosin staining. Additionally, the effects of Ber on AC-induced arrhythmias in rats were observed. The changes in ECG following AC perfusion were observed, and the types and onset time of arrhythmias were analyzed. Furthermore, the effects of Ber and AC on papillary muscle action potentials were observed. The results suggested that Ber ameliorated myocardial injury induced by Chuan-wu, which was indicated by reduced arrhythmias and decreased LDH, CK and CK-MB levels in serum. Furthermore, histological damage, including dilation of small veins and congestion, was also markedly attenuated by Ber. In addition, the occurrence of arrhythmias was significantly delayed, and the dosage of AC required to induce arrhythmias was also increased by Ber pretreatment. Additionally, AC-induced changes in action potential amplitude, duration of 30% repolarization and duration of 90% repolarization in the papillary muscle were attenuated by Ber. All of these results indicate that Ber had a preventive effect on acute myocardial injury induced by Chuan-wu and arrhythmias caused by AC, which may be associated with the inhibition of delayed depolarization and triggered activity caused by AC. Thus, combination treatment of Ber with Aconitum plants may be a novel strategy to prevent AC-induced myocardial injury in clinical practice.

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Role of the Alternans of Action Potential Duration and Aconitine-Induced Arrhythmias in Isolated Rabbit Hearts

Cited by 10 publications

References 19 publications

Geometrical considerations in cardiac electrophysiology and arrhythmogenesis

Geometrical considerations in cardiac electrophysiology and arrhythmogenesis

Selective inhibition of late sodium current suppresses ventricular tachycardia and fibrillation in intact rat hearts

Protective effect of berberine on aconite‑induced myocardial injury and the associated mechanisms

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