Antiarrhythmic effects of an aconitine-like compound, TJN-505, on canine arrhythmia models

Arita, Jiro; Yi, Xue; Aye, Nu Nu; Fukuyama, Kiyoshi; Wakui, Yoko; Niitsu, Kazuaki; Maruno, Masao; Chen, Siying; Hashimoto, Keitaro

doi:10.1016/s0014-2999(96)00793-5

Cited by 3 publications

(3 citation statements)

References 23 publications

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“…The type 2 receptor site on voltage-gated Na + channels is a binding site for aconitine that increases Na + channel permeability and shifts the action potential towards a more hyperpolarized state in voltage-clamp studies (7, 8). Thereby causing a persistent activation of the Na + channels, as well as the prolongation of the QT interval and APD, which become more refractory to subsequent stimulation (1, 9). One explanation is that the 2:1 conduction block occurred at a longer pacing cycle length with aconitine compared to the baseline.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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Under conditions of Na+ channel hyperactivation with aconitine, the changes in action potential duration (APD) and the restitution characteristics have not been well defined in the context of aconitine-induced arrhythmogenesis. Optical mapping of voltage using RH237 was performed with eight extracted rabbit hearts that were perfused using the Langendorff system. The characteristics of APD restitution were assessed using the steady-state pacing protocol at baseline and 0.1 µM aconitine concentration. In addition, pseudo-ECG was analyzed at baseline, and with 0.1 and 1.0 µM of aconitine infusion respectively. Triggered activity was not shown in dose of 0.1 µM aconitine but overtly presented in 1.0 µM of aconitine. The slopes of the dynamic APD restitution curves were significantly steeper with 0.1 µM of aconitine than at baseline. With aconitine administration, the cycle length of initiation of APD alternans was significantly longer than at baseline (287.5 ± 9.6 vs 247.5 ± 15.0 msec, P = 0.016). The functional reentry following regional conduction block appears with the progression of APD alternans. Ventricular fibrillation is induced reproducibly at pacing cycle length showing a 2:1 conduction block. Low-dose aconitine produces arrhythmogenesis at an increasing restitution slope with APD alternans as well as regional conduction block that proceeds to functional reentry.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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“…Aconitine-induced arrhythmias or abnormal electrical activity were used to study antiarrhythmic effects in mice, rat, dog, guinea pig, and rabbit models (Winslow, 1980;Honerjager and Meissner, 1983;Sawanobori et al, 1987;Lu and Clerck, 1993;Arita et al, 1996). In the whole-animal models, various types of ventricular tachyarrhythmias were induced as PVC, VT, torsades de pointes, and VF.…”

Section: Discussionmentioning

confidence: 99%

Effects of Sodium-Calcium Exchange Inhibitors, KB-R7943 and SEA0400, on Aconitine-Induced Arrhythmias in Guinea Pigs in Vivo, in Vitro, and in Computer Simulation Studies

Amran¹,

Hashimoto²,

Homma³

2004

J Pharmacol Exp Ther

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The sodium-calcium exchange (NCX) plays a pivotal role in regulating contractility and electrical activity in the heart. However, the effects of NCX blockers on ventricular arrhythmias are still controversial. We examined the effects of KB-R7943 (KBR) and SEA0400 (SEA), two NCX blockers, on aconitine-induced arrhythmias in guinea pigs using the ECG recordings and the current-clamp method. Using Luo's and Rudy's computer model (1991 Circ Res 68:1501-1526) for ventricular myocytes, we simulated abnormal membrane activity produced by NCX inhibition. In the whole-animal model, KBR in a dose range of 1 to 30 mg/kg (intravenous) suppressed aconitine-induced arrhythmias dose-dependently, but 10 mg/kg of SEA did not suppress these arrhythmias. There was a difference in isolated ventricular myocytes also. KBR (10 M) suppressed abnormal electrical activity induced by aconitine, but SEA (100 M) did not show such effects. KBR (10 M) significantly changed the shape of the action potential configurations (action potential duration at 50% repolarization), but SEA (1-100 M) did not change these configurations. In the computer simulation study, the aconitine-induced abnormal electrical activity was mimicked by a negative shift of the kinetics of Na ϩ channels, and this was followed by additional suppression of NCX activity by 90% (mimicking the effect of NCX inhibitors), which enhanced abnormal membrane activity. Our results indicate that the inhibition of aconitine-induced arrhythmias by KBR, not by SEA, might result from a mechanism other than the inhibition of NCX, and thus the involvement of the NCX system plays an insignificant role in the aconitine-induced arrhythmias.

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“…In the study, the actions of mexiletine and disopyramide were additive, but those of mexiletine and aprindine were not. As shown in Table 1, TJN-505 is a chemically aconitine-like drug acting on Na + channels and was effective on the two-stage coronary ligation arrhythmia, but there is no data on this drug as a Na + -channel-blocking drug in the in vitro cardiac tissue (38). HNS-32 is also such a drug with Na + -channel-blocking activity and was shown to be effective on this arrhythmia (39).…”

Section: -1-3 Antiarrhythmic Drugsmentioning

confidence: 99%

Arrhythmia Models for Drug Research: Classification of Antiarrhythmic Drugs

Hashimoto

2007

J Pharmacol Sci

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Abstract. The aim of this study was to classify antiarrhythmic drugs based on their effectiveness on 6 in vivo arrhythmia models, mainly using dogs. The models were produced by two-stage coronary ligation, digitalis, halothane-adrenaline, programmed electrical stimulation in old myocardial infarction dogs, coronary artery occlusion / reperfusion, or chronic atrioventricular block. Na + -channel-blocking drugs suppressed two-stage coronary ligation and digitalis arrhythmias. Ca 2+ -channel blockers and β-blockers suppressed halothane-adrenaline arrhythmia. Positive inotropic drugs aggravated halothane-adrenaline arrhythmia, but did not aggravate digitalis arrhythmia. K + -channel blockers suppressed programmed electrical stimulation induced arrhythmia, but induced torsades de pointes type arrhythmia in chronic atrioventricular block dogs and aggravated halothane-adrenaline arrhythmia. Na

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Antiarrhythmic effects of an aconitine-like compound, TJN-505, on canine arrhythmia models

Cited by 3 publications

References 23 publications

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

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

Effects of Sodium-Calcium Exchange Inhibitors, KB-R7943 and SEA0400, on Aconitine-Induced Arrhythmias in Guinea Pigs in Vivo, in Vitro, and in Computer Simulation Studies

Arrhythmia Models for Drug Research: Classification of Antiarrhythmic Drugs

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