Inhibitory effect of the class III antiarrhythmic drug nifekalant on HERG channels: mode of action

Kushida, Shunichi; Ogura, Takehiko; Komuro, Issei; Nakaya, Haruaki

doi:10.1016/s0014-2999(02)02666-3

Cited by 26 publications

(18 citation statements)

References 25 publications

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“…1,2 Nifekalant (NIF) hydrochloride is a new class III antiarrhythmic drug developed in Japan that causes dose-dependent prolongation of action potential duration (APD) in both atrial and ventricular muscle, mainly by reducing the rapid component of the delayed rectifier potassium current (IKr). [3][4][5][6][7] The 2000 American Heart Association Guidelines for cardiopulmonary resuscitation (CPR) recommends intravenous amiodarone to prevent recurrent VT/VF, 8,9 but amiodarone has not yet been approved for CPR in Japan and intravenous NIF is used, often in combination with lidocaine (LID), as an alternative. 10 Nifekakant and LID are also used sequentially to treat recurrent VT/VF resistant to DC shocks; 11-13 however, little information is available on the electropharmacological basis for the combined use of these drugs.…”

mentioning

confidence: 99%

Combined Effects of Nifekalant and Lidocaine on the Spiral-Type Re-Entry in a Perfused 2-Dimensional Layer of Rabbit Ventricular Myocardium

Amino

Yamazaki

Nakagawa

et al. 2005

Circ J

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piral-type excitation is the principal mechanism of functional re-entry for the genesis of life-threatening ventricular tachycardia and ventricular fibrillation (VT/VF). 1,2 Nifekalant (NIF) hydrochloride is a new class III antiarrhythmic drug developed in Japan that causes dose-dependent prolongation of action potential duration (APD) in both atrial and ventricular muscle, mainly by reducing the rapid component of the delayed rectifier potassium current (IKr). [3][4][5][6][7] The 2000 American Heart Association Guidelines for cardiopulmonary resuscitation (CPR) recommends intravenous amiodarone to prevent recurrent VT/VF, 8,9 but amiodarone has not yet been approved for CPR in Japan and intravenous NIF is used, often in combination with lidocaine (LID), as an alternative. 10 Nifekakant and LID are also used sequentially to treat recurrent VT/VF resistant to DC shocks; 11-13 however, little information is available on the electropharmacological basis for the combined use of these drugs. The present study was designed to investigate the effects of NIF and NIF + LID on the spiral-type excitation in a perfused 2-dimensional (D) layer of rabbit ventricle by using our custom-made high-resolution optical mapping system. Methods Experimental ModelJapanese White rabbits of both sexes weighing 1.7-2.0 kg (n=13) were anesthetized with thiamylal sodium (10-15 mg/kg), and after opening the thorax, the heart was rapidly removed. Complete atrioventricular block was produced by ligating the His bundle with fine silk thread. The aorta was then cannulated, and the heart was connected to a Langendorff perfusion apparatus. The coronary arteries were perfused with modified Krebs Ringer solution at a constant flow (35-45 ml/min). The solution was equilibrated with 95% O2 and 5% CO2 to maintain its pH at 7.4, and its temperature was maintained at 35°C.Because of its 3-D structure with variable filament configuration, vortex-type excitations appear only transiently and incidentally in the intact heart, 14 thereby hampering detailed analysis of spiral dynamics by optical mapping. To avoid this problem, we created a 2-D preparation by the method described by Schalij et al. 15 In brief, the Langendorff-perfused rabbit heart was immersed in a tissue bath containing perfusion fluid at 35°C, and a cryoprobe made of copper was inserted into the left ventricular cavity, and the probe was then filled with liquid nitrogen (-192°C) for 5 min. This freezing procedure destroyed the endocardial and intramural layers of the free wall of the left ventricle and the total interventricular septum, leaving only Background Spiral re-entry plays the principal role in the genesis of ventricular tachycardia and ventricular fibrillation (VT/VF). The specific IKr blocker, nifekakant (NIF) has, often in combination with lidocaine (LID), recently been used in Japan to prevent recurrent VT/VF, but the combined effects of these drugs on spiral reentry had never been investigated. Methods and ResultsA ventricular epicardial sheet was obtained from 13 Langendorff-pe...

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confidence: 99%

Combined Effects of Nifekalant and Lidocaine on the Spiral-Type Re-Entry in a Perfused 2-Dimensional Layer of Rabbit Ventricular Myocardium

Amino

Yamazaki

Nakagawa

et al. 2005

Circ J

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“…In the present study, ICD shock increased the QTc‐D, as has been reported previously [5,6]; however, the deterioration of QTc‐D did not continue for 30 min because there were no differences in any parameter between the CONTROL‐1 and CONTROL‐2 groups. NIF is known to block the delayed rectifier K + channel, especially the I kr channel [9,10], which results in a prolonged action potential duration. The blocking effect of NIF on the I kr channel has been reported to occur rapidly, but recovery from the block is slow [9].…”

Section: Discussionmentioning

confidence: 99%

“…Few therapeutic options are currently available for controlling electrical storms. Nifekalant hydrochloride (NIF) is a class III antiarrhythmic drug that causes dose‐dependent prolongation of the action potential duration in both atrial and ventricular muscle, mainly by reducing the rapid component of the delayed rectifier K + current ( I kr ) [9,10]. Several clinical studies have demonstrated the effectiveness of intravenous NIF for recurrent ventricular tachyarrhythmias that are resistant to other antiarrhythmic drugs and ICD shock [11], especially electrical storms [12].…”

Section: Introductionmentioning

confidence: 99%

The effects of nifekalant hydrochloride on the spatial dispersion of repolarization after direct current defibrillation in patients with oral amiodarone and β‐blocker therapy

Maeda

Takagi

Tatsumi

et al. 2013

Journal of Arrhythmia

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a b s t r a c tBackground: Although nifekalant hydrochloride (NIF) has been demonstrated to suppress ventricular tachyarrhythmias, especially electrical storms, the mechanism by which it does so is still unclear. We examined the effects of NIF on the spatial dispersion of repolarization (SDR) after implantable cardioverter-defibrillator (ICD) shock. Methods and Results: In 35 patients with oral amiodarone and β-blocker therapy, and an ICD, we recorded the 87-lead electrocardiogram during sinus rhythm (CONTROL-1 group) under general anesthesia, and just after the termination of induced ventricular fibrillation (VF) by ICD shock, with or without NIF administration. In all recordings, the corrected QT interval (QTc) was measured in each lead. The dispersion of QTc (QTc-D; maximum QTc minus minimum QTc) was also measured. Compared with that in the CONTROL-1 group, the QTc-D exhibited significant deterioration after ICD shock (61 7 14 and 907 19 ms 1/2 , respectively; po0.05). However, after the termination of induced VF by ICD shock with NIF administration, the QTc-D did not differ significantly from that in the CONTROL-1 group (637 20 and 61 7 14 ms 1/2 , respectively). Conclusions: NIF suppressed the deterioration of the SDR after ICD shock. This might be one of the mechanisms by which NIF suppresses recurrence of ventricular tachyarrhythmia just after ICD shock in patients with oral amiodarone and β-blocker therapy.

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“…10) Nifekalant has been shown to selectively inhibit the rapid component of the delayed rectifier K + current (IKr) in cardiomyocytes. 11,12) and relatively high doses of nifekalant prolong the QT interval leading to torsades de pointes. 13) This study was designed to examine the antiarrhythmic effects of nicorandil on nifekalantinduced EADs, premature ventricular contractions (PVCs), and ventricular tachycardia (VT) in a chronic atrioventricular conduction block model because previous studies have demonstrated that the electrical remodeling occurring after complete atrioventricular block predisposes the heart to acquired torsades de pointes.…”

Section: P Olymorphic Ventricular Tachycardia (Pvt) Ie Torsadesmentioning

confidence: 99%

Effect of the ATP-Sensitive K+ Channel Opener Nicorandil in a Canine Model of Proarrhythmia

et al. 2011

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SummaryIncreased action potential duration (APD) induces early afterdepolarization (EAD) in vitro and torsade de pointes in vivo, and ATP-sensitive K + channel openers decrease APD in cardiac tissue. We tested whether the ATP-sensitive K + channel opener nicorandil has antiarrhythmic effects on class III antiarrhythmic drug-induced ventricular arrhythmia. In 10 anesthetized dogs with chronic atrioventricular block, we recorded monophasic action potentials (MAPs) from the left and right ventricular (LV and RV) endocardium. The class III antiarrhythmic drug nifekalant (1 mg/kg, IV) was administered at 5 minute intervals (total doses; 2-6 mg/kg) until the appearance of EADs, premature ventricular contractions (PVCs), or polymorphic ventricular tachycardias (PVTs). Five minutes after the end of nifekalant administration, nicorandil (1.0 mg/kg) was administered over 5 minutes. Nifekalant decreased the ventricular escape rate from 75 ± 5 beats/minute to 45 ± 10 beats/minute and increased RV-MAP duration (MAPD) from 217 ± 32 msec to 308 ± 2 msec (P < 0.01) and LV-MAPD from 232 ± 32 msec to 353 ± 82 msec (P < 0.01). EADs were recorded in 9 dogs, frequent premature ventricular contractions (PVCs) developed in 10 dogs, incessant PVTs developed in 3 dogs, and monomorphic ventricular tachycardia developed in 3 dogs after nifekalant administration. Nicorandil decreased RV-MAPD to 267 ± 57 msec and LV-MAPD to 279 ± 44 msec. It suppressed EADs, decreased the incidence of PVCs, and abolished PVT. Nicorandil may be clinically useful for treatment of PVCs and PVTs accompanying acquired long QT syndrome. (Int Heart J 2011; 52: 318-322)

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Inhibitory effect of the class III antiarrhythmic drug nifekalant on HERG channels: mode of action

Cited by 26 publications

References 25 publications

Combined Effects of Nifekalant and Lidocaine on the Spiral-Type Re-Entry in a Perfused 2-Dimensional Layer of Rabbit Ventricular Myocardium

Combined Effects of Nifekalant and Lidocaine on the Spiral-Type Re-Entry in a Perfused 2-Dimensional Layer of Rabbit Ventricular Myocardium

The effects of nifekalant hydrochloride on the spatial dispersion of repolarization after direct current defibrillation in patients with oral amiodarone and β‐blocker therapy

Effect of the ATP-Sensitive K+ Channel Opener Nicorandil in a Canine Model of Proarrhythmia

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