Possible Involvement of Altered Na+-Ca2+ Exchange in Negative Inotropic Effects of Class I Antiarrhythmic Drugs on Rabbit and Rat Ventricles

Ito, Katsuaki; Nagafuchi, Kazunori; Taga, Atsuo; Yorikane, Ryosuke; Koike, Hiroyuki

doi:10.1097/00005344-199603000-00007

Cited by 22 publications

(10 citation statements)

References 25 publications

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“…In this study, all class I antiarrhythmic drugs exerted a dose-dependent negative inotropic effect, which is in good accordance with our previous reports [6][7][8]12], and those of others [20][21][22][23], indicating the reliability and reproducibility of the currently used bloodperfused preparations. In addition, this model can be used to study more subtle, yet potentially important, inotropic effects of class I drugs.…”

Section: Discussionsupporting

confidence: 93%

“…For example, class Ib drugs, including lidocaine, mexiletine, tocainide, and phenytoin, showed a negative inotropic action at a pacing rate of 120 beats/rain, although the negative inotropic actions of class Ib drugs are commonly said to be clinically insignificant [24]. Since the negative inotropic effects of the class I drugs correlated well with their antiarrhythmic potency on the canine ventricular arrhythmia models, which was demonstrated to be a direct function of the extent of sodium channel inhibition [9], the blockade of sodium channels may account for a major part of the negative inotropic effect of class I antiarrhythmic drugs, as already suggested in previous reports [7,20,21,25]. Moreover, procainamide, quinidine, and verapamil decreased the contraction of papillary muscle with a transient increase, which is in accordance with previous reports [7,26].…”

Section: Discussionmentioning

confidence: 54%

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Negative chronotropic and inotropic effects of class I antiarrhythmic drugs assessed in isolated canine blood-perfused sinoatrial node and papillary muscle preparations

et al. 1999

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The present study was designed to assess the negative chronotropic and inotropic effects of 10 class I antiarrhythmic drugs, using isolated canine blood-perfused sinoatrial node and papillary muscle preparations. Each drug showed negative chronotropic and inotropic effects in a dose-related manner. The potency of the suppressive effect on the sinoatrial automaticity was in the order of aprindine, quinidine, flecainide, lidocaine, mexiletine, cibenzoline, disopyramide, procainamide, tocainide, and phenytoin, while the effect on the ventricular contraction was in the order of aprindine, flecainide, cibenzoline, lidocaine, mexiletine, disopyramide, tocainide, phenytoin, quinidine, and procainamide. The differences in the suppressive effects could not necessarily be explained by their subclassification, based either on action potential duration or kinetic properties of dissociation or association with sodium channels. On the other hand, we found a good correlation between the negative inotropic effects of class I drugs in this study and the canine antiarrhythmic plasma concentrations for the digitalis- and coronary ligation-induced ventricular arrhythmia models in our previous studies. However, the negative chronotropic effects of the drugs showed a poor correlation with the antiarrhythmic plasma drug concentrations. The data shown in this paper may provide a convenient guideline for predicting acute cardiosuppressive effects of antiarrhythmic drugs, especially in patients with reduced cardiac function.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 54%

Negative chronotropic and inotropic effects of class I antiarrhythmic drugs assessed in isolated canine blood-perfused sinoatrial node and papillary muscle preparations

et al. 1999

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“…Under these conditions, a potent sodium channel blocker like flecainide can reduce the oscillatory potentials that initiate BVT. In support of this hypothesis, in rabbit myocardium, inhibition of sodium channels by flecainide and other class I antiarrhythmic drugs alter the sodium‐calcium exchange, resulting in a decrease in calcium through the exchanger and the calcium content in the sarcoplasmic reticulum 12,13 …”

Section: Discussionmentioning

confidence: 92%

Flecainide Suppresses Bidirectional Ventricular Tachycardia and Reverses Tachycardia‐Induced Cardiomyopathy in Andersen‐Tawil Syndrome

Pellizzón

Kalaizich

Ptáček

et al. 2007

Cardiovasc electrophysiol

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BVT and Andersen-Tawil Syndrome. Bidirectional ventricular tachycardia (BVT), although a rare arrhythmia in the general population, is frequently observed in patients with Andersen-Tawil syndrome and long QT interval. However, the pharmacologic treatment of this arrhythmia remains unknown. In the present study, we documented the favorable antiarrhythmic action of flecainide in a young woman with sustained BVT and Andersen-Tawil syndrome. She presented with incessant BVT that could only be terminated with flecainide. During sinus rhythm, a prolonged QT interval was observed. Genetic studies revealed a mutation in the K + channel gene KCNJ2. Over a 4-year follow-up period, recurrence of her arrhythmia occurred twice. The first episode was due to noncompliance and resolved with resumption of flecainide therapy. The second recurrence was associated with a tachycardia-induced cardiomyopathy and resolved when the dose of flecainide was increased from 200 to 300 mg daily. This report suggests that flecainide can be effective in controlling BVT associated with Andersen-Tawil syndrome and indicates that the left ventricular dysfunction is secondary to the arrhythmia and not due to an associated phenotypic manifestation of the disorder. (J Cardiovasc Electrophysiol, Vol. 19, pp. 95-97, January 2008.) bidirectional ventricular tachycardia, long QT syndrome, Andersen-Tawil syndrome, flecainide Case Report A 16-year-old female was referred for evaluation of sustained bidirectional ventricular tachycardia (BVT) associated with dizziness. The patient had no known heart disease, was on no medications, and had no family history of heart disease or sudden death. Physical examination was normal except for mild symmetric lower extremity weakness. Serum laboratory assessments, chest x-ray, echocardiography, and cardiac magnetic resonance imaging were all normal. On admission, an electrocardiogram showed BVT with alternating QRS complexes (Fig. 1). Atrial and ventricular transesophageal stimulation failed to terminate the arrhythmia. Multiple drugs given intravenously were also unsuccessful, including lidocaine, propranolol, diltiazem, potassium chloride, and magnesium sulfate. Administration of oral flecainide 100 mg twice a day suppressed the arrhythmia and allowed resumption of sinus rhythm with a distinct long QT interval and biphasic T waves (Fig. 2). Genetic analysis demonstrated an R67W mutation in the K+ channel gene KCNJ2. The patient refused ICD implantation and was discharged on flecainide therapy. A complete cardiovascular evaluation of her parents and three brothers disclosed no abnormalities. During a 4-year follow-up period, the patient had two recurrences of BVT. The first episode was due to noncompliance and the arrhythmia disappeared when the patient resumed flecainide treatment. The second episode occurred 3 years later while on flecainide and was associated with congestive heart failure and globally depressed left ventricular function (ejection fraction 25%). The arrhythmia was controlled when the daily dose of...

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“…In mouse cardiomyocytes preparations, Na + influx during the rapid upslope of the action potential reverses NCX (Na + outward and Ca + inward), facilitating Ca + entry into the cell which further triggers the release of intracellular Ca + from the sarcoplasmic reticulum . In tissue models, Na + channel blockade by class I antiarrhythmics altered NCX, thereby reducing Ca + ‐induced Ca + release . Although not studied with phenytoin, inhibition of reverse NCX could be another potential mechanism of action.…”

Section: Discussionmentioning

confidence: 99%

Short‐term response to phenytoin sodium in Andersen‐Tawil syndrome‐1 with a cardiac‐dominant phenotype

Maneesh

Pai

Prabhu

et al. 2018

Pacing Clinical Electrophis

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Background Andersen‐Tawil syndrome (ATS) is a rare familial periodic paralysis that typically also affects the heart and skeletal system. Ventricular arrhythmias (VAs) are profound and difficult to control, but minimally symptomatic. In this report, we describe an atypical phenotype of ATS in two related families. We also report our experience with phenytoin sodium for the control of resistant VAs in these patients. Methods and Results Between 2014 and 2018, seven siblings were diagnosed with ATS on the basis of cardiac arrhythmias and genetic evaluation. Heterozygous mutation with c.431G > C (p.G144A) in exon 2 of KCNJ2 gene was observed in all patients. Characteristic cardiac manifestations were noted in all patients but periodic paralysis or objective neurological involvement was distinctly absent. Phenytoin was considered for control of symptomatic VA in three patients. Intake of oral phenytoin (5 mg/kg/day) for 1 month completely suppressed VA (<1% in 24‐h Holter monitoring) in two patients, and significantly in the third (8% per 24 h) patient. Phenytoin was well‐tolerated in all three patients. Conclusions We describe a cardiac‐predominant phenotype in ATS. ATS should be suspected in patients with typical cardiac manifestations even in the absence of periodic paralysis. Our initial experience with short‐term use of phenytoin for control of resistant VAs is encouraging.

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Possible Involvement of Altered Na+-Ca2+ Exchange in Negative Inotropic Effects of Class I Antiarrhythmic Drugs on Rabbit and Rat Ventricles

Cited by 22 publications

References 25 publications

Negative chronotropic and inotropic effects of class I antiarrhythmic drugs assessed in isolated canine blood-perfused sinoatrial node and papillary muscle preparations

Negative chronotropic and inotropic effects of class I antiarrhythmic drugs assessed in isolated canine blood-perfused sinoatrial node and papillary muscle preparations

Flecainide Suppresses Bidirectional Ventricular Tachycardia and Reverses Tachycardia‐Induced Cardiomyopathy in Andersen‐Tawil Syndrome

Short‐term response to phenytoin sodium in Andersen‐Tawil syndrome‐1 with a cardiac‐dominant phenotype

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