Diphenylhydantoin Sodium in Cardiac Arrhythmias

Conn, Robert D.

doi:10.1056/nejm196502112720602

Cited by 126 publications

(38 citation statements)

References 10 publications

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“…In preliminary results in our laboratory we find that under the ionic conditions in which DPH enhances ATPase activity, DPH also enhances the uptake of potassium into synaptosomes. 3 Another present limitation of ascribing the action of, DPH to its stimulatory effect on Na-KATPase activity exists. The neuronal intracellular sodium concentration in the seizure state is not known; and at present there is no evidence that the ratios which cause stimulation in vitro exist in the seizure state in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Under all ionic conditions examined, DPH produced no apparent change in enzyme affinity for ATP. INTRODUCTION Diphenylhydantoin sodium (DPH) has been effective in the treatment and management of major motor and psychomotor seizures as well as in the control of certain cardiac arrhythmias (1)(2)(3)(4). Our knowledge of the distribution, metabolism, and excretion of the drug in man and experimental animals is extensive (5), but its mechanism of action on excitable membranes has not yet been clearly defined.…”

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confidence: 99%

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Effect of diphenylhydantoin on synaptosome sodium-potassium-ATPase

Festoff¹,

Appel

1968

J. Clin. Invest.

111

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A B ST R A C T Previous studies have demonstrated that electrically induced seizures in rat result in an increased brain intracellular sodium which can be decreased by treatment with sodium diphenylhydantoin (DPH). The correlation of cation transport with membrane-oriented sodiumpotassium-adenosine triphosphatase (Na-K-ATPase) prompted an investigation of the effect of DPH upon ATPase enzyme activity.Rat cerebral cortical synaptosomes isolated in Ficoll gradients were employed as the source for Na-K-ATPase. With 50 mm Na, 10 mm K, 7.5 mm Mg, and 1.8 mm ATP, the specific activity of the preparation was 70 ptmoles Pi released/mg synaptosomal protein per 30 min. The ionic and substrate concentrations yielding one-half maximal velocity were 0.5 mm K, 5 mm Na, and 8.5 X 10-5 M ATP, respectively.At 50 mm Na and 0.2 mm K, DPH produced an average of 92% stimulation of Pi release above control. The ratio of Na: K rather than the absolute levels of the ions was critical in determining the effect of DPH. DPH produced significant stimulation of enzyme activity under conditions of a high Na: K ratio (25-50: 1). At ratios of 5-10: 1, DPH produced little or no effect, and at low Na: K ratios (less than 5: 1), DPH was inhibitory. Under all ionic conditions examined, DPH produced no apparent change in enzyme affinity for ATP.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Effect of diphenylhydantoin on synaptosome sodium-potassium-ATPase

Festoff¹,

Appel

1968

J. Clin. Invest.

111

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“…• Recent reports indicate that diphenylhydantoin sodium (DPH) is effective in abolishing many ventricular arrhythmias (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Among the atrial arrhythmias, only supraventricular tachycardia, paroxysmal atrial tachycardia, and digitalis-induced atrial arrhythmias usually respond to DPH therapy 4 6 4…”

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confidence: 99%

Actions of Diphenylhydantoin on the Electrical Properties of Isolated Rabbit and Canine Atria

Strauss

Bigger

Bassett

et al. 1968

Circulation Research

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The effects of diphenylhydantoin (DPH), 1(H to 1(HM, were studied on the various types of cells in the isolated right atrial preparation and on the specialized cells of Bachmann's bundle in atrial preparations obtained from puppies. High concentrations of DPH (1(HM) slowed sinoatrial rate but lower concentrations had little effect. These chronotropic effects of DPH were direct. DPH in concentrations above 10~5M decreased the slope of phase 4 depolarization in cells in the sinoatrial node and venous automatic tissue. DPH in concentrations of 1C H to ICHM had no effect on transmembrane action potentials recorded from any cell studied; concentrations of ICMM, however, prolonged the terminal phase of repolarization. High concentrations (ICHM) also prolonged the effective refractory period of Bachmann's bundle and ordinary atrial and perinodal fibers by an average of 10%. DPH markedly increased the dv/dt of phase 0 of the action potential and membrane responsiveness of ordinary atrial and specialized Bachmann's bundle fibers under control conditions and produced more striking increases when these two variables had been decreased by ouabain. DPH was also proved capable of reversing ouabain-induced sinoatrial block. This unique ability of DPH to enhance membrane responsiveness and to improve conduction in the absence of significant effects on the effective refractory period and automaticity of atrial cells suggests that this may be the sole mechanism of its antiarrhythmic action.ADDITIONAL KEY WORDS automaticity transmembrane potentials effective refractory period antiarrhythmic activity reactivation membrane responsiveness acetylcholine atropine catecholamines• Recent reports indicate that diphenylhydantoin sodium (DPH) is effective in abolishing many ventricular arrhythmias (1-11). Among the atrial arrhythmias, only supraventricular tachycardia, paroxysmal atrial tachycardia, and digitalis-induced atrial arrhythmias usually respond to DPH therapy From the

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“…Diphenylhydantoin is an antiarrhythmic agent which seems to have particular value in the treatment of digitalis-induced arrhythmias (10)(11)(12)(13). Experimental studies indicate that in the treatment of digitalis toxicity, diphenylhydantoin may be superior to agents such as procaine amide, since diphenylhydantoin decreases ventricular automaticity without affecting intraventricular conduction, thus minimizing the possibility of causing reentry (14).…”

Section: Discussionmentioning

confidence: 99%

Electrophysiological Effects of Direct Current Countershock before and after Ouabain Sensitization and after Diphenylhydantoin Desensitization in the Dog

Helfant

Scherlag

Damato

1968

Circulation Research

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The effects of synchronized direct current countershock on ventricular automaticity, intraventricular conduction, and atrioventricular conduction were studied before and after ouabain administration and after diphenylhydantoin. At the level of electrical energy that induced ventricular arrhythmias, averaging 159 watt-seconds, countershock transiently increased ventricular automaticity and prolonged both intraventricular and atrioventricular conduction time. Immediately after ouabain-induced ventricular tachycardia returned to regular sinus rhythm, underlying ventricular automaticity and intraventricular and atrioventricular conduction times were increased. An average of 23 watt-seconds produced overt and persistent ventricular tachycardias due to enhanced automaticity or re-entry. Atrioventricular and inrraventricular conduction times were also prolonged, and transient complete heart block occurred in two experiments. Diphenylhydantoin administration at this time depressed ventricular automaticity, caused a speeding of atrioventricular and intraventricular conduction times and increased the electrical energy necessary to produce ventricular tachycardia to 355 watt-seconds.ADDITIONAL KEY WORDS intraventricular conduction heart block ventricular automaticity atrioventricular conduction re-entry• Synchronized direct current countershock is an accepted procedure for the termination of a number of cardiac arrhythmias. However, despite its widespread use, the electrophysiological effects of direct current countershock on the heart have only recently received attention (1). This is particularly important in understanding why some patients taking digitalis develop serious postshock arrhythmias (2-5). Although it has been demonstrated experimentally that digitalis administration greatly increases the sensitivity to postshock arrhythmias (6), the electrophysio- Accepted for publication March 20, 1968. logical mechanism for this sensitivity phenomenon remains unknown. In addition, a recent experimental study in our laboratory demonstrated that diphenylhydantoin greatly increases the amount of electrical energy required to produce an arrhythmia by countershock after digitalis sensitization (7). The electrophysiological effects of these interventions were explored in the present study by ascertaining the effects of direct current countershock on ventricular automaticity, intraventricular conduction and atrioventricular conduction before and after ouabain sensitization and after diphenylhydantoin desensitization. MethodTwenty-three adult mongrel dogs were anesthetized with intravenous sodium pentobarbital (30 mg/kg) after an overnight fast. A polyethylene catheter was inserted into the femoral

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Diphenylhydantoin Sodium in Cardiac Arrhythmias

Cited by 126 publications

References 10 publications

Effect of diphenylhydantoin on synaptosome sodium-potassium-ATPase

Effect of diphenylhydantoin on synaptosome sodium-potassium-ATPase

Actions of Diphenylhydantoin on the Electrical Properties of Isolated Rabbit and Canine Atria

Electrophysiological Effects of Direct Current Countershock before and after Ouabain Sensitization and after Diphenylhydantoin Desensitization in the Dog

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