Digitalis-induced Ventricular Arrhythmias Research Articles

Ivabradine Reduces Digitalis-induced Ventricular Arrhythmias.

The I(f) channel inhibitor ivabradine is recommended for treatment of heart failure but also affects potassium currents and thereby prolongs ventricular repolarization. The aim of this study was to examine the electrophysiological effects of ivabradine on digitalis-induced ventricular arrhythmias. Thirteen rabbit hearts were isolated and Langendorff-perfused. After obtaining baseline data, the digitalis glycoside ouabain was infused (0.2 μM). Monophasic action potentials and ECG showed a significant abbreviation of QT interval (-34 ms, p < 0.05) and action potential duration (APD90 ; -27 ms, p < 0.05). The shortening of ventricular repolarization was accompanied by a reduction in effective refractory period (ERP; -27 ms, p < 0.05). Thereafter, hearts were additionally treated with ivabradine (5 μM). Of note, this did not exert significant effects on QT interval (-4 ms, p = ns) or APD90 (-15 ms, p = ns) but resulted in an increase in ERP (+17 ms, p < 0.05). This led to a significant increase in post-repolarization refractoriness (PRR, +32 ms, p < 0.01) as compared with sole ouabain treatment. Under baseline conditions, ventricular fibrillation (VF) was inducible by a standardized pacing protocol including programmed stimulation and burst stimulation in four of 13 hearts (31%; 15 episodes). After application of 0.2 μM ouabain, eight of 13 hearts were inducible (62%, 49 episodes). Additional infusion of 5 μM ivabradine led to a significant suppression of VF. Only four episodes could be induced in two of 13 hearts (15%). In this study, ivabradine reduced digitalis-induced ventricular arrhythmias. Ivabradine did not affect ventricular repolarization in the presence of digitalis treatment but demonstrated potent anti-arrhythmic properties based on an increase in both ERP and PRR. The study further characterizes the beneficial electrophysiological profile of ivabradine.

Anesthetics and Automaticity in Latent Pacemaker Fibers III. Effects of Halothane and Ouabain on Automaticity of the SA Node and Subsidiary Atrial Pacemakers in the Canine Heart

Atrial tachyarrhythmias are a common manifestation of digitalis toxicity. Such arrhythmias could be due to enhanced automaticity of subsidiary atrial pacemakers (SAP) compared to the sinoatrial (SA) node. Halothane is known to oppose digitalis-induced ventricular arrhythmias. Its effect on digitalis-caused atrial arrhythmias is unknown. Therefore, we tested two hypotheses, as follows. First, increasing ouabain concentrations would enhance automaticity of SAP compared to the SA node and that such enhanced automaticity could explain digitalis-caused atrial tachyarrhythmias. Second, halothane would oppose such enhanced automaticity of SAP, thereby opposing digitalis-caused atrial tachyarrhythmias. A canine right atrial preparation was perfused via the SA node artery with Krebs' solution (36.0 +/- 0.5 degrees C) equilibrated with 97% oxygen-3% carbon dioxide. Four bipolar extracellular electrodes recorded the site of earliest activation (SEA), which in this preparation could be the SA node or increasingly remote sites of SAP approximately 1, 2, and 3 cm distal to the SA node along the sulcus terminalis. Pacemaker shifts to SAP during exposure to drugs were scored for magnitude of shift as 1, 2, or 3 depending on which SAP site was the SEA. Magnitude scores were summed for each test condition and normalized by dividing the total number of preparations tested. Preparations (n = 48) were exposed to 1 or 2% halothane (perfusate concentrations of 0.51 +/- 0.01 or 0.79 +/- 0.03 mM, respectively) and/or to low- or mid-therapeutic (2.5 or 5 x 10(-8) M) or borderline toxic ouabain (1 x 10(-7) M). Normalized magnitude scores were not significantly different from zero (control value) with any halothane or ouabain concentration alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Localization of the Neurally Mediated Arrhythmogenic Properties of Digitalis

Available evidence suggests that the propensity of digitalis glycosides to produce cardiac arrhythmias is due in part to their neuroexictatory effects. We have performed experiments in cats which support the existence of a neurogenic component in the etiology of digitalis-induced ventricular arrhythmias. Our data further indicate that the locus of this neural effect lies within an area of the medulla 2 millimeters above to 2 millimeters below the obex. These findings, when considered with the effects of polar cardiac glycosides that do not cross the blood-brain barrier, suggest that the area postrema may be the site of neural activation.

Effect of diazepam on digitalis-induced ventricular arrhythmias in the cat

The capacity of diazepam to counteract cardiac arrhythmias was studied in barbiturate-anesthetized cats treated with digitalis (i.e., deslanoside, 25 μg/kg given every 15 min iv). Diazepam dissolved in commercial propylene glycol solvent was administered in repeated doses of 10 mg iv at approximately 45-sec intervals to five animals exhibiting deslanoside-induced ventricular arrhythmias. Conversion of the arrhythmia to sinus rhythm was observed in two animals, while development of more serious rhythm changes was observed in the other three animals. One explanation for the deleterious effect seen with diazepam in the three animals is that the solvent itself may produce significant cardiocirculatory changes. To test this possibility, seven animals were intoxicated with deslanoside and the diazepam solvent was administered in doses of 1.0 ml every 45 sec until a total dose of 5.0 ml was given. In each animal, the administration of the solvent was associated with the development of more serious rhythm changes. Ventricular fibrillation (VF) developed 10.8 ± 1.6 min after the onset of deslanoside-induced ventricular tachycardia (VT). The corresponding time interval between deslanoside-induced VT and VF was 26.7 ± 5.0 min when no solvent was administered. These results indicate that propylene glycol solvent is deleterious to cardiac rhythm and should not be employed as a vehicle for antiarrhythmic drugs.

Effects of serotonin antagonists on digitalis-induced ventricular arrhythmias

The present study was performed to determine whether pharmacological blockade of serotonin receptors would counteract digitalis-induced ventricular arrhythmias. The effect of the serotonin receptor blocking drugs, methysergide, cinanserin, and cyproheptadine on ventricular arrhythmias produced by ouabain was studied in anesthetized dogs. Each of the three serotonin receptor blocking drugs given as a bolus i.v. injection of 1.5–3.0 mg/kg produced an antiarrhythmic effect. In addition, methysergide administered in the above doses to cats intoxicated with deslanoside, restored an abnormal ventricular arrhythmia to either sinus or junctional rhythm. Methysergide, administered to cats intoxicated with deslanoside but pretreated with p-chlorophenylalanine, exerted an antiarrhythmic effect in less than half of the animals tested. These data indicate that serotonin antagonist are effective in counteracting digitalis-induced ventricular arrhythmias and support the notion that a serotonergic mechanism may be mediating the arrhythmogenic effect of digitalis.

Role of adrenergic influences in digitalis-induced ventricular arrhythmia

Role of adrenergic influences in digitalis-induced ventricular arrhythmia

The effectiveness of magnesium chloride in the treatment of ventricular tachyarrhythmias due to digitalis intoxication

Efficacy of magnesium chloride in treatment and prevention of digitalis toxicity was studied in 39 dogs. A persistent ventricular tachycardia, lasting more than five minutes was induced in 29 dogs by deslanoside, 0.18 mg. per kilogram intravenously. In 19 animals, administration of magnesium chloride (5 to 10 ml. of a 20 per cent solution) administered intravenously converted the ventricular tachycardia into a sinus rhythm. The cardiac output was found to be increased following this treatment (P < 0.01). The serum electrolytes and digoxin levels remained unchanged. With larger doses of magnesium chloride, significant bradycardia occurred in two instances following abolition of ventricular tachycardia. When pretreatment with magnesium chloride (10 ml. intravenously and 20 ml. intramuscularly of a 20 per cent solution) was employed in a group of five dogs prior to administration of deslanoside, ventricular tachycardia from the usual or greater doses of the glycoside was invariably prevented. Deslanoside dosage larger by 83.3 per cent was then required to produce cardiotoxicity; however, VT appeared in only one out of five dogs, whereas serious A-V conduction impairment was seen in other dogs. None of the magnesium-pretreated animals developed ventricular fibrillation in spite of marked bradycardia. In 10 dogs used as control animals, the ventricular tachycardia either persisted or deteriorated into ventricular fibrillation. In conclusion, the experimental data demonstrate that magnesium chloride is effective in treatment of digitalis-induced ventricular arrhythmias.

Simultaneous measurement of atrial and ventricular pacemaker activity.

The isolated perfused rat heart with surgically-induced heart block was used to determine the effect of drugs on the activity of the atrial and ventricular pacemaker simultaneously. Complete atrio-ventricular dissociation was produced by tying a ligature around the Bundle of His under direct vision. Pacemaker rates remained stable for at least 2 hours. Perfusion of the hearts with quinidine produced a decrease in the rate of both the atrial and ventricular pacemaker. The ventricular pacemaker was more susceptible to the depressant action of quinidine than the atrial pacemaker.

Effects of lidocaine, propranolol, and sotalol on ouabain-induced changes in transmembrane potential of canine Purkinje fibers.

Isolated canine papillary muscle-false tendon preparations stimulated at 95/min were perfused with Tyrode's solution containing ouabain, 2.1 x 10 -7 M. Action potentials of Purkinje fibers were recorded. Initially ouabain increased the slope of phase-4 depolarization. Subsequently it decreased the maximum diastolic potential and the rising velocity of phase 0, the amplitude, and the duration of the action potential. The slope of phase-4 depolarization increased progressively, and eventually the configuration of the action potential changed to resemble that of sinoatrial node fibers. Onset of enhanced phase-4 depolarization was delayed significantly by treatment before exposure to ouabain with lidocaine, 3.7 x 10 -5 M, or propranolol, 2.1 x 10 -5 M, but not with sotalol, 3.2 x 10 -4 M. Enhanced phase-4 depolarization produced by exposure to ouabain was reduced in slope by subsequent treatment with lidocaine or propranolol but not sotalol. Application of lidocaine or propranolol to fibers with action potentials in the configuration characteristic of sinoatrial node fibers returned the contour of the action potentials toward normal; sotalol was not effective in this regard. These results, coupled with the relative effectiveness of these drugs in intact animals with digitalis arrhythmias, support the hypothesis that enhanced phase-4 depolarization of Purkinje fibers is a factor in the production of digitalis-induced ventricular arrhythmias.

Effect of reserpine on 22Na and 42K exchange in the cat papillary muscle.

SummaryReserpine pretreatment (1 mg/kg) given either 4 or 24 hr prior to the experiment did not affect the transmembrane exchange of Na and K in cat papillary muscles. In addition, changes occurring in Na, K, and H2O content of the muscle were not influenced by reserpine. Since it is known that quinidine causes changes in Na and K exchange and in the total Na and K content of cardiac muscle, it is unlikely that the action of reserpine to antagonize digitalis-induced ventricular arrhythmias is related to a quinidine-like effect on cardiac muscle.

Antagonism of ventricular arrhythmias induced by digitalis — a neural phenomenon

d, l-Pronethalol, d-pronethalol, d, l-propranolol, d-propranolol, d, l-INPEA, d-INPEA and l-INPEA, drugs effective in antagonizing the digitalis-induced ventricular arrhythmia, were examined for neurodepressant properties. All of these agents produced depression of the motor nerve terminals of the soleus nerve of the cat. The more potent antiarrhythmics, pronethalol, propranolol and their respective d-isomers proved to be more potent depressants of motor nerve terminal function than the less antiarrhythmic INPEA and its d- and l-isomers. However, in all cases the neurodepressant dose range is identical with the antiarrhythmic dose range. This correlation between nerve terminal depression and blockade of digitalis-induced cardiac arrhythmias suggests that neurodepression plays a role in the antiarrhythmic action of these materials.

THE EFFECTS OF A BETA-ADRENERGIC BLOCKING AGENT, PRONETHALOL, ON DIGITALIS-INDUCED VENTRICULAR ARRHYTHMIAS

Abstract The ability of pronethalol, a beta-adrenergic blocking agent, to protect against and to reverse digitalis-induced ventricular arrhythmias has been studied. Pronethalol quickly and permanently reverses arrhythmias due to acetylstrophanthidin. The dose of pronethalol required to restore promptly a sinus mehcanism was far in excess of that which produced acute beta-adrenergic blockade. Pretreatment with pronethalol, in a dose that yielded effective and prolonged beta-adrenergic blockade, failed to protect dogs against acetylstrophanthidin-induced arrhythmias in these experiments. Pretreatment with reserpine or guanethidine did not alter the ability of pronethalol to restore a sinus mechanism. It is concluded that the ability of pronethalol to reverse ventricular arrhythmias due to digitalis is not related to its action as an adrenergic blocking agent, but may be a function of its quinidine-like effect.

Autonomic nervous system and control of cardiac rhythm.

THE advent of drugs with the capacity to block the cardiac effects of catecholamines has provoked new interest in the study of the induction and blockade of rhythm disorders of the heart. Many of these new agents, such as pronethalol, depress disorders of the ventricular rhythm induced by both catecholamines and digitalis1–3. Initially, it was thought that depression of ventricular arrhythmia induced by digitalis was caused by the action of pronethalol in blocking the effect of catecholamines on the heart. It is now apparent, however, that the capacity of pronethalol to depress ventricular arrhythmia induced by digitalis is not related to the blockade of catecholamines4–6. Recently, Roberts and his colleagues6,7 have noted similar effects on digitalis-induced ventricular arrhythmia by pronethalol and β-TM10, an agent which prevents release of catecholamines from the adrenergic nerve terminals8, and have suggested that the anti-arrhythmic effect of pronethalol, like that of β-TM10, may be caused by an action of the drug on adrenergic nerve terminals.

The effects of a beta-adrenergic blocking agent, pronethalol, on digitalis-induced ventricular arrhythmias

The ability of pronethalol, a beta-adrenergic blocking agent, to protect against and to reverse digitalis-induced ventricular arrhythmias has been studied. Pronethalol quickly and permanently reverses arrhythmias due to acetylstrophanthidin. The dose of pronethalol required to restore promptly a sinus mehcanism was far in excess of that which produced acute beta-adrenergic blockade. Pretreatment with pronethalol, in a dose that yielded effective and prolonged beta-adrenergic blockade, failed to protect dogs against acetylstrophanthidin-induced arrhythmias in these experiments. Pretreatment with reserpine or guanethidine did not alter the ability of pronethalol to restore a sinus mechanism. It is concluded that the ability of pronethalol to reverse ventricular arrhythmias due to digitalis is not related to its action as an adrenergic blocking agent, but may be a function of its quinidine-like effect.

Effects of ryanodine in normal dogs and in those with digitalis-induced arrhythmias: Hemodynamic and electrocardiographic studies

The hemodynamic and electrocardiographic effects of ryanodine were studied in normal anesthetized dogs and in those with digitalis-induced ventricular arrhythmias. The electrocardiographic effects of ryanodine may be divided into three sequential overlapping phases: (1) Peaking of the T waves, broadening and flattening of the P waves, loss of the P-R segment, S-T segment depression and sinus slowing; (2) complex paroxysmal supraventricular tachycardias without impairment of A-V conduction; (3) prolonged periods of sinoatrial arrest or bradycardia with A-V block. In all phases the QRS complex was unchanged, and ectopic ventricular beats did not occur. Ryanodine reversed digitalis-induced ventricular arrhythmias in the dog by suppressing ventricular pacemakers without prolonging intraventricular conduction. The conversion to sinus rhythm was usually transient, since complex supraventricular arrhythmias probably attributable to the combined action of the two drugs often supervened. A profound negative inotropic action of ryanodine, previously demonstrated in vitro, was shown to be significant in the intact animal. This was manifested by a significant fall in the cardiac output and a rise in the left ventricular end-diastolic pressure prior to a change in rate or rhythm. The electrocardiographic and negative inotropic effects of ryanodine are similar to those of hyperkalemia, although it is probable that all the observed changes cannot be explained by this mechanism. Since the negative inotropic effects of ryanodine were observed at the same dose required for reversal of the digitalis-induced ventricular arrhythmia, it is likely that the toxicity of this drug precludes its use in the treatment of digitalis intoxication in human beings. However, it may be useful for the study of myocardial metabolism and function.

Influence of Reserpine and βTM 10 on Digitalis-Induced Ventricular Arrhythmia

Influence of Reserpine and βTM 10 on Digitalis-Induced Ventricular Arrhythmia

INFLUENCE OF RESERPINE AND BETA TM 10 ON DIGITALIS-INDUCED VENTRICULAR ARRHYTHMIA.

After catecholamine depletion by reserpine, the capacity of the digitalis materials to induce ventricular arrhythmia is diminished. In papillary muscles from cats pretreated with reserpine, the incidence of ouabain-induced extra beats is reduced. The dose of ac. stroph. necessary to induce ventricular arrhythmia in combination with vagal stimulation is increased by reserpine pretreatment. Threshold doses comparable to those in cats not pretreated with reserpine produced arrhythmia after the catecholamine stores were repleted with norepinephrine or isoproterenol. In dogs with A-V block, βTM 10, an agent which prevents the release of catecholamines, markedly reduces the response of the ventricular pacemaker to ac. stroph. Since the arrhythmias induced by large doses of ac. stroph. are not affected by reserpine pretreatment, it is concluded that while catecholamine release is the primary mechanism involved in the arrhythmia produced by small doses, another mechanism also plays a role in this action after larger doses. Only in the dose of 10 mg/kg did it appear that catecholamine depletion did not account entirely for the action of reserpine. The ac. stroph. threshold dose was not increased to the same degree as with the smaller doses of reserpine, and the incidence of ventricular fibrillation induced by the large dose of ac. stroph was reduced. Hypotension produced by reserpine and βTM 10 did not seem to be an important factor in depression of the responsiveness of the ventricular pacemaker to ac. stroph. While the incidence of ouabain-induced extra beats was reduced by reserpine pretreatment, the action of ouabain to increase the tension developed by isolated papillary muscles was not affected.

The effect of diphenylhydantoin sodium (dilantin), procaine hydrochloride, procaine amide hydrochloride, and quinidine hydrochloride upon ouabain-induced ventricular tachycardia in unanesthetized dogs.

Ventricular tachycardia has been produced in unanesthetized dogs by the intravenous injection of ouabain, and the ability of various agents to produce reversion to normal sinus rhythm has been tested. Diphenylhydantoin sodium, procaine amide hydrochloride, procaine hydrochloride and quinidine hydrochloride were approximately equally effective; however the procaine hydrochloride effect was shorter and the drug was more toxic than the other three. It is suggested that diphenylhydantoin sodium may merit a trial for the treatment of digitalis-induced ventricular arrhythmias.