Toxic Doses Of Digitalis Research Articles

Cellular electrophysiologic effects of vertebrate digitalis-like substances

Substances structurally and functionally similar to digitalis glycosides are produced by several vertebrate species. There also is evidence for a digitalis-like substance of human origin. Standard microelectrode techniques were used to study the direct effects on the cellular electrophysiology of canine Purkinje fibers of 1) bufalin, an unconjugated cardiotonic steroid molecule that is produced by the toad Bufo marinus, and 2) an extract of human bite that showed digitalis-like immunoreactivity on radioimmunoassay. The goal of this study was to determine whether these substances have arrhythmogenic effects comparable with those seen with toxic doses of digitalis glycosides.Bufalin, 2 × 10−8M, significantly (p < 0.05) reduced maximal diastolic potential, action potential amplitude and duration and maximal rate of rise of phase 0 (Vmax) within 40 min of onset of exposure. All six fibers developed delayed afterdepolarizations and two developed triggered rhythms. Ouabain was less potent, in that a 2 × 10−7Mconcentration was required to comparably reduce maximal diasolic potential, action potential amplitude and duration and Vmaxwithin 30 min. These Purkinje fibers also developed delayed afterdepolarizations and triggered rhythms. A sample of an extract of human bile that showed digitalislike immunoreactivity with an antibufalin serum also reduced maximal diastolie potential, action potential amplitude and duration and Vmax, and produced delayed afterdepolarizations and triggered activity. In contrast, immunologically unreactive bile extracts had no appreciable effect on the action potential.In summary, the cardiac toxicity of digitalis substances produced by lower vertebrates is comparable with that induced by the glycosides. Moreover, it appears that humans may produce digitalis-like substances that may be cardiotoxic.

Effects of digitalis intoxication on pacemaker rhythm and synchronization in rabbit sinus node.

Toxic doses of digitalis can induce severe arrhythmias in the sinus node. Since digitalis is known to induce electrical uncoupling in heart tissues, it is possible that the arrhythmias may be mediated by cell-to-cell uncoupling leading to desynchronization of pacemaker cells. We investigated this possibility using intracellular recordings and two different preparations of isolated rabbit sinus node. First, the whole sinus node region with the crista terminalis and a portion of right atrium were exposed to 2 microM ouabain in the presence of atropine (0.09 microM) and propranolol (0.77 microM). With ouabain superfusion, there was a gradual increase in spontaneous discharge, conduction delay, pacemaker shifts, and arrhythmias associated with multiple pacemaker sites. Interaction between pacemakers rapidly decreased, and finally atrial arrest was observed. Second, thin strips of sinus node were placed in a three-compartment bath. Superfusion of the central segment (1.0-1.5 mm) with 1-5 microM ouabain led to tachycardia and apparent conduction delay, followed by asynchronous firing and phasic interactions between pacemakers across the central segment. These interactions diminished in the course of intoxication, indicating a gradual increase of electrical uncoupling induced by the drug. All effects were reversible on washout. We conclude that digitalis-induced arrhythmias in the sinus node result from cell-to-cell uncoupling and loss of synchrony between pacemaker cells. The pattern of arrhythmias can be predicted by the phasic interactions between the pacemakers.

Lack of protection against ouabain cardiotoxicity after chronic ablation of the area postrema in cats

We evaluated the hypothesis that the area postrema facilitates the cardiac arrhythmias caused by toxic doses of digitalis. The arrhythmic dose of ouabain was determined in four cats with chronic selective destruction of the area postrema, and in a control group of two sham-operated cats and three normal unoperated cats. The cats were anesthetized with pentobarbital, and polygraph records were made of end-tidal P co 2, arterial blood pressure, heart rate, and the electrocardiogram (lead II and a bipolar lead in the superior vena cava). The vagosympathetic trunks were cut bilaterally, and 1 h later an i.v. infusion of [ 3H]ouabain was begun at the rate of 1.71 nmol/kg/min. This was continued until ventricular tachycardia appeared, as determined electrocardiographically. The total ouabain dosage required for ventricular tachycardia was recorded, and the ouabain concentrations in the arterial plasma and in the myocardium were determined by liquid scintillation counting. No statistically significant difference was found between the chronically postremectomized cats and the controls in any of these measures of ouabain cardiotoxicity. These results indicate that the area postrema plays no important role in the cardiotoxic action of ouabain in pentobarbital-anesthetized, vagotomized cats.

Lack of effect on brain stem and cerebral cortex Na +, K +-ATPase during heart block produced by chronic digoxin treatment

The autonomic nervous system has been shown to play an important role in digitalis toxicity. In order to determine whether the central nervous system could be digitalis' site of action, the effect of chronic treatment with toxic doses of digitalis on brain Na +, K +-ATPase was studied in the dog. After four weeks of digoxin treatment, Na +,K +-ATPase activity of the brainstem of cerebral cortex was unaffected at the time when digitalis toxicity (heart block) was apparent. ATP-dependent ( 3H)-ouabain binding to these tissues was also unaffected indicating that a significant occupancy of brain Na +,K +-ATPase by digoxin did not occur during chronic drug treatment. In contrast, cardiac Na +,K +-ATPase was markedly inhibited with the concomitant binding of digoxin to the enzyme. Since Na +,K +-ATPase is the most digitalis sensitive system identified to date, it appears that digoxin does not affect neuronal function directly.

Increasing the inotropic effect and toxic dose of digitalis by the administration of antikaliuretic drugs—further evidence for a cardiac effect of diuretic agents

In prior studies, we have shown that the antikaliuretic drugs, triamterene and amiloride, through a direct cardiac effect reduce the loss of cardiac potassium induced by the administration of digitalis. Since loss of myocardial potassium is thought to underlie digitalis arrhythmias, this study was performed to determine whether triamterene and amiloride also extend the toxic dose and thus the therapeutic effect of digitalis. In twelve dogs, acetylstrophanthidin was infused (100 μg per minute) serially at 2.5-hour intervals. Triamterene (400 mg. in divided doses) was infused before the third acetylstrophanthidin infusion. This extended the dose required to produce a toxic arrhythmia by 110 per cent. In fourteen additional studies, nine dogs received 400 mg. of triamterene prior to the third acetylstrophanthidin infusion and five animals received 100 mg. of amiloride during the same period. In these fourteen studies, not only was the toxic dose of digitalis extended, but its inotropic effect effect dp/dt CPIP (common peak developed isovolumic ventricular pressure) was also increased. These studies have demonstrated that through a cardiac effect, by reducing the digitalis-induced loss of cardiac potassium, the potassium-sparing drugs, triamterene and amiloride, extend the toxic dose of digitalis and thus permit extension of its inotropic activity.

Further studies on the effect of papaverine upon the cardiotoxic lesions of digitalis in the dog

The fact that toxic doses of digitalis may produce myocardial lesions in experimental animals has been emphasized in many publications. 1–3 One of us (F. A. K. 3) has recently submitted evidence that aminophylline and theobromine sodium acetate, by virtue of their dilating effect upon the coronary arteries, are more efficient than is papaverine in preventing myocardial lesions induced by toxic doses of digitalis. Since papaveine is known to be a potent coronary dilator, we have been perplexed by these results, and this work is presented to clarify further the previously reported experiment. 3

Experiments with calculated therapeutic and toxic doses of digitalis: II. Effects on the electrocardiogram

Calculated therapeutic amounts (20 or 30 per cent of minimal lethal dose) of digitalis, in single doses, or in divided doses over a period of forty-eight hours, produced the following types of RS-T segment and T-wave changes: (1) No significant change; (2) positive T 3 changed to negative T 3; (3) negative T 3 changed to positive T 3; (4) decrease of height of T wave in one or more leads; (5) increase of height of T wave in one or more leads. Similar electrocardiographic patterns were noted when animals were digitalized rapidly with a calculated therapeutic dose of digitalis and then were given daily doses which were estimated to be equivalent to 1 or 2 cat units a day for a 70-kilogram man. The electrocardiographic studies were made during experiments which lasted from six to fifty-six days. Myocardial lesions were not observed in any of these two groups of animals. In our experiments there were no constant changes in the RS-T segment or T wave which could be taken as a reliable index to the presence of a calculated therapeutic amount of digitalis. The cardiac rate was also unreliable; a therapeutic dose of digitalis produced an increase, decrease, or no change in the cardiac rate over a period of days. Toxic amounts of digitalis, when administered in single doses (40 to 80 per cent of the minimal lethal dose), or when given daily to digitalized animals in an amount which corresponded to 3,4 5.5, or 6 cat units for a 70-kilogram man, produced the following electrocardiographic alterations: (1) no significant change; (2) positive T 3 changed to negative T 3; (3) decrease of height of T wave in one or more leads; (4) increase of height of T wave in one or more leads; (5) depression of the RS-T segment in one or more leads; (6) change in the RS-T segment, the initial portion of which began above the isoelectric position and the terminal portion of which ended below the isoelectric line; (7) elevation of the RS-T segment (“plateau type”) in one or more leads; (8) cove-plane, negative T 2 and T 3, with positive T 1; (9) cove-plane, negative T 1 and positive T 2 and T 3. Changes (1) to (5), inclusive, were usually not associated with myocardial lesions, whereas patterns (6) to (9) were associated with myocardial lesions produced by digitalis. Two animals that had microscopic evidence of myocardial lesions failed to show any significant changes in the daily electrocardiograms. The electrocardiogram returned to normal in all animals which did not die spontaneously or were not killed for experimental reasons. The electrocardiograms returned to normal while microscopic evidence of active inflammation persisted in the myocardium. The electrocardiogram was normal in those animals in which the myocardial lesions had healed (focalized zones of fibrosis).