Effects Of Digitalis Research Articles

Effects of inhibitors of glycolysis on the inotropic and toxic effects of digitalis

Effects of inhibitors of glycolysis on the inotropic and toxic effects of digitalis

Effect of digitalis on central demyelinative conduction block in vivo

In searching for agents effective in treating multiple sclerosis, we studied the effect of a short-acting digitalis, ouabain, on conduction block in an animal model of central nervous system demyelination. The electrogenic sodium/potassium pump, which digitalis specifically inhibits, is responsible for part of the resting membrane potential and also the activity-related membrane hyperpolarization following high-frequency impulses. The latter causes intermittent conduction block in demyelinated fibers. Therefore, digitalis might be expected to reverse demyelinative conduction blocks by reducing the threshold at the blocking node. Somatosensory evoked potentials were monitored in 11 rats with spinal cord demyelination before and after systemic administration of ouabain (0.1-0.6 mg or 0.21-1.58 mg/kg IP). In all rats, slowed conduction velocity of the compound action potential through the lesion was significantly reversed, and failure to transmit high-frequency impulses was improved upon. The amplitude of the cortical somatosensory evoked potentials also increased significantly. Digitalis is a promising therapeutic agent for trial in patients with multiple sclerosis.

Metabolic Requirement for the Inotropic Effects of Digitalis and BAY K 8644

The positive inotropic effects of ouabain and of BAY K 8644 are not apparent in rabbit atria suspended in substrate free medium or in a medium containing 5 mM pyruvate. Addition of glucose in graded concentrations (1-11 mM) during continued exposure of the preparations to the inotropic agents yields graded inotropic effects. The possible involvement of the glycolytic pathway to the development of the inotropic effect of ouabain and BAY K 8644 was tested by using inhibitors of glycolysis that act at two different steps. Iodoacetic acid completely blocks the inotropic effect of ouabain in atria at 0.1 mM and papillary muscles at 0.05 mM. The inotropic effect of BAY K 8644 was blocked partially in atria and papillary muscles. Iodoacetic acid did not change the inotropic effects of isoproterenol and Ca2+. Addition of 1 mM fluoride did not affect significantly the inotropic effect of either ouabain or BAY K 8644 in atria but partially blocked the effect of BAY K 8644 in papillary muscles. The response of atria to ouabain was not changed significantly when glyceraldehyde (10 mM) was substituted for glucose. We suggest that glycolytic ATP may be important for the full inotropic effect of ouabain and BAY K 8644.

Are there stress resistant and susceptible myocardia?

The satisfactory analysis of the Na K ATPase, its pumping component and the mechanism of action of the inhibitor digitalis remains elusive; yet the controversial inotropic effect of digitalis in the clinical setting has been known for over a century. There are also conflicting reports of the effect of urea and uremia on the cardiovascular system, and the evidence as it exists, suggests that urea may have two effects on the intact heart, by virtue of its extent of action on hydrogen bonding of water molecules, determined by which type of muscle constitutes the myocardium. If different types of myocardium do exist, they could well respond differently to inotropic agents. Evidence suggests that two types of myocardia, relatively stress resistant or susceptible may exist, analagous to known skeletal muscle differences.

Effect of digoxin on the heart in normal subjects: influence of isometric exercise and autonomic blockade: a noninvasive study.

1. Eight healthy subjects were studied before digoxin and after successive therapy periods of 1 week 0.125, 0.25 and 0.50 mg of digoxin. The mean serum concentrations (+/- s. d.) were 0.4 +/- 0.2, 0.6 +/- 0.3 and 1.4 +/- 0.5 nmol l-1, respectively. The effects of digitalis were studied by echocardiography and systolic time intervals at rest and after 3 min handgrip exercise. Effects of simultaneous autonomic blockade induced by atropine and propranolol were also examined. 2. Digoxin in increasing doses slowed the heart rate at rest; with the daily dose of 0.50 mg from 63 +/- 10 to 53 +/- 6 beats min-1, and fractional shortening rose from 28 +/- 6 to 33 +/- 3% (P less than 0.05 for both). Preload, afterload and cardiac output did not change. The electromechanic systolic time index (QS2I) decreased (P less than 0.001) and the observed alteration of QS2I was dose-related. 3. The influence of digoxin was similar during isometric exercise, except for unchanged fractional shortening. 4. During autonomic blockade digoxin slowed the intrinsic heart rate from 93 +/- 6 to 86 +/- 6 beats min-1 (0.25 mg) and to 83 +/- 6 beats min-1 (0.50 mg) (P less than 0.01 for both). QS2I was shortened (P less than 0.01). Echocardiographically determined ejection phase indices remained unchanged. 5. When handgrip stress was induced during autonomic blockade, digoxin evoked a clearcut increase in contractile function, resembling the effects of digoxin alone at rest. Thus, fractional shortening increased by 14% and QS2I decreased by 16 ms (P less than 0.01 for both). 6. We conclude that digoxin increases the contractility in normal heart without changes in loading conditions. The rise in inotropy at rest is obvious from both fractional shortening by echo and systolic time intervals. The same takes place during handgrip with autonomic blockade, when the heart lacks sympathetic support. The influence of long-term digoxin on heart rate is partly direct without autonomic mediation. The effect of digoxin is dose-dependent.

Supraventricular Arrhythmias in the Late Hospital Phase of Acute Q-Wave Myocardial Infarction: Supraventricular Arrhythmia in Myocardial Infarction

To assess the correlates of supraventricular arrhythmia (SA) in the late hospital phase of acute Q-wave myocardial infarction (MI), continuous 24-h ambulatory electrocardiographic monitoring, gated cardiac pool scan, modified exercise test, and chest x-ray were reviewed in 102 patients. Supraventricular tachyarrhythmias were seen in 11 patients, atrial premature beats in 42 patients; 49 patients did not have SA. Multiple discriminant analysis was used to determine the important variables contributing to the occurrence of SA. Variable included age, sex, history of previous MI, hypertension, location of MI, moist rales at time of admission, cardiothoracic ratio, ejection fraction, wall motion abnormality, exercise test result, duration of exercise and use of digitalis. Moist rales, digitalis, age and cardiothoracic ratio were the predictors of SA. Aging, hemodynamic change imposed on the left ventricle, and arrhythmic effects of digitalis are the major factors associated with SA in the late hospital phase of acute MI.

Effect of digitalis on the diaphragm in anesthetized dogs.

We examined the effect of digitalis on diaphragmatic contractility and fatigability in 19 anesthetized mechanically ventilated dogs. The diaphragmatic force was assessed from transdiaphragmatic pressure (Pdi) developed at functional residual capacity against an occluded airway during cervical phrenic nerve stimulation. In a first group of five dogs, Pdi-stimulus frequency relationships were compared before and after administration of ouabain in doses of 0.01, 0.02, and 0.04 mg/kg. In a second group, diaphragmatic fatigue was produced by bilateral phrenic nerve stimulation at 30 Hz. Ten seconds of stimulation and 15 s of mechanical ventilation were repeated for 30 min. The rates of decrease in Pdi were compared between two groups, one of 0.05 mg/kg deslanoside-treated dogs (n = 7) and one of nontreated dogs (n = 7). After ouabain administration Pdi was significantly greater at each frequency in a dose-dependent manner. On the other hand, the rate of decrease in Pdi in the deslanoside group was significantly smaller than that in the nontreated group, whereas deslanoside did not greatly change the Pdi-frequency curves in fresh diaphragm. We conclude that ouabain improves contractility of the fresh diaphragm and that deslanoside has a protective effect against fatigability.

The effect of digitalis on experimental myocardial infarct size and hemodynamics

Early studies suggested that digitalis exacerbated ischemia (ST segment data); however, there are no studies assessing the effect of this agent on anatomic infarct size with the use of a risk zone technique. Therefore, the aim of this study was to assess quantitatively whether digitalis extends necrosis in a model of coronary artery occlusion. Anesthetized dogs were subjected to 6-hour occlusion and, 30 minutes after occlusion, were randomized to digoxin (250 μg bolus/5 min intravenously, n = 9) or saline (n = 9) groups. At 6 hours, in vivo area at risk was determined by monastral blue dye injection and area of necrosis was assessed by tetrazolium staining. Heart rate and blood pressure were not different between groups before treatment or at 6 hours after occlusion. Left ventricular dPdt was similar in both groups before occlusion (2350 ± 293 mm Hg/sec digoxin vs 1839 ± 122 mm Hg/sec saline, p = NS), but after 6 hours of coronary occlusion, had increased in the digoxin group to 2583 ± 340 mm Hg/sec while it decreased in the saline group to 1517 ± 128 mm Hg/sec (p < 0.05 between groups at 6 hours), suggesting that digoxin increased contractility. Area at risk was 17.7 ± 1.3% of the left ventricle in the digoxin group and 20.9 ± 2.0% of the left ventricle in the saline group (p = NS). Area of necrosis, expressed as a percentage of area at risk, was 90.0 ± 3.5% in the digoxon group vs 88.6 ± 2.1% in the saline group (p = NS). Therefore, during acute myocardial infarction, digitalis confers a moderate increase in contractility without extending necrotic damage.

Two Na,K-ATPase isoenzymes in canine cardiac myocytes. Molecular basis of inotropic and toxic effects of digitalis.

Canine cardiac myocytes contain two distinct molecular forms of the Na,K-ATPase catalytic subunit. They are resolved by gel electrophoresis and identified using immunological techniques. The apparent molecular weights of the catalytic subunits are 95,000 (alpha) and 98,000 (alpha +). As judged by [3H]ouabain-binding measurements and Na,K-ATPase assays, the two forms are active and differ by a factor of 150 in their respective affinity for digitalis (ouabain and digitoxigenin). The dissociation constant of the high affinity form (alpha +) is KD, 2 nM, and that of the low affinity molecular form (alpha) is KD, 300 nM. According to both enzymatic and binding assays, up to 70% of maximum inhibition is caused by occupation of the high affinity sites (alpha +). Inasmuch as the pharmacological and toxic concentrations of digitalis in dog are 1 and 200 nM, respectively, and as maximum inhibition of Na+ pump in vivo should not exceed 80% to avoid toxicity (Akera, T. and Brody, T. (1982) Annu. Rev. Physiol. 44, 375-388), it appears that the high affinity molecular form (alpha +) is the pharmacological receptor exclusively related to positive inotropy, whereas the low affinity form (alpha) is mainly associated with toxicity.

Interaction of ischemia and reperfusion with subtoxic concentrations of acetylstrophanthidin in isolated cardiac ventricular tissues: Effects on mechanisms of arrhythmia

The aim of this study was to determine if "ischemia" and/or reperfusion potentiate digitalis toxicity through effects on oscillatory afterpotentials. Isolated canine Purkinje tissue-papillary muscle preparations were studied using standard microelectrode techniques. Tissues were superfused for 10 min with an "ischemic" solution that mimicked hypoxia, acidosis, elevated lactate, zero substrate and normo- or hyperkalemia. Reperfusion with "normal" Tyrode's solution was then reinstated for 60 min. Next, subthreshold oscillatory after potentials were induced with acetylstrophanthidin (ACS) and the protocol was repeated with ACS in all solutions. Without ACS, ischemic conditions with 4 mM KCl caused depolarization of Purkinje and muscle tissues. Reperfusion resulted in hyperpolarization of Purkinje tissue followed by mild depolarization, and then recovery. Purkinje tissue exposed to ischemic conditions with hyperkalemia responded similarly, except that hyperpolarization upon reperfusion was absent. In the presence of ACS, ischemic conditions with 4 mM KCl abolished oscillatory afterpotentials and caused marked depolarization of Purkinje tissue. Reperfusion decreased the coupling intervals and increased the amplitude of oscillatory afterpotentials relative to pre-ischemic levels, and frequently elicited arrhythmic activity. Arrhythmias ceased and tissues recovered by 60 min of reperfusion. Ischemic conditions incorporating hyperkalemia also abolished ACS-induced oscillatory afterpotentials and delayed their reappearance upon reperfusion. All other reperfusion responses were similar. This study demonstrates that "ischemic" suppresses oscillatory afterpotential-mediated effects of digitalis in canine Purkinje tissue, whereas reperfusion potentiates oscillatory afterpotential-induced arrhythmias.

Management of atrial fibrillation and flutter. A reappraisal of digitalis therapy.

PreviewDigitalis has long been used as an antiarrhythmic drug in treatment of paroxysmal supraventricular tachycardia, atrial fibrillation and flutter, and arrhythmias associated with congestive heart failure. However, newer evidence indicates that this cardiac glycoside has limited potency as an antiarrhythmic drug. In this review, the authors describe the effect of digitalis on cardiovascular function in management of atrial fibrillation and flutter. They conclude that while widespread use of digitalis as initial treatment for these supraventricular arrhythmias is justified by its low cost, ease of administration, and relatively few noncardiac side effects, newer drugs may ultimately prove more useful.

The applicability of noninvasive His bundle electrogram to assessing the effect of digitalis on atrioventricular conduction.

His bundle electrograms were recorded by a signal averaging technique using the Takayasu vectorial lead system, and effects of ouabain on the atrioventricular conduction were investigated using Wistar rats. Ouabain was given intraperitoneally at 30 min intervals in doses of 1-40 mg/kg. When ouabain dosage was increased to 20 mg/kg, the prolongation of PQ interval became prominent and P waves were hidden on the preceding T waves. Dose-related prolongation of PQ and AH intervals was observed in the 1-15 mg/kg dosages. Ouabain-induced ventricular arrhythmias occurred in the 30 mg/kg dosage. Dose-related prolongation of QRS duration and HV interval was observed in the 1-25 mg/kg dosages. These prolongations were significant by the analysis of variance (p less than 0.01). Prolongation of PQ and AH intervals is probably due to a digitalis-induced increase in parasympathetic nerve activity. However, the reason for the prolongation of HV interval and QRS duration was uncertain. Direct effects of ouabain on the conduction system, or central nervous system effects of ouabain on cardiovascular function were speculated. These results suggest the applicability of the noninvasive record of His bundle electrogram to assessing the digitalis effect even on the human atrioventricular conduction.

Effects of digitalis on cardiopulmonary baroreflex in man.

We examined whether digitalis augments cardiopulmonary baroreflex control of forearm vascular resistance in normal young men. Cardiopulmonary baroreceptor input was reduced with lower body negative pressure (LBNP) at 10 and 20 mmHg which decreased central venous pressure (CVP) but did not alter blood pressure (BP) or heart rate (HR). Decreases in forearm blood flow and increases in forearm vascular resistance with LBNP were greater after cedilanid than before and the slope of the regression line relating changes in central venous pressure and those in forearm vascular resistance was steeper after cedilanid. Vasoconstrictor responses to a cold pressor test did not differ before and after cedilanid, which suggested that augmented responses to LBNP after cedilanid were not due to a generalized change in reflex control. These results suggest that cedilaniid augments the tonic inhibitory influence of cardiopulmonary baroreceptors in normal men.

Enhanced sensitivity to the arrhythmogenic effects of digitalis in dogs with previous myocardial infarction

Enhanced sensitivity to the arrhythmogenic effects of digitalis in dogs with previous myocardial infarction

Therapeutic and toxic effects of digitalis: William Withering, 1785

William Withering's classic description of the effects of digitalis was published in 1785. Although he was largely unaware of the drug's cardiac effects, he successfully treated many patients with congestive heart failure. He also recorded many striking examples of digitalis toxicity. This review highlights Withering's experience with “the foxglove,” and summarizes modern concepts of digitalis efficacy and toxicity.

The effects of digitalis on intracellular calcium transients in mammalian working myocardium as detected with aequorin

The effects of positive inotropic agents on the amplitude and time course of the light signal and corresponding tension response were studied in cat and human working myocardium microinjected with the bioluminescent Ca2+ indicator aequorin. Distinctive patterns of light and tension responses were identified that are consistent with known actions of the various agents on the release of Ca2+ from intracellular stores, rate of uptake of Ca2+ by the sarcoplasmic reticulum and sensitivity of the myofilaments to Ca2+. In common with most other inotropic drugs, the cardiotonic steroid, acetylstrophanthidin, in doses of 4 X 10(-7) to 2 X 10(-6)M increases the amount of Ca2+ available for excitation-contraction coupling in the heart. However, in contrast to most other agents, acetylstrophanthidin does not affect the time course of the calcium transient. In common with changes in [Ca2+]o, acetylstrophanthidin does not alter the relationship between the amplitude of the aequorin light signal and developed tension, which, in contrast to caffeine and isoproterenol, indicates that the increase in tension is fully accounted for by the increase in systolic free calcium. These findings suggest that the cardiotonic steroids increase loading of intracellular calcium stores without affecting the kinetics of subcellular handling of Ca2+. In doses of 8 X 10(-7) to 2 X 10(-6)M, acetylstrophanthidin produces a calcium-overload state characterized by 'after-contractions' and 'after-glimmers' that are associated with the development of automatic and triggerable dysrhythmias. These studies provide direct evidence that the inotropic and toxic effects of digitalis on animal and human working myocardium are produced by changes in intracellular Ca2+.

200 years of digitalis: the emerging central role of the sodium ion in the control of cardiac force

Digitalis has been used therapeutically for two centuries, but the mechanism by which it enhances the ability of cardiac muscle to produce force (the positive inotropic effect) has not been fully elucidated. The major controversy concerns the question of whether the inhibition of the Na+-K+ pump by digitalis, particularly at low (therapeutic) concentrations, increases the intracellular Na+ concentration and thus is causally related to the positive inotropic effect. Na+-selective microelectrodes, introduced recently, have made it possible to measure small changes in intracellular Na+ activity (aiNa) in beating preparations of cardiac muscle and, in particular, to follow the exact time course of change in both aiNa and contractile force during the positive inotropic effect of digitalis. It has been demonstrated that digitalis at low and high concentrations produces a parallel increase in aiNa and in contractile force during the onset of its effect; washout of the drug results in a parallel and complete recovery of aiNa and contractile force. Additional strong evidence for a correlation between the pump inhibition and digitalis inotropy is the fact that the magnitude of increase in aiNa and contractile force produced by digitalis depends on the level of aiNa and therefore on the rate of Na+ extrusion by the Na+-K+ pump. The study on the quantitative relationship between aiNa and contractile force reveals that the force of contraction is a power function of aiNa, such that a small rise in aiNa produces a significant increase in contractile force. Direct measurements of aiNa and intracellular free Ca2+ during digitalis inotropy strongly support the hypothesis that an increase in aiNa raises intracellular Ca2+ via Na+-Ca2+ exchange, thus producing the positive inotropic effect. In conclusion, the recent data available from the simultaneous and continuous measurements of aiNa and contractile force strongly indicate that the inhibition of the Na+-K+ pump is causally related to the positive inotropic effect of digitalis on cardiac muscle.

Comparison of ouabain receptors in sheep myocardium and purkinje fibres

The conducting system of the heart has been reported to be more sensitive to the toxic effects of digitalis than the working myocardium. To investigate the molecular basis of these observations, we have characterized the ouabain receptor in Purkinje fibres and ventricular muscle of the digitalis-sensitive sheep heart using cell membrane preparations, crude homogenates and contracting heart tissues. [ 3H]-Ouabain binding has the following characteristics: (1) in sheep left ventricular cell membranes, specific binding was of high affinity ( K D 1.9 × 10 −9M at 37); was co-incident with an inhibition of (Na + + K +-ATPase activity; and was inhibited by K + and unlabelled cardiotonic steroids; (2) in crude homogenates, the maximal binding capacity but not the affinity for ouabain varied in different parts of the sheep heart with Purkinje fibres containing markedly fewer binding sites (0.33 × 10 14/g wet weight; left ventricle, 1.3 × 10 14/g wet weight) and (3) in isolated, contracting Purkinje fibres and right ventricular moderator band strips, concentration-response curves for [ 3H]-ouabain binding, increase in force of contraction and inhibition of [ 86Rb +]-uptake were co-incident. In both contracting tissues, a ouabain concentration of 3 × 10 −7 M occupied about 50% of the specific binding sites, gave the maximal inotropic effect without toxicity and inhibited [ 86Rb +]-uptake by about 50%. The maximal binding capacity was lower in contracting Purkinje fibres (2 × 10 14 binding sites/g wet weight) than in contracting moderator band strips (3.9 × 10 14 binding ites/g wet weight). The maximal inotropic effects were reached slightly faster in Purkinje fibres but toxicity also occurred faster in these fibres. We conclude that the specific ouabain binding site is the receptor mediating positive inotropy and inhibition of (Na + + K +-ATPase in the sheep heart. Further, this receptor is identical in both the conducting system and working myocardium but the conducting system contains many fewer receptors. This change in receptor number, rather than affinity, may underlie the increased ouabain toxicity observed in Purkinje fibres.

The Arrhythmias of Digitalis Intoxication

In the 200 years since Withering¹published<i>An Account of the Foxglove</i>, we have gained enormous sophistication in administering digitalis glycosides. We prescribe uniform preparations and dosages, we can measure their concentration in the serum, and we have introduced other drugs for the treatment of heart failure and supraventricular tachycardias. Nonetheless, digitalis intoxication is still with us and may be just as frequent as in the past.²Cardiac arrhythmias are a common presentation of intoxication, and they may require therapy while the intoxication resolves. The arrhythmias of digitalis intoxication arise from two actions of the drug. One is<i>atrioventricular</i>(AV)<i>block</i>, which is an important therapeutic action as well as a potentially toxic one; the other is enhanced<i>automaticity</i>, which is never of therapeutic value. Both actions are caused indirectly by the effects of digitalis on the autonomic nervous system; in addition, enhanced automaticity is a direct effect

Digitalis and the autonomic nervous system

Digitalis produces many of its effects in intact animals and human beings by modifying the properties of the autonomic nervous system. The parasympathetic limb of the autonomic nervous system is most sensitive to these effects of digitalis, and its properties are significantly altered with therapeutic concentrations of the drug. These actions are particularly important in mediating the electrophysiologic effects of digitalis. With toxic concentrations of digitalis, stimulation of sympathetic nerve activity may also occur. This latter action may be involved in the arrhythmogenic effects of digitalis. These effects of digitalis on the autonomic nervous system play a major role in determining the pharmacodynamic actions of the drug in patients. The effects of digitalis on the autonomic nervous system also provide a setting for important interactions with other drugs that modify the properties of the sympathetic and parasympathetic nervous systems.