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PubMed1991

Deleterious effects of digitalis on newborn rabbit myocardium after simulated cardiac surgery.

We studied the effect of the digitalis glycoside ouabain on isolated blood-perfused neonatal (4- to 6-day-old) rabbit hearts during 60 minutes of hypothermic/ischemic arrest (at 15 degrees C), simulating conditions during cardiac surgery. Compared with a control (no ouabain) group, both low- and high-dose ouabain groups had increased left ventricular diastolic chamber stiffness ("contracture") during and after the arrest period. The high-dose ouabain group also showed less recovery of contractile function than did the control group. We conclude that digitalis glycosides have the potential to impair recovery of myocardial function in the newborn infant after hypothermic/ischemic arrest; myocardial relaxation and diastolic function appear more sensitive to this manifestation of digitalis toxicity than does contractile function.

Animals↗
PubMed1989

[Basic therapy of chronic heart failure with digitalis or diuretics?].

Sixteen patients in heart failure and sinus rhythm were, after a four-week treatment-free period, randomly assigned to receive, for four to six weeks, either a diuretic combination (hydrochlorothiazide + triamterene) or a digitalis glycoside. Subsequently the treatment was exchanged between the two groups. Without treatment nine patients were in stage II (New York Heart Association classification), seven in stage III. Pulmonary wedge pressure at rest was 27 +/- 14, on exercise 32 +/- 8 mm Hg, cardiac output 5.3 +/- 1.0 at rest and 7.8 +/- 2.3 l/min on exercise. Digitalis glycosides improved symptoms by one stage in three of 16 patients. All objective measures showed slight but not significant improvement. Diuretic treatment improved symptoms in five patients, while heart size and echocardiographically measured ventricular volume decreased slightly. Cardiac output decreased at rest, but not significantly, and on exercise not at all. Pulmonary arterial pressure (21 +/- 9 mm Hg), pulmonary wedge pressure (13 +/- 7 mm Hg) and pulmonary artery pressure on exercise (39 +/- 11 mm Hg) were significantly lower on diuretics than without treatment. The results support the primary use of diuretics in the treatment of chronic heart failure.

Aged↗
PubMed1987

The relation of membrane-ATPase activity with congestive heart failure.

By the use of the phosphate method the activity of the (Na+ + K+)-ATPase system (E. C. 3.1.6.1.) of human left ventricle was measured in one tissue sample each obtained from 47 autopsied patients. The subjects between the ages of 20 and 79 years had suffered from congestive heart failure of different functional classes NYHA), from diseases of the heart and circulation, or from tumors. Only 23 of the patients of the entire group took digitalis glycosides. With the exception of one sample (8.58 mumol Pi.mg-1.h-1), the enzyme activity amounted from 0.45 to 4.84 mumol Pi.mg-1. The ATPase activity depends on the age (A), the functional classes of congestive heart failure (CF; CF greater than A), and the time between death and autopsy. Chronic hypoxic alterations decreased the enzyme activity. Digitalization did not influence the post-mortem enzyme activity. Due to the small therapeutic range of digitalis glycosides and a distinctly reduced ATPase activity of the ageing patient, enhanced glycoside maintenance doses will not improve myocardial contractility, but provoke arrhythmias.

Adenosine Triphosphatases↗
PubMed1997

Effect of chronic digoxin on beta-adrenergic receptors in rabbits with heart failure.

This study investigated the effect of chronic digitalis glycoside use on beta-adrenergic sympathetic activities in heart failure. Twenty-two Japanese white rabbits were anesthetized by intravenous injection of chloral hydrate. Aortic regurgitation (AR) was produced by perforating aortic valves in 14 rabbits. Digoxin was given for 1 week to 7 rabbits with AR (AR + Dig) and saline to 7 rabbits with AR (AR + C). Sham operation was performed in the remaining 8 rabbits (S). The left ventricular end-diastolic pressure was higher in AR + C than S (p < 0.05). It was lower in AR + Dig than AR + C (p < 0.05). Cardiac output was lower in AR + C than S (p < 0.05). There was no difference between AR + Dig and S. Both the left ventricular end-diastolic and end-systolic diameters were larger in AR + C (p < 0.05) than S, but they were similar between AR + Dig and S. Plasma norepinephrine level was lower in AR + Dig than AR + C. Myocardial beta-adrenergic receptors number determined by radioligand binding assay using 30-800 pM 125I-iodocyanopindolol was lower in AR + C than S (28.8 +/- 7.9 vs. 69.9 +/- 12.3 fmol/mg protein, p < 0.05). It was higher in AR + Dig (39.9 +/- 9.8) than AR + C (p < 0.05). Myocardial norepinephrine content was lower in both AR + C (p < 0.05) and AR + Dig than S (p < 0.05). Thus, digitalis glycosides exert favorable effects on beta-adrenergic sympathetic activities in addition to the effects on hemodynamic variables in this animal model of heart failure.

Animals↗
PubMedDate not supplied

[Digitalis--selected problems and controversies].

Atrial was undertaken of assessment of the usefulness and the place of digitalis glycosides in the treatment of chronic congestive cardiac failure, in myocardial infarction and in mitral stenosis. There is no consensus of opinions of the effectiveness of digitalis treatment in cases of cardiac failure which is due to lack of uniformity of qualification of patients for studies and absence of accepted universally haemodynamic parameters of the effectiveness of the positive inotropic action of these glycosides. The usefulness of these glycosides in patients with cardiac failure and paroxysmal or stable atrial fibrillation and ventricular tachycardia is unquestionable. Digitalis is effective in the treatment of mild cardiac failure, but is ineffective in its IV stage (NYHA). There is still a controversy on the use of digitalis glycosides in acute myocardial infarction with associated myocardial failure. In acute myocardial infarction digitalis glycosided should not be used, with the exception of cases with coexistent supraventricular arrhythmia and ventricular tachycardia. It is still difficult to establish unequivocally the effect of digitalization of patients after acute phase of myocardial infarction and after discharge from hospital on further survival. The future place of digitalis glycosides in the treatment of cardiac failure will depend on the results of studies comparing them with new positive inotropic drugs. The place of digitalis glycosides in the treatment of haemodynamic cousegnences of mitral stenosis, but they are useful in supraventricular arrhythmias during mitral stenosis, and for alleviation of right-ventricular cardiac failure.

Arrhythmias, Cardiac↗
PubMed1978

The effect of thyroxine on (Na+, K+)-ATPase from the heart and the kidney of rabbit.

The effect of thyroxine on membrane bound (Na+, K+)-ATPase isolated as a microsomal fraction from rabbit heart and kidney was investigated. In the heart, thyroxine administration produced an increased Ki value (a concentration of ouabain required for half maximal inhibition of (Na+, K+)-ATPase activity) without alteration of the specific activity of cardiac (Na+, K+)-ATPase, indicating that the digitalis sensitivity of cardiac (Na+, K+)-ATPase was decreased. On the contrary, a significant increase of the specific activity of renal (Na+, K+)-ATPase was observed without change in its digitalis sensitivity. These results suggest that (1) a decreased sensitivity of cardiac (Na+, K+)-ATPase to digitalis glycosides in thyrotoxic animals may contribute to the decrease in the inotropic and toxic effects of the digitalis glycosides in the hyperthyroid state, and that (2) there may be an organ difference in (Na+, K+)-ATPase.

Animals↗
PubMed1992

Effect of digitalis on norepinephrine kinetics in congestive heart failure.

OBJECTIVE: The aim of this study was to test the hypothesis that digitalis glycosides would reduce sympathetic activity as reflected by forearm venous norepinephrine kinetics in patients with congestive heart failure. BACKGROUND: Digitalis glycosides have been reported to decrease sympathetic nervous system activity with baroreceptor sensitization in experimental animals. Such effects could be of therapeutic importance in congestive heart failure. METHODS: Double-blind randomized assessment was made of the effects of low dose intravenous deslanoside (Cedilanid-D, 0.002 mg/kg body weight) and vehicle on heart rate, arterial pressure, forearm blood flow, plasma norepinephrine, norepinephrine clearance and norepinephrine spillover in nine patients with stable congestive heart failure, New York Heart Association functional class II or III. Open label assessment of the responses to 0.6 mg of deslanoside was made in an overlapping group of seven patients. All measurements were made 30 and 60 min after intravenous injection of drug or vehicle and after 15 min of 30 degrees head-down tilt as a test of the sympathetic response to baroreceptor loading. RESULTS: Heart rate, arterial pressure and forearm blood flow were unchanged by low dose deslanoside. Heart rate decreased slightly with the 0.6 mg dose with the patients in the supine position. Norepinephrine spillover and clearance decreased with time on each study day in the supine position, but no effect was attributable to digitalis. Plasma norepinephrine and norepinephrine clearance and spillover all remained unchanged during head-down tilt on each study day. CONCLUSIONS: Nonpressor doses of deslanoside do not suppress sympathetic activity as reflected by venous norepinephrine and norepinephrine spillover in patients with congestive heart failure. Further, deslanoside did not normalize the sympathetic response to mild baroreceptor loading produced by head-down tilt. These data do not support sympathoinhibition through baroreceptor sensitization as a likely effect of digitalis in congestive heart failure.

Deslanoside↗
PubMed1987

Reversal of toxic and non-toxic effects of digoxin by digoxin-specific Fab fragments in isolated human ventricular myocardium.

The time course of the reversal of toxic and nontoxic effects of digoxin by digoxin-specific antibody fragments (Fab) was measured in isolated human ventricular myocardium. A concentration of 2 X 10(-6) mol/l digoxin was used to produce positive inotropy followed by mechanical signs of toxicity. After addition of a 1.5-fold higher molar concentration of digoxin-specific Fab, signs of toxicity disappeared within 30 min and digoxin-induced force of contraction decayed with a monoexponential time course with a half-life of 52 min. This rate of decay was almost identical to that observed for the dissociation of the digoxin-(Na+ + K+)-ATPase complex in human heart cell membranes. It is concluded that digoxin-specific Fab are capable of completely removing digoxin from its binding sites, the maximal rate of removal of digitalis glycosides from the (Na+ + K+)-ATPase is limited by the dissociation rate constant, and there is a close correlation between the degree of binding of digitalis glycosides to the (Na+ + K+)-ATPase and the increase in force of contraction.

Binding Sites↗
PubMed1993

Effect of ouabain, digoxin and digitoxigenin on potassium uptake and histamine release from rat peritoneal mast cells.

Rat peritoneal mast cells were used to study the effects of digitalis glycosides on potassium uptake and histamine release induced by compound 48/80, substance P and egg-albumin (immunological release). In the absence of calcium all glycosides inhibited potassium uptake. Ouabain and digoxin enhanced the histamine release while digitoxigenin either had no effect or was slightly inhibitory. In the presence of calcium, the glycosides only affected potassium uptake and histamine release slightly. In the presence of lithium or lanthanum the enhancement of the histamine release was counteracted. Hydrophilic digitalis glycosides seem to enhance histamine release secondary to an increase in intracellular sodium. Lipophilic glycosides have no effect on the release.

Animals↗
PubMed1971

Interruption of the enterohepatic circulation of digitoxin by cholestyramine. II. Effect on metabolic disposition of tritium-labeled digitoxin and cardiac systolic intervals in man.

Previous studies of digitalis glycoside metabolism and excretion have indicated that these compounds undergo a significant enterohepatic cycle in some species. It has been suggested that the existence of such a cycle in man contributes to the prolonged action of certain cardiac glycosides. Previous studies have demonstrated that cholestyramine binds digitoxin and digoxin in vitro and accelerates the metabolic disposition of digitoxin in rats and guinea pigs, presumably by interrupting the enterohepatic circulation. In order to assess the role of the enterohepatic circulation in the metabolism of digitalis glycosides in humans, maintenance doses of cholestyramine were administered to 7 of 15 normal human subjects beginning 8 hr after digitalization with 1.2 mg of digitoxin-(3)H. All subjects had frequent measurements of serum radioactivity, left ventricular ejection time (LVET), and electromechanical systole (QS(2)), the latter recorded as the interval from onset of Q wave to first major component of second heart sound. Measurement of the LVET and QS(2) intervals affords a sensitive index of the cardiac response to digitalis. In addition, chloroform extraction of serum was performed to separate unchanged digitoxin and active metabolites from cardioinactive metabolites of digitoxin. Cholestyramine treatment resulted in reduction in half-life to total serum radioactivity from 11.5 to 6.6 days, and in chloroform-extractable radioactivity from 6.0 to 4.5 days, as compared to controls. In addition, cholestyramine treatment was accompanied by more rapid return to base line values of digitoxin-induced changes in the LVET and QS(2) intervals. A significant positive correlation was found between QS(2) values and chloroform-extractable radioactivity, the latter reflecting unchanged digitoxin-H(3) (r=0.64; P=<0.01). The results indicate that administration of cholestyramine to digitalized human subjects accelerates the metabolic disposition of digitoxin and abbreviates the physiologic response to the glycoside. This effect is presumably mediated by interruption of the enterohepatic circulation of digitoxin by cholestyramine.

Administration, Oral↗
PubMed1985

Extracardiac and coronary vascular effects of digitalis.

The administration of digitalis glycosides causes a variety of extracardiac effects. In both normal human subjects and in other species, digitalis increases smooth muscle tone of resistance and capacitance vessels. The vasoconstriction is mediated, in part, by a direct action of these glycosides on smooth muscle and, in part, by an increase in alpha-adrenergic tone. Constriction of coronary and splanchnic vessels may lead to myocardial or mesenteric ischemia. In contrast to normal subjects, patients with congestive heart failure demonstrate arteriolar and venodilation in response to these glycosides, possibly because the myocardial effect, to increase cardiac output and peripheral blood flow, overcomes the vasoconstrictor properties of these drugs. Other important actions of digitalis glycosides occur in the central and peripheral nervous systems. Their effects on the area postrema of the medulla oblongata are largely responsible for the alpha-adrenergic-mediated peripheral vasoconstriction, as well as the nausea and vomiting that frequently accompany digitalis intoxication. Actions of glycosides on the cerebral cortex are responsible for the wide range of neurotoxic effects that range from visual disturbances and headaches to seizures and coma. Finally, peripheral neurologic effects of digitalis glycosides on baroreceptor and cardiac afferent fibers may: improve the depressed function of these receptors in the situation of heart failure, and reflexly lower peripheral vascular resistance, thereby partially preventing the vascular constrictor action of these glycosides.

Animals↗
PubMed1988

Combination of positive inotropic and vasodilating substances in congestive heart failure.

Therapy combining vasodilators and inotropic agents is considered to be one of the most powerful means of improving cardiac function in patients with congestive heart failure (CHF). The vasodilators enhance the effectiveness of inotropic agents by providing a reduction in preload and/or afterload. Inotropic drugs with different mechanisms of action, such as digitalis glycosides, ephedrine, dopamine, dobutamine, ibopamine, terbutaline, salbutamol, pirbuterol, prenalterol, amrinone, and milrinone, have been tested in combination with vasodilators with a predominant effect on preload (nitrates, molsidomine), with a predominant effect on afterload (hydralazine, nifedipine), or with a balanced action on both arterial and venous beds (nitroprusside, prazosin, captopril), showing positive results. The problem of the combination of digitalis glycosides and vasodilators with different sites of action has been considered by our group. In 42 patients with CHF, digoxin (DIG, 0.01 mg/kg intravenously) was tested in combination with molsidomine (MLS, 4 mg sublingually) (12 patients), a nitrate-like agent with a predominant vasodilating action on the capacitance vessels, nifedipine (NFP, 10 mg sublingually) (22 patients), a Ca2+ antagonist drug with a predominant action on the resistance vessels, and captopril (CPT, 25 mg orally) (8 patients), an ACE inhibitor with a balanced effect on both preload and afterload. The combination DIG plus MLS caused a reduction in left ventricular filling pressure (LVFP) greater than that achieved with either agent alone. The hemodynamic improvement was obtained without side effects, in spite of the striking fall in preload. We stress that this investigation was performed on patients with CHF following acute myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiotonic Agents↗
PubMed1978

Appropriateness of the use of serum digoxin and digitoxin assays.

The use of 145 digoxin and digitoxin assays was studied in a teaching hospital to determine if performance of assays was appropriate and therapeutically beneficial. Patient charts (121) were randomly selected from a list of all patients for whom digoxin or digitoxin assays were performed. Charts were compared with established criteria to determine whether the assay was indicated and performed correctly and whether dosage was adjusted correctly based on assay results. Of the assays reviewed, 49% were performed for irrational indications; 86% were performed appropriately under steady-state conditions; and 96% used serum samples appropriately drawn more than six hours after administration of the last digitalis glycoside dose. Of the assays performed at appropriate times in relation to dose and at steady-state plasma concentrations (120), 31 should have and 89 should not have resulted in a dosage change. Of the latter, 98% were evaluated correctly. Of the former, 36% were not evaluated correctly (i.e., indicated dosage adjustments were not made). Control of the use of digitalis glycoside assays is needed. Pharmacists should become involved in monitoring drug assays to assure appropriateness of assay request, interpretation and follow-up.

Digitoxin↗
PubMed1987

[Treatment of heart failure: status of therapy with vasodilator agents].

Treatment of heart failure comprises the use of diuretics, vasodilators and inotropic substances. Unloading of the heart and the circulation in hydropic states is classically achieved with diuretics. The retention of salt and water in chronic heart failure requires chronic treatment with diuretics. This mode of treatment is basic to all forms of hydropic heart failure. Inotropic substances such as digitalis glycosides, sympathomimetic amines or phosphodiesterase inhibitors have certain disadvantages: Inotropic stimulation increases energy demand of the working heart muscle. Most of the substances used today increase energy consumption inordinately, thereby decreasing economy of myocardial contraction. This aspect calls for caution in the application of these substances in chronic heart failure, although they seem indispensable (sympathomimetic amines) in acute hypotensive failure and shock. Digitalis glycosides, basically suited for longterm treatment, exert only mild inotropic effects. In addition inotropic stimulation brings with it arrhythmogenic effects. All inotropic substances can induce ventricular arrhythmias already at therapeutic levels. Vasodilating substances have found increasing acceptance as a particularly useful and safe group of drugs for the treatment of heart failure. Nitrates: With the different nitrate compounds and nitrate preparations an effective venodilation with preload reduction can safely be achieved. At higher doses, arteriolar also dilatation can be induced. Although tolerance may be a problem with chronic application, this can be avoided with prudent dosing. The strong venodilating property makes these drugs together with their rapid onset of action ideally suited for the treatment of acute heart failure with pulmonary congestion.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

Management of congestive heart failure in the elderly.

A universally accepted description of appropriate therapy for treatment of congestive heart failure (CHF) has yet to be agreed upon, especially in the elderly. Numerous studies have provided data that question use of a digitalis glycoside as the agent of choice in treatment of chronic CHF. Several clinicians have suggested that diuretics, particularly thiazide diuretics, be used as initial agents in the treatment of this condition. Evidence now demonstrates that drug therapy with enalapril or the combination of hydralazine and isosorbide dinitrate reduces the mortality related to chronic CHF. Additional studies are required to clarify respective roles of diuretics, digitalis glycosides, and vasodilators in the management of chronic CHF.

Aged↗
PubMed1991

[Effects of amrinone on isolated heart preparations: comparative study with other inotropic agents].

We compared the effects of the phosphodiesterase inhibitor amrinone, the beta-adrenergic partial agonist xamoterol and the digitalis glycoside, ouabain, on isolated rabbit hearts perfused with the Langendorff technique. Heart rate, left ventricular pressure, as an index of myocardial contractility and coronary perfusion pressure, as an index of coronary resistances, were assessed before and after each drug. Perfusion with concentrations of each agent varying from 10(-9) to 10(-4) M induced a dose-dependent increase of left ventricular systolic pressure averaging 32.5 +/- 1.5% after amrinone (10(-5) M), 46.2 +/- 0.5% after xamoterol (10(-5) M) and 19.0 +/- 2.1% after ouabain (10(-4) M). Among the 3 agents, only amrinone was able to reduce basal coronary perfusion pressure (18.4 +/- 1.2% at the dose of 10(-5) M) and inhibit vasopressin-induced coronary spasm (86.8 +/- 2.5% inhibition at 10(-5) M); no significant change of coronary perfusion pressure was noted with either xamoterol or ouabain. Heart rate was not significantly modified by amrinone whereas, at the doses of 10(-5)-10(-4) M, xamoterol increased it by 21.6 +/- 0.7% and ouabain reduced it by 12.3 +/- 1.1%. Our results show that amrinone, in comparison with digitalis glycosides and beta-adrenergic agonists, presents the unique property to increase myocardial contractility with concomitant coronary vasodilation without significant changes of heart rate. Ouabain has a less potent positive inotropic activity and a slight negative chronotropic action, whereas xamoterol inotropic effect is accompanied by an increase of heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗