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Digitalis and the Na+,K(+)-ATPase.

Recent clinical, physiological, biochemical, and molecular biology studies strongly suggest that digitalis glycosides function in a complex manner through differential binding to and inactivation of multiple distinct Na+,K(+)-ATPase isoforms that are differentially expressed and regulated throughout the cardiovascular system. The alpha 1 isoform predominates in the ventricular: myocardium, whereas the alpha 2 and alpha 3 isoforms may localize to the conducting system structures. The peripheral vasculature also potentially expresses three digitalis receptors, as do neurons in the central nervous system. It is likely that similar heterogeneity exists in the autonomic nervous system as well as in the cardiopulmonary baroreceptor structures. Therefore, differential regulation of these isoforms, by either genetic predisposition or hormones, could dissociate contractile from conduction function and play a role in determining the degree, if any, of therapeutic response to digitalis glycosides. Similarly, genetic polymorphism of the alpha subunits has been observed in humans and rats and may play an important functional role in the ion transport function in a strain of hypertensive rats. Genetic differences in the regulation or structure and function of each isoform could confer allele-specific functional and pharmacological features such as predisposition to digitalis toxicity. Alterations in the degree and type of Na+,K(+)-ATPase isoforms expressed during cardiac hypertrophy and cardiac development may mediate increases or decreases in cardiac sensitivity to digitalis glycosides. This unexpected complexity of the digitalis receptor raises new questions about the role of digitalis glycosides in the treatment of congestive heart failure.

Animals↗
PubMed1995

The Na+/K(+)-pump in rat peritoneal mast cells: some aspects of regulation of activity and cellular function.

The mast cell contains potent mediators of inflammation which are released after IgE-directed and non-IgE-directed stimulation of the cell. This highly specialized cell is therefore ascribed a role in the pathogenesis of disease states in which the inflammatory response plays a role for the development of the clinical symptoms. Thus, besides being of interest in basic research, studies of the cellular processes leading to release of inflammatory mediators from the mast cell also have important clinical implications. The aim of the present work has been to document the existence of the Na+/K(+)-pump in rat peritoneal mast cells, to investigate the regulation of the pump activity and to explore whether modulation of the pump activity interferes with the cellular stimulus/secretion coupling mechanism. The Na+/K(+)-pump activity following stimulation of the mast cell was also investigated. The pump activity was assessed as the ouabain-sensitive cellular potassium uptake with 86Rb+ as a tracer for potassium. The histamine release from the mast cell following IgE-directed and non-IgE directed stimulation of the cell was used as a parameter for cellular degranulation. Histamine was measured by spectrofluorometry. The finding of an ouabain-sensitive uptake mechanism in the mast cell documents the presence of a functional Na+/K(+)-pump in this cell. The pump activity is inhibited by lanthanides and by the divalent cations calcium, magnesium, barium and strontium. The pump has a large reserve capacity which probably is caused by a low intracellular concentration of sodium. This enables the pump to respond to changes in the intracellular sodium concentration. The inhibitory effect of di- and trivalent ions on the pump activity is probably a result of the inhibitory effect of these ions on the cellular sodium uptake. The digitalis glycosides, ouabain and digoxin, but not the more lipophilic drug digitoxigenin, increase both IgE-directed and non-IgE-directed histamine release from the mast cell in a calcium-free medium, while there is no effect of digitalis glycosides in a medium containing physiologically relevant concentrations of calcium. The effect of digitalis glycosides on the histamine release is dependent on the drug concentrations used and the time of preincubation. An increase in the intracellular concentration of sodium secondary to inhibition of the Na+/K(+)-pump is the effector mechanism likely to explain the effect of digitalis glycosides on the mast cell histamine release. Increases in intracellular sodium might affect the intracellular concentration of calcium via changes in Na+/Ca(2+)-exchange. IgE-directed and non-IgE-directed stimulation of the mast cell activates the Na+/K(+)-pump. In case of compound 48/80-induced histamine release, the pump is stimulated for at least 2 hr. It is proposed, that the poststimulatory activation of the Na+/K(+)-pump is due to increased cellular sodium uptake associated with the release process. This sodium uptake may occur via Na+/Ca(2+)-exchange, Na+/H(+)-exchange, Na+/K+/2Cl(-)-cotransport or a non-selective ion channel. Besides describing aspects of the function and regulation of the Na+/K(+)-pump in the rat peritoneal mast cells, this thesis points to the potential role of sodium transport mechanisms in mast cell physiology. Pharmacological manipulations of such transport mechanisms might in the future add to the treatment of allergic diseases.

Animals↗
PubMed1984

Selective impairment of baroreflex-mediated vasoconstrictor responses in patients with ventricular dysfunction.

Cardiac dysfunction in animals has been associated with impairment of arterial and cardiopulmonary baroreflex control of the circulation. Chronic heart failure in human beings is associated with neurohumoral excitation, which could result in part from impairment in the inhibitory influence of baroreflexes. We postulated that (1) patients with left ventricular dysfunction (LVD) have impaired baroreflex modulation of vascular resistance and (2) administration of a digitalis glycoside would immediately restore baroreflex sensitivity. Eleven patients with LVD (NYHA class, 2.8 +/- 0.2, mean +/- SEM; baseline left ventricular ejection fraction, 18 +/- 2%; cardiac index, 2.4 +/- 0.21/min/m2; and pulmonary capillary wedge pressure, 26.0 +/- 3.2 mm Hg) were compared with 17 normal control subjects. We measured forearm vasoconstrictor responses to simulated orthostatic stress with use of lower body negative pressure (LBNP) at -10 and -40 mm Hg to unload cardiopulmonary and arterial baroreceptors. Baseline forearm vascular resistance (FVR) was higher in patients with LVD than in normal subjects: FVRLVD, 68.8 +/- 15.3 U; FVRN, 23.2 +/- 2.1 U (p less than .001). During unloading of baroreceptors with LBNP -10 mm Hg, normal subjects developed vasoconstriction (delta VRN at LBNP -10 mm Hg, +5.7 +/- 1.6 U) but patients with LVD failed to have vasoconstriction and tended to develop vasodilation (delta FVRLVD at LBNP -10 mm Hg, -8.6 +/- 8.5 U) (p = .05, normals vs patients with LVD at LBNP -10 mm Hg). A more marked disparity in response was seen during unloading of baroreceptors of LBNP -40 mm Hg: delta FVRN at LBNP -40 mm Hg, +16.6 +/- 1.5 U; delta FVRLVD at LBNP -40 mm Hg, -10.3 +/- 9.6 U (p less than .001, normals vs patients with LVD). Despite high baseline values for FVR, patients with LVD developed vasoconstriction during intra-arterial infusions of norepinephrine, thereby excluding a nonspecific depression of vascular reactivity as the mechanism for abnormal responses to LBNP in patients with LVD. We also studied the short-term effects of administration of a digitalis glycoside, ouabain 0.0075 mg/kg (seven patients) or lanatoside C (Cedilanid-D) 0.02 mg/kg (three patients), on baroreflex-mediated vasoconstrictor responses to LBNP in the patients with LVD. Digitalis glycoside reduced baseline FVR from 71.8 +/- 16.6 to 48.6 +/- 12.0 U (p less than .02). Responses to LBNP tended to be normalized after administration of digitalis glycoside: delta FVR during LBNP -40 mm Hg, -11.1 +/- 10.5 U before and +7.8 +/- 5.6 U after the drug (p less than .05).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed2001

P-glycoprotein-mediated transport of digitoxin, alpha-methyldigoxin and beta-acetyldigoxin.

Digoxin is a drug with a narrow therapeutic index, which is substrate of the ATP-dependent efflux pump P-glycoprotein. Increased or decreased digoxin plasma concentrations occur in humans due to inhibition or induction of this drug transporter in organs with excretory function such as small intestine, liver and kidneys. Whereas particle size, dissolution rate and lipophilic properties have been identified as determinants for absorption of digitalis glycosides, little is known about P-glycoprotein transport characteristics of digitalis glycosides such as digitoxin, alpha-methyldigoxin, beta-acetyldigoxin and ouabain. Using polarized P-glycoprotein-expressing cell lines we therefore studied whether these compounds are substrates of P-glycoprotein. Polarized transport of digitalis glycosides was assessed in P-glycoprotein-expressing Caco-2 and L-MDR1 cells (LLC-PK1 cells stably transfected with the human MDR1 P-glycoprotein). Inhibition of P-glycoprotein-mediated transport of these compounds in Caco-2 cells was determined using the cyclosporine analogue PSC-833 (valspodar) as inhibitor of P-glycoprotein. No polarized transport was observed for ouabain. However, basal-to-apical transport of digitoxin, alpha-methyldigoxin and beta-acetyldigoxin was greater than apical-to-basal transport in Caco-2 and L-MDR1 cells. In Caco-2 cells net transport rates of these compounds were similar to those of digoxin (digoxin: 16.0+/-4.4%, digitoxin: 15.0+/-3.3%, beta-acetyldigoxin: 16.2+/-1.6%, alpha-methyldigoxin: 13.5+/-4.8%). Furthermore, polarized transport of these compounds could be completely inhibited by 1 microM PSC-833. In summary, these data provide evidence that not only digoxin, but also digitoxin, alpha-methyldigoxin and beta-acetyldigoxin are substrates of P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

A new pregnane glycoside and a furostanol glycoside from Digitalis cariensis.

Chemical investigation of the aerial parts of Digitalis cariensis Boiss. ex Jaub. & Spach resulted in the isolation of a new pregnane glycoside, cariensisoside (1) and a furostanol glycoside, uttroside A (2), along with the two known phenylethanoid glycosides, lugrandoside (3) and maxoside (4). On the basis of spectral (UV, IR, NMR, MS) and chemical methods, compounds 1 and 2 were identified as digifologenin-3-O-beta-glucopyranosyl-(1-->4)-beta-oleandropyranoside and 3-O-(beta-lycotetraosyl)-26-O-(beta-glucopyranosyl)-(25R)-22 alpha-methoxy-5-furostane-3 beta,26-diol, respectively.

Acetylation↗
PubMed1990

Different patterns of autonomic nerve activity produced by a polar vs. a neutral cardiac glycoside.

Digitalis agents react with various peripheral reflex receptor areas (i.e., carotid artery baroreceptors and cardiac mechanoreceptors) to alter autonomic nerve activity. Physical characteristics of these reflex receptors differ and thus they may respond differently to polar and neutral cardenolides. Our purpose was to determine the effect of progressive i.v. infusion of either ASI-222, a polar aminocardenolide agent, or digoxin, a neutral cardenolide, on cardiac sympathetic, efferent vagal, and carotid sinus nerve activity. Digoxin or ASI-222 were infused into anesthetized dogs at dose rates which caused cardiac arrhythmias in about 2 hr. Nerve activities were monitored and recorded by a system of differential amplifiers and by a digital storage oscilloscope. Infusion of ASI-222 progressively reduced sympathetic nerve activity (approximately 55%) through the toxic dose; sympathetic nerve activity remained depressed even through the onset of cardiac arrhythmias. Digoxin also depressed cardiac sympathetic nerve activity but only at intermediate dose levels; sympathetic activity rose near the toxic dose. Digoxin increased both carotid sinus and vagal efferent nerve activity with progressive doses. In contrast, ASI-222 did not alter carotid sinus and efferent vagal nerve activity. In summary, digoxin activates carotid sinus baroreceptors; ASI-222 does not. Digoxin and ASI-222 produce different profiles of changes in cardiac autonomic nerve activity and appear to differ in autonomic reflex receptor interactions.

Animals↗
PubMed1989

Current concepts in the use of digitalis.

After more than two centuries of administration of digitalis glycosides to patients with cardiac disease, empirical observation and tradition remain the basis for much of the clinical application of these drugs. Many questions remain, and the role of digitalis in the management of congestive heart failure and cardiac rhythm disturbances is changing with improvement in our understanding of the pathophysiology of these conditions and the availability of newer effective agents that may have less potential to cause life-threatening toxicity. Nevertheless, digitalis glycoside therapy is a familiar therapeutic intervention for the majority of physicians and remains appropriate in carefully selected patients. The development of digoxin-specific Fab fragments has led to improvement in treatment of advanced and refractory digitalis toxicity and opens up the possibility of improvement in diagnosis of less clinically obvious cases of digitalis intoxication. The role of digitalis glycosides in the management of supraventricular tachyarrhythmias and congestive heart failure in the presence of sinus rhythm should now be revised. In each of these clinical circumstances, alternative drugs or other modes of therapy have been developed that reduce the dependence of clinicians on digitalis as the sole or primary approach to management. In the immediate management of paroxysmal reentrant supraventricular tachyarrhythmias, verapamil has largely replaced digoxin as the drug of choice, although digoxin has an ancillary role, especially in patients with impaired ventricular function. In the management of patients with atrial fibrillation or atrial flutter with a rapid ventricular response, verapamil or diltiazem and beta-adrenergic-blocking drugs will effectively slow the ventricular response, thus reducing the likelihood of approaching the threshold of digitalis toxicity to achieve adequate rate control. In the treatment of patients with congestive heart failure and normal sinus rhythm, one must now recognize a subset of patients with diastolic rather than systolic dysfunction who are best treated by correcting underlying causes of left ventricular hypertrophy or ischemia rather than inotropic support with cardiac glycosides. Symptomatic patients with dilated ventricles and impaired contractile function should undergo correction of abnormalities of preload with vasodilators acting on the venous bed as well as diuretics, and reduction of elevated afterload with vasodilators that reduce arteriolar resistance and thus improve ventricular emptying.(ABSTRACT TRUNCATED AT 400 WORDS)

Digitalis Glycosides↗
PubMed1995

New and simple method for estimating metildigoxin dosing regimens by multiple trough screen analysis.

The pharmacokinetics of digitalis glycosides were studied using routine therapeutic drug monitoring data to evaluate the role of patient characteristics for estimating metildigoxin dosing regimens. The 232 serum glycoside concentration data at steady-state after repetitive oral administration in 144 hospitalized patients was analyzed using NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data. Pharmacokinetic analysis of digitalis glycosides was described using a simple steady-state pharmacokinetic model. The effect of a variety of developmental and demographic factors on glycoside clearance was investigated. NONMEM estimates indicated that this digitalis glycoside clearance was influenced by the demographic variables of age, total body weight, serum creatinine, gender, daily dose and the coadministration of spironolactone. An elderly patient was expected to have a lower rate of clearance than a young patient of equal body weight and serum creatinine. The interindividual variability in glycoside clearance was modelled with proportional error with an estimated coefficient of variation of 19.7% and the residual variability was 21.8% The dosing method based on glycoside clearance value obtained by NONMEM analysis allowed the prediction of the minimum steady-state glycoside concentration as a function of metildigoxin maintenance dose with acceptable error for therapeutic drug monitoring.

Adolescent↗
PubMed1982

[Incidence of side effects in digitalis therapy].

In a literature research program concerning side effects during digitalis therapy 75 publications had been evaluated. Comparing 15 drug monitoring studies with different types of drugs, cytostatics, antibiotics and analgetics most frequently led to side effects. Digitalis glycosides ranged on the place 3-9. Adverse reactions rates up to 20% had been observed in hospitalized patients. The average of all data, however, was near 10%. Because of their generally low-risk rate of intoxication ambulant patients--with 96-97% glycoside prescriptions the dominant part of digitalis recipients--evidently had a lower incidence of adverse reactions. In this group of patients the rate of side effects ranged about 3% for digoxin and digitoxin, respectively. Comparative clinical studies with digoxin and digitoxin showed no signs of differences in the rate of adverse reactions between these two digitalis glycosides.

Ambulatory Care↗