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PubMed1988

Neurobehavioral contributions to cardiac arrhythmias during aversive pavlovian conditioning in the rabbit receiving digitalis.

Clinical observations suggest that a prevalent condition for the occurrence of cardiac arrhythmias is the synergistic interaction of several risk factors including digitalis glycosides, myocardial ischemia and psychological stress. However, little research has been directed toward controlled, systematic investigations of such synergistic interaction, particularly with respect to psychological stress and digitalis glycosides. The present research was undertaken to develop an animal model with which to study the behavioral and neurobiological contributions to arrhythmias during psychological stress in the presence of digitalis. The model used the rabbit as the experimental animal, a pavlovian aversive conditioning procedure and ouabain, a digitalis glycoside. Rabbits received pavlovian conditioning trials in which a tone as a conditioned stimulus (CS) was paired with an eyelid shock as an unconditioned stimulus (US). Twenty-four hours later, a retention test was given in which either of two doses of ouabain or saline was given, followed by 20 CS presentations alone. The CS presentations were given every 120 s (+/- 10 s). During ouabain infusion, the CS significantly increased the frequency of arrhythmic episodes compared to pre-CS baseline frequencies. These arrhythmic episodes were invariably preceded by CS-induced bradycardia. Both parasympathetic and sympathetic involvement were suggested in arrhythmogenesis, since the CS-induced increase in arrhythmic episodes was blocked by pretreatment with either atropine methylnitrate or atenolol. Furthermore, electrical stimulation of the amygdaloid central nucleus, an area implicated in the expression of bradycardia to a pavlovian CS in the rabbit produced arrhythmic episodes in the presence of ouabain. These arrhythmic episodes were similar in topography to CS-induced arrhythmias within any one animal and were decreased by atropine methylnitrate pretreatment. Insights into central and peripheral nervous system mechanisms by which psychological stress is capable of evoking cardiac arrhythmias in the presence of ouabain should ultimately lead to more effective treatment strategies for the prevention of these arrhythmias.

Amygdala↗
PubMed2005

Effects of phenylethanoid glycosides from Digitalis purpurea L. on the expression of inducible nitric oxide synthase.

We have isolated four different phenylethanoid glycosides (purpureaside A, desrhamnosyl acteoside, calceolarioside B and plantainoside D) from the leaves of Digitalis purpurea (foxglove). The effects of these glycosides on activator protein-1 (AP-1)-mediated inducible nitric oxide synthase (iNOS) gene expression in the Raw264.7 macrophage cell line have been studied. Of these four glycosides, purpureaside A potently inhibited iNOS induction by lipopolysaccharide (LPS). Increase in iNOS mRNA by LPS was completely suppressed by purpureaside A. Purpureaside A did not significantly affect LPS-inducible nuclear factor-kappaB (NF-kappaB) activation or the nuclear translocation of p65. Moreover, a reporter gene assay using AP-1 specific luciferase reporter revealed that the enhanced activity of AP-1 by LPS was completely abolished in cells treated with purpureaside A. These results demonstrated that purpureaside A inhibited LPS-inducible iNOS expression in macrophages through the suppression of AP-1, but not of NF-kappaB.

Cell Line↗
PubMed2001

Treatment of congestive heart failure--current status of use of digitoxin.

Digitalis glycosides exert a positive inotropic effect, i.e. an increase in myocardial contractility associated with a prolongation of relaxation period, and glycosides lower the heart rate (negative chronotropic), impede stimulus conduction (negative dromotropic) and promote myocardial excitability (positive bathmotropic). They seem to influence the activities of both the vagal and the sympathetic systems. Digitalis glycosides that belong to different substance classes are closely comparable concerning pharmacodynamics but differ substantially in regard to pharmacokinetics. Digoxin and its derivatives are less lipophilic, show lower protein binding and shorter half-life, are mainly eliminated via the kidney and accumulate rather rapidly in cases of insufficient kidney function. Digitoxin is highly lipophilic and extensively bound to plasma proteins, has a longer half-life, is mainly eliminated in the metabolized state via urine and faeces and does not accumulate in kidney dysfunction. As a result of a more stable pharmacokinetic profile, the incidence of toxic side effects seems to be lower with digitoxin than with digoxin. Since the beginning of the 1990s, the antagonists of the RAAS qualified as the standard treatment for congestive heart failure, often in combination with diuretics, vasodilators or beta-antagonists. However, the important role of digitalis glycosides as therapeutic comedication or alternative was never denied, especially in atrial fibrillation with tachycardia. The PROVED and RADIANCE trials proved a detrimental effect of the withdrawal of digoxin therapy on exercise capacity, left-ventricular ejection fraction and clinical symptoms. The DIG trial revealed that digoxin comedication in sinus rhythm patients with congestive heart failure was associated with a lower morbidity (as taken from death or hospitalization because of worsening heart failure) and an unchanged overall mortality--being a unique feature among the available inotropic drugs. Comparable studies for digitoxin have not yet been performed but, because of its higher pharmacological stability, it might well be associated with even more advantages in this regard than digoxin.

Cardiotonic Agents↗
PubMed2000

A non-fatal case of intoxication with foxglove, documented by means of liquid chromatography-electrospray-mass spectrometry.

The non-fatal self-poisoning of a 36-year-old female patient, who ingested a concoction of foxglove (Digitalis Purpurea), is presented. On the admission, initial symptoms were nausea and vomiting, abdominal pain, and cardiovascular shock with sinus bradycardia. Blood and urine were assayed for 17 cardiotonic hetorosides, using a highly specific LC-MS procedure. Serum and urine specimens were collected over five days and analyzed by liquid chromatography-electrospray-mass spectrometry (LC-ES-MS). This accurate procedure allowed the determination of the digitalis glycosides and their metabolites in serum and urine. The serum concentrations of digitalis glycosides were maximum on the first day (gitoxin 13.1 ng/mL, digitoxin 112.6 ng/mL, digitoxigenin 3.3 ng/mL, and digitoxigenin mono-digitoxoside 8.9 ng/mL) and decreased over five days. We observed a peak gitaloxin level (112.6 ng/mL) on the fifth day only. After administration of atropine as well as dimeticone, alginic acid, and metoclopramide, health status improved. The peak urine concentrations were reached at hour 30 and were respectively 91.3 and 69.9 ng/mL for gitaloxin and digitoxin, while those of digitoxigenin, digitoxigenin mono-digoxoside and gitoxin were lower (respectively 0.7, 1, and 5.6 ng/mL). The patient was discharged on the fifth day when there were no residual symptoms.

Adult↗
PubMed1985

Prescription of digitalis in a health centre serving a defined rural population in Iceland.

The use of digitalis glycosides in the Egilsstadir district in eastern Iceland was studied. The district which has a well-defined catchment area has a health centre with three general practitioners serving a registered population of 2802 inhabitants. This is 1.2% of the total population of Iceland with similar age and sex distribution. Twenty-four patients (0.9%) were treated with digitalis glycosides. The most common patient complaint before starting therapy was shortness of breath. The general practitioners started therapy in 17 cases, consultants in seven. Ecg was taken before therapy in 22 cases and showed 15 patients with sinus rhythm. The most common diagnosis was heart failure (62%). The only glycoside used was digoxin. The use of cardiac glycosides in the Egilsstadir health district was low both compared with Iceland as a whole and with other Nordic countries. Considering studies on discontinuation of maintenance digoxin therapy in general practice and also the findings in this study it is suggested that the use of digitalis glycosides in the Egilsstadir health district and in Iceland could be even lower.

Adolescent↗
PubMed1980

T-cell functions in nude mice: proliferation of spleen cells from athymic mice in the one-way xenogeneic mixed leucocyte reaction.

Spleen cells from nude mice proliferate in vitro when stimulated with xenogeneic (human) lymphoid cells rendered unresponsive by addition of digitalis glycosides. In digitalis-sensitive species, such as humans, DNA, RNA, carbohydrate, and protein synthesis is completely blocked by addition of low concentrations of glycoside, whereas no impairment is found in digitalis-resistant species such as mouse. Since T cells have been implicated to be the cells responding in the mixed leucocyte reaction, this finding may suggest the occasional existence of "T-like" cells in the spleens of nude mice.

Animals↗
PubMed1987

Digitalis toxicity: mechanisms, diagnosis, and management.

Digitalis glycosides have a narrow margin between therapeutic and toxic levels. Although the incidence of digitalis toxicity appears to be decreasing, continuation of digoxin therapy in the face of overt toxicity carries a substantial risk of life-threatening cardiac rhythm disturbances. This review will focus primarily on toxicity produced by digoxin and discuss the mechanisms, clinical manifestations, and current management of digitalis toxicity. The appropriate methodology for measurement and interpretation of serum digoxin levels is emphasized. The varied cardiac dysrhythmias induced by digoxin are detailed and their specific management outlined. Immunological (antibody) treatment has now been established and approved for the therapy of advanced, life-threatening digitalis toxicity and the multicenter trial of digitalis antibodies is described. Proper understanding of the pharmacokinetics of digitalis glycosides and careful followup of digitalis treated patients for early evidence of toxicity should help to decrease further the prevalence of toxic reactions.

Arrhythmias, Cardiac↗
PubMed1981

Age dependence of myocardial Na+-K+-ATPase activity and digitalis intoxication in the dog and guinea pig.

Infants and young animals tolerate higher doses of digitalis glycosides, relative to body weight, than adults. One possible explanation for this could be an age-dependent difference in the myocardial digitalis receptor, the Na+-K+-ATPase. Two functions of this enzyme were studied in adult, 1- and 6-week-old dogs and guinea pigs: in vitro myocardial uptake of rubidium (86Rb) and binding of ouabain. In guinea pigs, rubidium uptake (pmol Rb/mg LV per 15 min) was: 1 week old: 100.9 +/- 7.1 (mean +/- SE); 6 week: 79.8 +/- 6.7 adult: 55.2 +/- 7.9; (1 week: 6 week: P less than 0.025; 1 week: adult, P less than 0.001; 6 week: adult, P less than 0.025). Similarly in dogs, rubidium uptake was significantly greater at 1 week than at 6 weeks (208 +/- 13 vs. 144 +/- 9; P less than 0.001) and the latter greater than in adults (111 +/- 4) (P less than 0.005). Other groups of anesthetized adult and 6-week-old dogs were given digoxin, 0.3 mg/kg, iv. The young dogs took significantly longer to become cardiotoxic (17.3 +/- 3.4 min vs. 9.3 +/- 1.4 min; P less than 0.025), while their myocardial digoxin uptake was at least as great. Rubidium uptake showed an average decrease of 56% after digoxin but residual uptakes were not different in the two groups. Data for ouabain binding showed similar differences between the various groups of dogs studied. Increased myocardial Na+-K+-ATPase activity, reflected in greater active cation transport and specific enzyme binding, has been demonstrated in young animals and may be partly responsible for their greater tolerance to digitalis glycosides.

Age Factors↗
PubMed1985

Cellular mechanisms of digitalis action.

Although the therapeutic actions of digitalis glycosides have been known for over 200 years, their direct inotropic actions on the heart were not established until the last 50 years. Digitalis has undergone intense research, particularly with respect to its mechanisms of action. Many authors have claimed to have found the true mechanism of action, compounding the complexity of literature. Recent subcellular studies have pointed to specific areas of action of the digitalis glycosides. Each discovery has been dependent on the greater understanding of the electrophysiologic characteristics of cardiac muscle and excitation-contraction coupling. The current hypothesis suggests that digitalis specifically inhibits Na-K ATPase. This produces an elevation in intracellular sodium level that in turn produces an increase in the intracellular calcium level. The increased quantities of calcium available to the contractile elements of cardiac muscle provide the observed increased inotropy.

Animals↗
PubMed1986

Positive inotropic drugs--digitalis.

Digitalis glycosides inhibit Na+K+-ATPase in the cells and have been used for scientific studies of cation transport over cell membranes. Furthermore, digitalis has a positive inotropic and antiarrhythmogenic effect. Specific binding sites for digitalis glycosides have been observed in erythrocytes, the myocardium and the central nervous system. Transcellular transport of digoxin has been found in the kidney, since digoxin is excreted by tubular secretion. Recent studies have discovered an endogenous digitalis-like substance both inhibiting Na-K-ATPase and displacing digoxin from specific binding sites at the erythrocytes. The concentration of this component in plasma seems to be higher in hypertension than in normotension. Future studies will have to disclose other effects of this substance in order to evaluate whether it can be used as a drug in heart failure.

Digitalis Glycosides↗