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PubMed2005

[The place of cardiac glycosides in the treatment of chronic heart failure. Part II. Results of small studies].

In a series of papers the authors analyze literature data on the use of cardiac glycosides for long term treatment of chronic heart failure. Part II is devoted to analysis of results of small controlled studies of pharmacological effects of low dose digoxin in patients with sinus rhythm. Low dose digoxin improves exercise tolerance and lowers risk of decompensation of heart failure but produces no substantial effect on contractility of left ventricular myocardium. Therefore its favorable action on clinical course and outcomes of chronic heart failure is most probably related to modulation of neuro-humoral systems. Retrospective analysis of some trials shows that digoxin is able to increase mortality of survivors of acute myocardial infarction. Hence great care is required when digoxin is used for long term treatment of chronic heart failure due to systolic left ventricular dysfunction after myocardial infarction.

Algorithms↗

PubMed1977

[Evaluation of the clinical effect of treatment with cardiac glycosides under conditions of ambulatory observation].

Thirty-four patients with rheumatic heart disease and 22 with atherosclerotic and post-infarction cardiosclerosis, signs of stage I-IIB circulatory insufficiency, and disorders of cardiac rhythm (auricular fibrillation) were kept under out-patient care for periods of 6 to 42 months. They all received cardiac glycosides per os in a maintenance dose determined in the clinic after intravenous digitalization. Clinical and echocardiographic examination of the patients was conducted every 4 to 6 months. Depending on the effect of long-term digitalization, all patients were divided into clinical groups in which the causes of the disturbed compensation were determined. The importance of regular doctor's control over proper intake of the maintenance dose of glycosides and its correction depending on each concrete clinical situation is stressed.

Adult↗

PubMed1978

Reduction of the equilibrium binding of cardiac glycosides and related compounds to Na+,K+-ATPase as a possible mechanism for the potassium-induced reversal of their toxicity.

The influence of potassium ions on the equilibrium state of the binding of cardiac glycosides and their derivatives to partially purified dog heart and rat brain enzyme preparations was studied in vitro. The addition of potassium to the incubation mixture containing enzyme preparation, 3H-ouabain, Na+, Mg2+ and ATP, at the time when the binding reaction is close to equilibrium, caused an immediate reduction of the bound drug concentration; the concentration apparently shifting toward a lower equilibrium state. The degree of the potassium-induced reduction in bound drug concentration was dependent on the potassium concentration and on the chemical structure of the compound. The binding of aglycones, pentacetyl-gitoxin and cassaine was affected to a greater extent than that of the glycosides. These data suggest that one of the mechanisms by which potassium antagonizes the toxic actions of digitalis on the heart is to reduce the drug binding to cardiac Na+,K+-ATPase.

Animals↗

PubMedDate not supplied

Release of adenine nucleotide metabolites by toxic concentrations of cardiac glycosides.

In isolated perfused guinea-pig hearts the effect of toxic concentrations of cardiac glycosides on the release of the adenine nucleotide metabolites adenosine, inosine, hypoxanthine, xanthine, and uric acid was investigated. Digoxin concentrations of 0.03-1 mumol.l-1 produced moderate to severe tachyarrhythmias. Large amounts of metabolites were released by concentrations of 0.1 mumol.l-1, and higher. Occurrence of glycoside-induced ventricular fibrillation was associated with a particularly high release. Metabolite release was also obtained when fibrillation was elicited electrically in normal control hearts, or in hearts receiving simultaneously a marginally toxic digoxin concentration (0.03 mumol.l-1). Digoxin-induced tachyarrhythmias and metabolite release were almost completely prevented by a high potassium concentration in the coronary perfusion fluid (8.1 mmol.l-1). The antiarrhythmic effect was also obtained with lidocaine (60 mumol.l-1), but the release was only partially antagonized. Similar results concerning arrhythmias and metabolite release as with digoxin were obtained with ouabain. The findings suggest that the decrease in myocardial ATP observed in glycoside-intoxicated heart preparations is partly due to the loss of nucleotide precursor substances. Moreover, it appears likely that liberated adenosine in the interstitium of severely intoxicated heart preparations reaches pharmacologically effective concentrations.

Adenine Nucleotides↗

PubMed1986

Cardiac glycosides with non-rotating steroid to sugar linkages: tools for the study of digitalis structure-activity relationships.

The 5 alpha H-cardenolide, gomphoside, is one of a small group of naturally occurring cardiac glycosides in which the sugar residue is bilinked to the steroid ring system. This arrangement prevents the sugar moiety from rotating and this makes gomphoside and related compounds potentially useful for structure-activity relationship (SAR) studies. When gomphoside was tested for inotropic activity using guinea pig left atria, the compound was found to have very high potency comparable to the most active 5 beta H-cardenolides. Removal of the sugar moiety reduced inotropic activity almost 500-fold indicating that it was the presence of the sugar moiety that was mainly responsible for the drug's high potency. Modification of the steroid or sugar residue of gomphoside reduced activity in all cases. It would thus appear that gomphoside with its high potency and non-rotatable glycosidic linkage is an excellent tool for SAR studies.

Animals↗

PubMed1992

Chick heart cells with high intracellular calcium concentration have a higher affinity for cardiac glycosides than those with low intracellular calcium concentration, as revealed by affinity labelling with a digoxigenin derivative.

Digital-imaging fluorescence microscopy with fura-2 allows the determination of intracellular calcium concentration ([Ca2+]i) in single cells. At a cell density of 10(5) cells/petri dish 44% of the chick embryo heart cells had a high [Ca2+]i of 99.4 +/- 7.1 nM and 56% of the cells a low [Ca2+]i of 27.8 +/- 4.4 nM (mean +/- SE). This laboratory previously reported that high-[Ca2+]i and low-[Ca2+]i cells from chick embryo hearts differ in their sensitivity to cardiac glycosides, as shown by measuring the increase in [Ca2+]i to reach a new steady state [Ahlemeyer, B., Weintraut, H., Seibold, G. & Schoner, W. (1991) in The sodium pump: recent developments (Kaplan, J. H. & De Weer, P., eds) pp. 653-656, Rockefeller University Press, New York]. This time we used N-hydroxysuccinimidyl digoxigenin-3-O-methylcarbonyl-epsilon-aminocaproate (HDMA) which binds irreversibly to amino groups of the Na+/K(+)-ATPase, and sheep anti-digoxigenin Fab fragments coupled with fluorescein isothiocyanate to identify different cardiac glycoside-binding sites. Half-maximal labelling of high-[Ca2+]i cells was obtained at 0.36 nM HDMA, and at 12.0 nM with the low-[Ca2+]i cells. Specific labelling of the cells by HDMA was 91% and 80% in high-[Ca2+]i and low-[Ca2+]i cells, respectively, as revealed by competition experiments with a 1000-fold excess of ouabain. HDMA half-maximally elevated the [Ca2+]i of high-[Ca2+]i cells at a concentration of 50 pM and that of low-[Ca2+]i cells at 8.0 nM. Concentrations higher than 0.1 microM produced signs of intoxication. When the labelled cells were subjected to a SDS/PAGE, a 100-kDa band was found to contain HDMA. The electrophoretic mobility of a protein labelled at 10 nM HDMA was slightly higher than that of a protein labelled at 1.0 microM. The data suggest that different isoforms of the alpha-subunit of Na+/K(+)-ATPase may exist in low-[Ca2+]i and high-[Ca2+]i cells of chick embryo heart.

Affinity Labels↗

PubMed1980

Toxicological study of the different organs of Corchorus olitorius L. plant with special reference to their cardiac glycosides content.

The acute toxicity of the alcoholic extracts of seeds, roots stems and leaves of the fully mature Corchorus olitorius L. plant was determined in mice by intraperitoneal injection. The cardiac glycosides content of each extract was estimated and the correlation between the two investigated parameters was established. The chronic toxicity of the alcoholic extract of the seeds was determined in term of its haematological and symptomatical effects on mice upon intraperitoneal injection for a period of two months.

Animals↗

PubMed1956