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At least 217 records · Page 12Linked to original sources
PubMed1986

Cellular basis for the species differences in sensitivity to cardiac glycosides (digitalis).

The relative toxicity of numerous cardiotonic steroids (viz. ouabain, digitoxin, digoxin, convallatoxin, SC4453, bufalin, gitaloxin, digoxigenin, actodigin, oleandrin, digitoxigenin, gitoxin, strophanthidin, gitoxigenin, lanatosides A, B and C, alpha- and beta-acetyl digoxin, alpha- and beta-methyl digoxin) and related compounds towards a number of independent cell lines established from human, monkey, mouse, Syrian hamster, and Chinese hamster have been determined. All cardiac glycosides and their genins, as well as the cardiotonic alkaloid cassaine, exhibited greater than 100-fold higher toxicity towards cultured human and monkey cells in comparison to the cell lines of mouse, Syrian hamster, and Chinese hamster origins. These differences are species-related as all cell lines (both normal as well as transformed) from any one species, as well as cells from the closely related species (e.g., man and monkey or mouse, Chinese hamster, and Syrian hamster), showed similar sensitivity towards these drugs. The failure to see any significant differences in cellular toxicity for a larger number of other compounds which either bear limited structural resemblance to cardiac glycosides (viz. estradiol 17-beta-acetate, testosterone propionate, 21-acetoxy pregnenolone, beta-estradiol, digitonin, tigogenin, and tomatine) or interact with the Na+/K+ ATPase in a different manner (viz. veratridine, sanguinarine nitrate, penicillic acid, vanadium pentoxide, harmaline-HCI,5,5'-diphenyl hydantoin, quindonium bromide, and methyl quinolizinum bromide) provides strong evidence that the observed species-related differences are highly specific for cardiotonic steroids. Studies on the binding of [3H]ouabain show that, in comparison to human and monkey cell lines, no significant binding of the drug is observed in cells derived from the resistant species (i.e., mouse and Chinese hamster). The Na+/K+ ATPase from cells of the resistant species is inhibited at much higher concentrations of ouabain and digitoxin in comparison to the enzyme from human cells, and a good correlation is observed between these concentrations and those reported for inhibition of the enzyme from isolated heart muscles of the same species. These results provide strong evidence that the species-related differences in sensitivity to digitalis have a cellular basis and that the cultured cells from various mammalian species provide a useful model system for investigating the mechanism of action of cardiac glycosides.

Animals↗
PubMedDate not supplied

Deleterious synergism of a cardiac glycoside and sodium diatrizoate.

Studies were performed in mice to determine if the cardiac glycoside, Strophanthin-K, and the contrast medium, sodium diatrizoate, interact synergistically to produce death. Intravenous injections of lethal and near lethal doses of the two agents produced a significantly greater mortality than the individual agents alone. Low or near clinical doses of Strophanthin-K, when given with doses of diatrizoate in the lethal range, produced mortalities significantly greater than did the diatrizoate alone. Similarly, low or near clinical doses of diatrizoate given with doses of Strophanthin-K in the lethal range produced mortalities significantly greater than for the Strophanthin-K alone. Isotonic or hypertonic saline, when substituted for diatrizoate or Strophanthin-K did not produce synergistic increases in mortality. Thus neither the injection volume, nor agent hypertonicity or ionic strength, seem to be the primary factors in the synergism to produce death. The diatrizoate anion appears to be an important factor. Until more information is available from other animal models it appears that patients receiving cardiac glycoside should be considered to have a higher than normal risk of serious reactions to contrast media in intravenous urography.

Animals↗
PubMed1985

Electron microscopic autoradiographic study of heart muscle calcium in experimental cardiac glycoside poisoning.

The role of calcium was investigated in myocardial cell necrosis induced by cardiac glycoside. Experimental poisoning caused an increase of Ca45. Excessive intracellular calcium uptake must be the determining factor in the aetiology of myocardial cell damage. The possible involvement of calcium increase in the genesis of cardiac glycoside induced myocardial cell necrosis is discussed.

Adenosine Triphosphatases↗
PubMed1986

Spatial relationship and conformational changes between the cardiac glycoside site and beta-subunit oligosaccharides in sodium plus potassium activated adenosinetriphosphatase.

(Na,K)-ATPase, the enzyme responsible for active transport of Na and K across the plasma membranes of animal cells, consists of a catalytic subunit (alpha) and a glycoprotein subunit (beta) with unknown function. We have determined the distance between fluorescent probes directed to specific sites on the alpha- and beta-subunits and ligand-induced changes in the fluorescence of a probe specifically attached to the beta-subunit. The cardiac glycoside site on the alpha-subunit was labeled with anthroylouabain [Fortes, P. A. G. (1977) Biochemistry 16, 531-540]. The oligosaccharides on the beta-subunit were labeled with lucifer yellow carbohydrazide [Lee, J. A., & Fortes, P. A. G. (1985) Biochemistry 24, 322-330]. Resonance energy transfer from anthroylouabain to lucifer yellow was measured by steady-state and time-resolved fluorescence spectroscopy. The distance between these probes was determined from the efficiency of energy transfer. The average distance between anthroylouabain and lucifer yellow was 47 A and was independent of the number of acceptor molecules attached to the beta-subunit. The measured distance corresponds to the distance between the cardiac glycoside site and the center of the labeled oligosaccharides on the beta-subunit within one alpha beta dimer. The distance was the same (47 A) when anthroylouabain was bound with ATP or Pi as phosphorylating ligands but increased to 49 A in the presence of vanadate. The change in average distance provides quantitative evidence of a conformational difference between the complexes of cardiac glycosides with (Na,K)-ATPase induced by phosphorylating ligands or by vanadate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

The effect of cardiac glycosides on the Na+ pump current-voltage relationship of isolated rat and guinea-pig heart cells.

1. Whole-cell recording from isolated rat and guinea-pig ventricular myocytes revealed a change of the cardiac Na+ pump current (Ip)-voltage (V) relationship by cardiac glycosides, specific inhibitors of the Na(+)-K+ pump. 2. Dihydro-ouabain (DHO) diminished Ip in rat ventricular cells at 0 mV in a concentration-dependent manner. 3. The concentration-response curve of Ip inhibition caused by DHO was shifted to higher [DHO] at higher extracellular K+ concentrations ([K+]o) or at more negative membrane potentials. 4. In rat myocytes, DHO immediately flattened the normalized cardiac Ip-V curve and evoked or enhanced a region of negative slope. 5. Ouabain, at concentrations which caused a comparable inhibition of Ip, exerted DHO-like effects on the Ip-V relationship of rat ventricular myocytes. However, the effects developed more slowly. 6. A slowly developing alteration of the Ip-V curve was also observed upon application of DHO to guinea-pig ventricular cells. The range of [DHO] used was about 100-fold lower than that applied to rat ventricular cells, but was equally effective for Ip inhibition. 7. Increasing the K+ concentration of DHO-containing media affected the existing equilibrium of DHO binding to the cardiac Na(+)-K+ pump. A new equilibrium was reached within about 3 s in rat ventricular myocytes, but only within about 50 s in guinea-pig ventricular cells under the experimental conditions chosen. 8. It is concluded that the changes of the cardiac Ip-V curve induced by cardiac glycosides are mediated by voltage-dependent variations of the local [K+]o at the K+ binding sites of the Na(+)-K+ pump in an 'access channel'. The variations were estimated by means of the Boltzmann equation. The estimations agreed with those derived from the measured DHO binding to the Na(+)-K+ pump at various [K+]o. A new equilibrium of glycoside binding to the pump is established at the altered [K+]o. The time necessary to reach the new binding equilibrium varies with the cardioactive steroid, its concentration and the glycoside sensitivity of the cardiac cells.

Animals↗
PubMed1981

Cardiac glycosides and their metabolites levels in plasma and heart of guinea-pigs after I. V. administration.

One hr, 3 hr and 6 hr after i.v. injection of tritiated gitoxin, digoxin and digitoxin to the guinea-pig, the chloroform-insoluble metabolites, mainly conjugates known to be cardio-inactive, represent two thirds of the cardiac glycoside and metabolites content of plasma for gitoxin, half for digitoxin and one quarter for digoxin. Most of the compounds taken up by the myocardium are chloroform-soluble and may be considered as cardio-active. Considering the nature and proportions of the unchanged cardiac glycoside and its cardio-active metabolites in the myocardium of the guinea-pig, the cardiac effects that would be measured after administration of digoxin ar due to unchanged digoxin only; after administration of digitoxin, these effects are partly due to unchanged digitoxin but also to 12 beta-hydroxylated metabolites; after administration of gitoxin, besides unchanged gitoxin, the hydrolysis products of the sugar chain of gitoxin may contribute to the cardiac effects. The data obtained in plasma and in myocardium between 1 and 6 hr after administration of digoxin or gitoxin show that the distribution of the unchanged cardiac glycoside and each chloroform-soluble metabolite, from plasma to myocardium, is achieved 1 hr after administration. This situation does not occur with digitoxin and its metabolites.

Animals↗
PubMed1980

Sodium dependence of the positive inotropic effect of cardiac glycosides.

We have investigated the inotropic effects of digoxin, digitoxin and ouabain in cat ventricular muscle under conditions of reduced Na influx in an effort to determine the role of Na in the positive inotropic effect of these cardiac glycosides. When the normal, Na-dependent action potential is inactivated by potassium depolarization, these glycosides retain a positive inotropic effect. In contrast, when muscles are bathed in Na-poor or Na-free solutions, these glycosides do not influence contraction. This suggests that the cardiac glycosides are dependent on Na for their positive inotropic effects.

Animals↗
PubMed1978

[Long-term study with the novel cardiac glycoside meproscillarin (author's transl)].

In a multicentre open therapeutic study 64 physicians provided 650 questionnaires of patients who had been treated with the new cardiac glycoside 14-Hydroxy-3beta-[(4-O-methyl-alpha-L-rhamnopyranosyl)oxy]-14beta-bufa-4,20,22-trienolide (meproscillarin, Clift) for more than 3 months; 647 questionnaires had been filled in completely and could be evaluated. The major part of all patients suffering from heart failure of the severity degrees I--III required 2 tablets of 0.25 mg, a smaller part 3 tablets to achieve complete recompensation and/or maintenance of compensation, which was possible in 79% of all cases. The rate of side effects corresponded to that of other cardiac glycosides.

Adult↗
PubMed1987

Cardiac glycoside toxicity resulting from cough linctus abuse.

Proprietry cough medicines are often abused by drug addicts as they are freely available and, in many instances, contain narcotic substances. A variety of other compounds are present in these products, including compounds structurally related to the commonly prescribed cardiac glycosides. We report a case in which severe cardiac glycoside toxicity resulted from the abuse of such a preparation.

Adult↗