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PubMed1986

Biochemical and cross-resistance studies with HeLa cell mutants resistant to cardiac glycoside SC4453. Regulation of the resistant form of Na+/K+-ATPase in the mutant cells.

In HeLa cells, stable mutants which are between 25-to about 200-fold resistant to the cardiac glycoside derivative SC4453 (a digoxin analog which contains a pyridazine ring in place of a lactone ring in the C-17 position) have been isolated after a single step selection in the presence of the drug. Based on their cross-resistance pattern towards various cardiac glycosides, the mutants resistant to SC4453 (SCR mutants) appear to be of two different kinds and they differ from the two classes of ouabain-resistant mutants described previously (Gupta, R. S., and Chopra, A. (1985) J. Biol. Chem. 260, 6843-6850). One type of SCR mutants (designated as group C) exhibit a high degree of cross-resistance to all cardiac glycosides and their genins (viz. ouabain, digitoxin, digoxin, digoxigenin, convallatoxin, gitoxin, strophanthidin, and bufalin). In contrast, the second type of SCR mutant (group D) exhibit considerable resistance to only SC4453, digoxin, and digoxigenin, but showed very little or no cross-resistance to the other cardiac glycosides examined. The cross-resistance of the mutants towards cardiac glycosides was highly specific as they exhibited no cross-resistance towards a large number of other structurally and functionally related compounds (viz. ethacrynic acid, sanguinarine nitrate, penicillic acid, methyl quinolizinum bromide, 5,5'-diphenylhydantoin, deoxycorticosterone, vanadium pentoxide, and adriamycin). The cellular uptake of 86Rb in the mutant cells was found to be resistant to specific cardiac glycosides. Studies on the sensitivity of plasma membrane Na+/K+-ATPase to cardiac glycosides show that about 10-15% of the enzymic activity in the mutant cells was highly resistant to inhibition by the specific drugs to which the mutants exhibit increased resistance. Very interestingly, when the mutant cells are grown in cardiac glycoside-containing medium, the resistant form of the enzyme accounts for about 50-60% of the total enzyme. These results show that both classes of SCR mutants are affected in Na+/K+-ATPase and that the amount of the resistant enzyme in the mutant cells is regulated in response to cardiac glycosides.

Cardiac Glycosides↗
PubMed1981

Preferential sensitivity of the left canine purkinje system to cardiac glycosides.

Previous studies have shown that the toxic effects of cardiac glycosides are not manifested uniformly throughout the myocardium. The purpose of our study was to determine whether cardiac glycosides exert different effects on the right vs. left peripheral Purkinje systems and to ascertain mechanisms involved. Control in vitro measurements of paired right and left canine Purkinje fibers showed higher spontaneous rates in left (24.2 +/- 1.75 beats/min) than in right (11.6 +/- 1.55 beats/min, P less than 0.01, n = 81) Purkinje fiber bundles. Following overdrive stimulation, left Purkinje fiber bundles also showed earlier escape beats. After ouabain exposure (2 X 10-7 M), left Purkinje fiber bundles showed earlier signs of toxicity in 20 of 28 experiments, as determined by changes in the maximum diastolic potential, the degree of diastolic depolarization, spontaneous escape intervals, and the magnitude of delayed after-depolarizations. The enhanced sensitivity of left Purkinje fiber bundles was independent of the extracellular potassium concentration and glycoside polarity, and was also observed in situ. We conclude that distal Purkinje fibers are functionally dissimilar and that the left Purkinje system shows greater sensitivity to cardiac glycosides than the right Purkinje system. These data also support the observation that digitalis-induced dysrhythmias arise in the left ventricle.

Action Potentials↗
PubMedDate not supplied

Cardiac glycosides induce resistance to tubulin-dependent anticancer drugs in androgen-independent human prostate cancer.

Due to high prevalence and mortality and the lack of effective therapies, prostate cancer is one of the most crucial health problems in men. Drug resistance aggravates the situation, not only in human prostate cancer but also in other cancers. In this study, we report for the first time that cardiac glycosides (e.g. ouabain and digitoxin) induced resistance of human prostate cancer cells (PC-3) in vitro to tubulin-binding anticancer drugs, such as paclitaxel, colchicine, vincristine and vinblastine. Cardiac glycosides exhibited amazing ability to reverse the G2/M arrest of the cell cycle and cell apoptosis induced by tubulin-binding agents. However, neither ionomycin (a Ca(2+) ionophore) nor veratridine (a Na(+) ionophore) mimicked the preventive action of cardiac glycosides, indicating that elevation of the intracellular Ca(2+) concentration and Na(+) accumulation were not involved in the cardiac glycoside action. Furthermore, cardiac glycosides showed little influence on the effects induced by actinomycin D, anisomycin and doxorubicin, suggesting selectivity for microtubule-targeted anticancer drugs. Using in situ immunofluorescent detection of mitotic spindles, our data showed that cardiac glycosides diminished paclitaxel-induced accumulation of microtubule spindles; however, in a non-cell assay system, cardiac glycosides had little influence on colchicine- and paclitaxel-induced microtubule dynamics. Using an isotope-labeled assay method, we found that ouabain modestly but significantly inhibited the transport of [(14)C]paclitaxel from the cytosol into the nucleus. It is suggested that cardiac glycosides inhibit the G2/M arrest induced by tubulin-binding anticancer drugs via an indirect blockade on microtubule function. The decline in transport of these drugs into the nucleus may partly explain the action of cardiac glycosides.

Androgens↗
PubMed2005

The highly conserved cardiac glycoside binding site of Na,K-ATPase plays a role in blood pressure regulation.

The Na,K-ATPase contains a binding site for cardiac glycosides, such as ouabain, digoxin, and digitoxin, which is highly conserved among species ranging from Drosophila to humans. Although advantage has been taken of this site to treat congestive heart failure with drugs such as digoxin, it is unknown whether this site has a natural function in vivo. Here we show that this site plays an important role in the regulation of blood pressure, and it specifically mediates adrenocorticotropic hormone (ACTH)-induced hypertension in mice. We used genetically engineered mice in which the Na,K-ATPase alpha2 isoform, which is normally sensitive to cardiac glycosides, was made resistant to these compounds. Chronic administration of ACTH caused hypertension in WT mice but not in mice with an ouabain-resistant alpha2 isoform of Na,K-ATPase. This finding demonstrates that the cardiac glycoside binding site of the Na,K-ATPase plays an important role in blood pressure regulation, most likely by responding to a naturally occurring ligand. Because the alpha1 isoform is sensitive to cardiac glycosides in humans, we developed mice in which the naturally occurring ouabain-resistant alpha1 isoform was made ouabain-sensitive. Mice with the ouabain-sensitive "human-like" alpha1 isoform and an ouabain-resistant alpha2 isoform developed ACTH-induced hypertension to greater extent than WT animals. This result indicates that the cardiac glycoside binding site of the alpha1 isoform can also mediate ACTH-induced hypertension. Taken together these results demonstrate that the cardiac glycoside binding site of the alpha isoforms of the Na,K-ATPase have a physiological function and supports the hypothesis for a role of the endogenous cardiac glycosides.

Adrenocorticotropic Hormone↗
PubMed1977

Elimination of cardiac glycosides through hemofiltration.

Elimination of three different cardiac glycosides by hemofiltration was investigated using the flat bed RP-6 (Rhône-Poulenc, Paris). At a filtration rate of 59 +/- 9 ml/min the mean clearance of 3-H-g-strophanthin was 54.9 +/- 10.4, that of a 3-H-digoxin and unlabelled digoxin 36.7 +/- 6.6 and that of digitoxin 4.6 +/- 2.8 ml/min. It is concluded from these results that hemofiltration is able to eliminate more than 50% of the amount excreted during the same period of time by normal kidneys. Elimination of cardiac glycosides by continuous hemofiltration is high enough to justify its use in digitalis intoxication, particularly because of the excellent control of electrolyte balance with this new method of detoxification.

Cardiac Glycosides↗
PubMed2000

Cardiac glycosides stimulate Ca2+ increases and apoptosis in androgen-independent, metastatic human prostate adenocarcinoma cells.

Cardiac glycosides are used clinically to increase contractile force in patients with cardiac disorders. Their mechanism of action is well established and involves inhibition of the plasma membrane Na+/K+-ATPase, leading to alterations in intracellular K+ and Ca(2+) levels. Here, we report that the cardiac glycosides oleandrin, ouabain, and digoxin induce apoptosis in androgen-independent human prostate cancer cell lines in vitro. Cell death was associated with early release of cytochrome c from mitochondria, followed by proteolytic processing of caspases 8 and 3. Oleandrin also promoted caspase activation, detected by cleavage poly(ADP-ribose) polymerase and hydrolysis of a peptide substrate (DEVD-pNA). Comparison of the rates of apoptosis in poorly metastatic PC3 M-Pro4 and highly metastatic PC3 M-LN4 subclones demonstrated that cell death was delayed in the latter because of a delay in mitochondrial cytochrome c release. Single-cell imaging of intracellular Ca(2+) fluxes demonstrated that the proapoptotic effects of the cardiac glycosides were linked to their abilities to induce sustained Ca(2+) increases in the cells. Our results define a novel activity for cardiac glycosides that could prove relevant to the treatment of metastatic prostate cancer.

Adenocarcinoma↗
PubMed2001

Effects of cardiac glycosides on 24-h ambulatory blood pressure in healthy volunteers and patients with heart failure.

Blood pressure effects of cardiac glycosides in humans have been infrequently reported. Although direct infusion of ouabain or digoxin causes vasoconstriction, indirect effects of cardiac glycosides may have the opposite effect, owing to changes in sympatho-vagal balance. This paper summarises three studies on the effects of cardiac glycosides on circadian blood pressure, utilizing automatic 24-h ambulatory blood pressure measurement (ABPM). In healthy volunteers, 10 days of oral digoxin or digitoxin caused decreases in diastolic blood pressure and heart rate during overnight sleep. No effect was detectable during daytime activities. In patients with heart failure (NYHA stage II), 7 days of oral digoxin also caused a decrease in diastolic blood pressure but only a small increase in systolic pressure during overnight sleep. Again, no effect was detectable during the day. Cardiac glycosides have significant effects on blood pressure, which only appear during overnight sleep, i.e. a phase when sympathetic background activity is lowest. Regular daytime activities may 'overwrite' these effects. Effects of cardiac glycosides on blood pressure may have therapeutic impact, depending on the stage of heart failure and concomitant diseases.

Blood Pressure↗
PubMed1984

Cardiac glycosides and intracellular Na+, K+, Ca2+.

From the fact that cardiac glycosides exert their positive inotropy most likely via a concentration-dependent inhibition of the Na+/K+-activated ATPase, a membrane-bound enzyme regulating the intracellular potassium and sodium homeostasis, one might assume that intracellular electrolyte changes may be easily detectable. Just the opposite holds true. In the literature there are very conflicting observations depending on the experimental model, the analytical method used etc. At the moment, nevertheless, there is great body of evidence that if the cardiac glycoside inotropy is mediated by an inhibition of Na+/K+-activated ATPase this is not accompanied by a measurable alteration of intracellular ionic composition. On the other hand toxic concentrations of cardiac glycosides significantly produce a loss of cellular potassium and a rise of cellular sodium and calcium content, especially if arrhythmias are present. The increase of intracellular free and bound calcium, which manifests itself functionally as contracture, is believed to be caused at least by two mechanisms: a stimulation of the Na-Ca-exchange and an inhibition of the specific Ca2+-activated ATPase in the plasma membrane catalyzing the uphill Ca2+ outward transport. In vitro studies show that this process is impeded by a local rise of the sodium ion concentration. As the determination of myocardial ion fluxes and cellular electrolyte content has its experimental limitations, further insight may be gained by new techniques which give an answer about possible changes of the electrolyte balance at the subcellular level.

Animals↗
PubMed1978

Comparison of the effects of aminosugar cardiac glycosides with ouabain and digoxin on Na+, K+ -adenosine triphosphatase and cardiac contractile force.

Two aminosugar cardiac glycosides, 3-beta-O-(4-amino-4,6-dideoxy-beta-D-galactopyranosyl) digitoxigenin (ASI-222) and its 4-aminoglucose analog (ASI-254) have been shown in our laboratory to have a greater therapeutic index than ouabain (O) or digoxin (D). We have now compared the ability of ASI-222, its nonamino galactose analog (ASI-253), ASI-254, ouabain and digoxin to inhibit swine brain Na+,K+-adenosine triphosphatase (Na+,K+-ATPase) and to increase contractile force of isolated, driven rabbit atria. As inhibitors of Na+,K+ -ATPase, both ASI-222 and ASI-254 were found to be about 10 times more potent than ASI-253, O or D (I50:ASI-222, 1.3 X 10(-7) M; ASI-254, 1.4 X 10(-7) M; ASI-253, 1.15 X 10(-6) M; D, 1.6 X 10(-6) M; O, 1.75 X 10(-6) 7). Moreover the potency of these glycosides in inhibiting Na+, K+ -ATPase correlates closely with the ability of these same glycosides to increase contractile force. The concentration needed to obtain 50% of the maximum increase in contractile force was 9.7 X 10(-8) M for ASI-254, 1.5 X 10(-7) M for ASI-222, 8.8 X 10(-7) M for ASI-253 8.4 X 10(-7) M for O and 1.2 X 10(-6) M for D. Since ASI-253, a nonaminogalactose analog of ASI-222, exhibits a potency in both of our test systems which is similar to the other neutral sugar cardenolides, our data also indicate that the presence of an aminosugar group at position 4 of a sugar in a cardiac glycoside confers greater potency.

Adenosine Triphosphatases↗
PubMed1985

[Effect of cardiac glycosides on whole body potassium concentration in circulatory insufficiency].

Variation of potassium levels produced by cardiac glycosides was assessed in patients with 1st- to 3d-stage circulatory insufficiency, by means of 40K radioactivity measurement in a low radioactivity background chamber. Total group figures demonstrated that total body potassium levels increased with the improvement of the patients' clinical condition. Total body potassium decreased in patients showing signs of cardiac glycoside intoxication. The analysis of the data with reference to pre-and post-treatment baseline tissue potassium concentrations, as compared to the desired level, showed tissue potassium to normalize under the effect of cardiac glycosides in cases of initially abnormal values, and to decrease irrespective of the initial values in cases of cardiac glycoside intoxication.

Adult↗
PubMed1985

Cardiac glycoside tolerance in cultured chicken heart muscle cells--a dose-dependent phenomenon.

In cultured heart muscle cells from 10-13 day-old chicken embryos, the effects of acute (4 h) and chronic (3 days) exposure of the cells to varying concentrations of ouabain have been studied. In these cells, the cardiac glycoside ouabain binds to a specific cardiac glycoside receptor (KD = 4 X 10(-7) M; 750,000 receptors/cell). Binding to this receptor results in inhibition of active Na+/K+-transport [EC50 for active (86Rb+ + K+)-influx = 4 X 10(-6) M], and in an increase in beating velocity ("positive inotropic effect"; EC50 = 4 X 10(-7) M); toxic signs (arrhythmias) appear at concentrations greater than or equal to 6 X 10(-7) M. During exposure of the cells to 3 X 10(-6) M ouabain for 3 days, tolerance develops with respect to both the positive inotropic and the toxic effect. The mechanism underlying this tolerance is identified as an increase in the number of active sodium pump molecules per cell, while the binding properties of the cardiac glycoside receptor remain unchanged. The development of cardiac glycoside tolerance is only observed in the presence of severe impairment of Na+/K+-homeostasis, due to cardiac glycoside-induced inhibition of active Na+/K+-transport. This, however, only occurs in the presence of toxic (receptor occupation greater than or equal to 60%), but not in the presence of positive inotropic, non-toxic (receptor occupation 20-60%), ouabain concentrations. We conclude that the development of cardiac glycoside tolerance during long-term treatment in patients with heart failure should not occur with submaximal dose regimens, when toxic signs (arrhythmias) are absent.

Animals↗
PubMed2002

The effect of three bufadienolide cardiac glycosides on contraction of isolated rat jejunum.

Three cardiac glycosides were screened for pharmacological effects on isolated rat jejunum. The contraction of rat jejunum with epoxyscillirosidin, a non-cumulative bufadienolide, and cotyledoside and tyledoside D, both cumulative neurotoxic bufadienolides were compared with methacholine. The results indicate that all three bufadienolides cause contraction of jejunal smooth muscle. When combined with atropine (1 x 10(-6) M) the response of epoxyscillirosidin and tyledoside D decreased, indicating suppression of a cholinergic response caused by the cardiac glycosides.

Animals↗
PubMed2006

Cardiac glycosides as novel inhibitors of human ether-a-go-go-related gene channel trafficking.

Direct block of the cardiac potassium channel human ether-a-go-go-related gene (hERG) by a large, structurally diverse group of therapeutic compounds causes drug-induced QT prolongation and torsades de pointes arrhythmias. In addition, several therapeutic compounds have been identified more recently that prolong the QT interval by inhibition of hERG trafficking to the cell surface. We used a surface expression assay to identify novel compounds that interfere with hERG trafficking and found that cardiac glycosides are potent inhibitors of hERG expression at the cell surface. Further investigation of digitoxin, ouabain, and digoxin revealed that all three cardiac glycosides reduced expression of the fully glycosylated cell surface form of hERG on Western blots, indicating that channel exit from the endoplasmic reticulum is blocked. Likewise, hERG currents were reduced with nanomolar affinity on long-term exposure. hERG trafficking inhibition was initiated by cardiac glycosides through direct block of Na(+)/K(+) pumps and not via off-target interactions with hERG or another closely associated protein in its processing or export pathway. In isolated guinea pig myocytes, long-term exposure to 30 nM of the clinically used drugs digoxin or digitoxin reduced hERG/rapidly activating delayed rectifier K(+) current (I(Kr)) currents by approximately 50%, whereas three other cardiac membrane currents--inward rectifier current, slowly activating delayed rectifier K(+) current, and calcium current--were not affected. Importantly, 100 nM digitoxin prolonged action potential duration on long-term exposure consistent with a reduction in hERG/I(Kr) channel number. Thus, cardiac glycosides are able to delay cardiac repolarization at nanomolar concentrations via hERG trafficking inhibition, and this may contribute to the complex electrocardiographic changes seen with compounds such as digitoxin.

Action Potentials↗
PubMed1976

Differential species sensitivity to the inhibitory effect of cardiac glycosides on 3H-1-noradrenaline accumulation by tissue slices.

Effects of three cardiac glycosides on the accumulation of 3H-1-noradrenaline (3H-1-NA) by slices of heart and spleen were studied. Ouabain, digitoxin and digoxin, all produced a concentration dependent inhibition of 3H-1-NA uptake in both types of tissue slices. The maximum amount of 3H-1-NA accumulated as well as the rate of uptake was decreased. Digitoxin and ouabain were equipotent; however, digoxin was significantly less potent. Tissues from different mamalian specis did not exhibit the same degree of sensitivity to the inhibitory effect of cardiac glycosides on 3H-1-NA accumulation. Dogs were most sensitive and guinea-pigs an order of magnitude less sensitive. Rats were least sensitive by roughly two orders of magnitude when compared with guinea-pigs. The relationship of the effect of digitalis on 3H-1-NA accumulation to digitalis-induced cardiac arrhythmias is discussed. Finally, the pattern of species sensitivity found here is compared with that observed in relation to inhibition of Na+-K+-ATPase by cardiac glycosides.

Animals↗
PubMed1986

The mode of action of cardiac glycosides.

Throughout the 200 years during which the cardiac glycosides have been in therapeutic use, they have challenged the understanding of clinician and scientist alike. For the clinician the task has been to define the circumstances in which drugs of this class are indicated and to tread the narrow line between pharmacological activity and serious toxicity; neither problem has been entirely solved. For the scientific investigator, a curious paradox has emerged: whereas early workers sought to identify the precise site of action of digitalis, recent research has revealed that cardiac glycosides specifically inhibit a ubiquitous membrane transport process and this makes the apparent tissue specificity of these drugs the more surprising. The gap between the empirical knowledge of clinical experience and the scientific insights derived from laboratory biochemistry and electrophysiology has not yet been closed.

Cardiac Glycosides↗