[Remarks on cardiac glycosides].
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Cardiac Glycosides↗
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[New data on the effect of cardiac glycosides].
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Cardiac Glycosides↗
Cardiac glycosides provide neuroprotection against ischemic stroke: discovery by a brain slice-based compound screening platform.
We report here the results of a chemical genetic screen using small molecules with known pharmacologies coupled with a cortical brain slice-based model for ischemic stroke. We identified a small-molecule compound not previously appreciated to have neuroprotective action in ischemic stroke, the cardiac glycoside neriifolin, and demonstrated that its properties in the brain slice assay included delayed therapeutic potential exceeding 6 h. Neriifolin is structurally related to the digitalis class of cardiac glycosides, and its putative target is the Na(+)/K(+)-ATPase. Other cardiac glycoside compounds tested also showed neuroprotective activity, although with lower apparent potencies. In subsequent whole-animal studies, we found that neriifolin provided significant neuroprotection in a neonatal model of hypoxia/ischemia and in a middle cerebral artery occlusion model of transient focal ischemia. The neuroprotective potential of Na(+)/K(+)-ATPase is of particular interest because of its known "druggability"; indeed, Food and Drug Administration-approved, small-molecule compounds such as digitoxin and digoxin have been in clinical usage for congestive heart failure and arrhythmias for several decades. Thus, an existing cardiac glycoside or closely related compound could provide an accelerated path toward clinical trial testing for ischemic stroke. Our findings underscore the important role that hypothesis-neutral, high-content, tissue-based screens can play in the identification of new candidate drugs and drug targets for the treatment of diseases for which validated therapeutic pathways are not currently available.
Aging↗
[Animal experiment studies of the ocular toxicity of cardiac glycosides].
The addition of different types of cardiac glycosides (strophanthin, digoxin, digitoxin) to the perfusion medium of isolated cat eyes, kept alive by extracorporeal perfusion, leads to changes in ERG. There is a dose-dependent reduction of the b-wave amplitude in scotopic and photopic electroretinogram (ERG). At the same time the implicit time of the potentials increases. In the scotopic-isolated P III component, both amplitude and implicit time increase. The concentrations inducing ERG changes that are fully reversible after cessation of drug application correlate well with the known toxic drug blood levels in humans. The disappearance rate of the drug induced effects was almost equal under these conditions (extracorporeal perfusion) for the different glycosides. In conclusion, our results indicate that at least part of the visual symptoms of glycoside intoxication are already evident at the retinal level.
Animals↗
The stereoisomers quinine and quinidine exhibit a marked stereoselectivity in the inhibition of hepatobiliary transport of cardiac glycosides.
BACKGROUND/AIMS: Certain basic (cationic) drugs are known to interact with the hepatic transport, and renal and/or biliary clearance of cardiac glycosides. The mechanisms behind these interactions are not fully understood. In the present study our aim was to investigate the effects of the two diastereomers, quinidine and quinine, as well as the calcium antagonist verapamil, on the hepatobiliary elimination of digoxin and ouabain in the isolated perfused rat liver. METHODS: Livers from male, fasting Wistar rats were perfused by recirculation of Krebs-Henseleit bicarbonate buffer supplemented with 1% BSA. Disposition of digoxin or ouabain was studied at an initial perfusion medium concentration (Ci) of 100 or 10 nmol/l for digoxin and a Ci of 30 micromol/l for ouabain. The Ci of quinine, quinidine or verapamil was 50 micromol/l. Concentrations of the drugs in perfusion medium and bile were followed up to 2 h. RESULTS: A marked reduction in the initial medium disappearance rate of digoxin and ouabain by quinine was found, whereas quinidine did not affect the hepatic disposition of the cardiac glycosides. The stereoselective inhibition of digoxin and ouabain clearance by quinine, and not by quinidine, was shown to be due to an effect on the hepatic uptake level rather than on the metabolic conversion and/or the biliary excretion steps. An allosteric type of inhibition by the basic drugs, exerted from the inside of the cells, is inferred. This interaction may occur at the sinusoidal plasma membrane on the level of multi-specific carrier proteins for cardiac glycosides and cationic drugs, as cloned recently by various groups. CONCLUSIONS: A marked stereoselective difference was found in the effect of the stereoisomers quinidine and quinine on the hepatic uptake of digoxin and ouabain, quinine being the potent inhibitor.
Animals↗
Demonstration and characterization of two classes of cardiac glycoside binding sites to rat heart membrane preparations using quantitative computer modeling.
Cardiac glycoside binding to rat heart membrane preparations was measured by rapid filtration technique. The binding data were analyzed using quantitative computer analysis. The experimental results using [3H]-ouabain as the labeled ligand were consistent with a model in which cardiac glycoside specific binding occurs at two independent classes of sites. The high affinity sites were characterized by a dissociation constants of 40 nM, 50 nM, and 61 nM for ouabain, digoxin and digitoxin, respectively, with a binding capacity of 1.3 pmoles/mg protein. The lower affinity sites for ouabain were characterized by dissociation constants of 2.3 microM, 67 nM and 71 nM for ouabain, digoxin and digitoxin, respectively, with a binding capacity of 3 pmoles/mg protein. Potassium ions inhibit [3H]-ouabain binding in a dose dependent manner with an IC50 of 500 microM. Quantitative computer modelling indicated that potassium inhibits ouabain binding at both binding sites.
Animals↗
Variation in cardiac glycoside content of monarch butterflies from natural populations in eastern North America.
A new spectrophotometric assay has been used to determine the gross concentration of cardiac glycoside in individual monarch butterflies. Adults sampled during the fall migration in four areas of eastern North America exhibited a wide variation in cardiac glycoside concentration. The correlation between spectrophotometrically measured concentrations and emetic dose determinations supports the existence of a broad palatability spectrum in wild monarch butterflies. The cardiac gylcoside concentration is greater in females than in males and is independent of the dry weight of the butterflies; contrary to prediction, both the concentration mean and variance decrease southward. The defensive advantage of incorporating cardiac glycosides may be balanced by detrimental effects on individual viability.
Analysis of Variance↗
Cardiac glycosides of Beaumontia brevituba and B. murtonii.
Cardiac glycosides from Beaumontia brevituba and B. murtonii were examined. Gentiobiosyl-beta-D-cymaroside and gentiobiosyl-alpha-L-cymaroside of digitoxigenin were isolated from the seeds, unripe fruits, and leaves of B. brevituba, and the leaves of B. murtonii. Oleandrigenin and/or delta 16-digitoxigenin glycosides having the same sugar moieties were not isolated from the leaves of B. brevituba but from the leaves of B. murtonii as well as the seeds of B. brevituba.
Cardiac Glycosides↗
Inhibition of export of fibroblast growth factor-2 (FGF-2) from the prostate cancer cell lines PC3 and DU145 by Anvirzel and its cardiac glycoside component, oleandrin.
Anvirzel is an extract of Nerium oleander currently undergoing Phase I clinical evaluation as a potential treatment for cancer. Two of the active components of Anvirzel are the cardiac glycosides oleandrin and oleandrigenin. Previous studies have demonstrated that, in vitro, cardiac glycosides may inhibit fibroblast growth factor-2 (FGF-2) export through membrane interaction with the Na(+),K(+)-ATPase pump. In continuing research on the antitumor activity of this novel plant extract, the relative abilities of oleandrin and oleandrigenin to inhibit FGF-2 export from two human prostate cancer cell lines, DU145 and PC3, were examined. An ELISA assay was utilized to determine the FGF-2 concentration in the cell culture medium before and after exposure to cardiac glycosides or the parent extract material Anvirzel. Both cell lines were exposed to non-cytotoxic concentrations of oleandrin (0.05 and 0.1 ng/mL) for up to 72 hr. Studies also were conducted with Anvirzel and ouabain. Oleandrin (0.1 ng/mL) produced a 45.7% inhibition of FGF-2 release from PC3 cells and a 49.9% inhibition from DU145 cells. Non-cytotoxic concentrations (100 ng/mL) of Anvirzel produced a 51.9 and 30.8% inhibition of FGF-2 release, respectively, in the two cell lines. The decrease in FGF-2 release from cells required continuous incubation for 48--72 hr; shorter incubation times were not effective. These results demonstrate that Anvirzel, like oleandrin, inhibited FGF-2 export in vitro from PC3 and DU145 prostate cancer cells in a concentration- and time-dependent fashion and may, therefore, contribute to the antitumor activity of this novel treatment for cancer.
Biological Transport↗
[Sireniotoxin; a new cardiac glycoside].
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Cardiac Glycosides↗
Suspected cardiac glycoside intoxication in sheep and goats in Namibia due to Ornithogalum nanodes (Leighton).
The main clinical and necropsy features of field and experimental cases of suspected cardiac glycoside intoxication following ingestion and dosing of the plant Ornithogalum nanodes, are described. The distribution of intoxication in the area as well as a description of the plant are given. Plant samples tested for cardiac glycosides by fluorescence polarization immuno-assay (FPIA) gave a strong positive reaction. This is a new finding, as other toxic Ornithogalum species in southern Africa are devoid of cardiac glycoside activity and poisoning with them result only in a severe, often fatal diarrhoea, without obvious cardiac involvement. It is also the first record of toxicity of this particular plant.
Animals↗
Interactions between cardiac glycosides and sodium/potassium-ATPase: three-dimensional structure-activity relationship models for ligand binding to the E2-Pi form of the enzyme versus activity inhibition.
Sodium/potassium-ATPase (Na/K-ATPase) is a transmembrane enzyme that utilizes energy gained from ATP hydrolysis to transport sodium and potassium ions across cell membranes in opposite directions against their chemical and electrical gradients. Its transport activity is effectively inhibited by cardiac glycosides, which bind to the extracellular side of the enzyme and are of significant therapeutic value in the treatment of congestive heart failure. To determine the extent to which high-affinity binding of cardiac glycosides correlates with their potency in inhibiting pump activity, we determined experimentally both the binding affinities and inhibitory potencies of a series of 37 cardiac glycosides using radioligand binding and ATPase activity assays. The observed variations in key structural elements of these compounds correlating with binding and inhibition were analyzed by comparative molecular similarity index analysis (CoMSIA), which allowed a molecular level characterization and comparison of drug-Na/K-ATPase interactions that are important for ligand binding and activity inhibition. In agreement with our earlier comparative molecular field analysis studies [Farr, C. D., et al. (2002) Biochemistry 41, 1137-1148], the CoMSIA models predicted favorable inhibitor interactions primarily at the alpha-sugar and lactone ring moieties of the cardiac glycosides. Unfavorable interactions were located about the gamma-sugar group and at several positions about the steroid ring system. Whereas for most compounds a correlation between binding affinity and inhibitory potency was found, some notable exceptions were identified. Substitution of the five-membered lactone of cardenolides with the six-membered lactone of bufadienolides caused binding affinity to decline but inhibitory potency to increase. Furthermore, while the removal of ouabain's rhamnose moiety had little effect on inhibitory potency, it caused a dramatic decline in ligand binding affinity.
Algorithms↗
Investigation of cardiac glycoside levels in human post mortem blood and tissues determined by a special radioimmunoassay procedure.
Even after the introduction of radioimmunological methods the question of a cardiac glycoside causing or contributing to the death of a patient can not be answered satisfactorily. By means of a special radioimmunoassay procedure for digoxin as well as for the structurally related methyl- and acetylderivatives we measured the concentrations in human blood and post mortem tissues. We investigated the glycoside contents in the blood of intravenously digitalised (Novodigal) al) patients before and after death. At autopsy blood specimens were taken from the heart and the femoral vein. We found an increase of the glycoside level up to a highly toxic range (7--15 ng/ml) especially in the heart blood. Thus post mortem blood levels of digoxin and its derivatives are not suitable for a final decision in alleged cases of fatal poisonings. Measuring various concentrations in tussues and body fluids of the above cardiac glycosides mentioned revealed the kidney concentration to be of high value in confirming a digitalis poisoning. This organ and the heart show the highest tissue concentrations. Interpretations of fatal digitalis poisonings should be based on the additional knowlege of these concentrations. Individual cardiac glycosides may be analyzed by a combination of thin layer chromatography and radioimmunoassay.
Cardiac Glycosides↗
[The effect of cardiac glycosides and electrolytes on cell membrane sodium, potassium-adenosine triphosphatase].
A brief summary is given of the structure of the cell membrane and the enzyme system which actively transports Na+ and K+ ions across it. The function of different ions in this process is discussed as well as the effect of cardiac glycosides on ion transport. The utilization of electrolytes to combat cardiac glycoside poisoning and an indirect method for demonstrating the presence of cardiac glycosides in the organs of ruminants, suspected of being poisoned by these toxins, is described.
Animals↗
Action of cardiac glycosides on diastolic and resting length of cardiac strips.
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Cardiac Glycosides↗
Amino acid residues of the Na,K-ATPase involved in ouabain sensitivity do not bind the sugar moiety of cardiac glycosides.
The identification of amino acid substitutions in the alpha subunit of the Na,K-ATPase that alter cardiac glycoside sensitivity provides a unique opportunity to examine the role these residues play in binding to the structural domains of these drugs. Substitution of a residue(s) involved in binding to the sugar moiety of cardiac glycosides would be expected to yield similar affinities for ouabain and its aglycone, ouabagenin. Sheep Na,K-ATPase alpha 1 subunit amino acid substitutions previously shown to influence ouabain sensitivity were tested for activity in the presence of ouabain and ouabagenin. These substitutions included both transmembrane and extracellular regions: C104F, D121E, N122D, Q111K, N122K, and Q111R, A112S. Na,K-ATPase activity versus drug concentration curves yielded I50 values over a 1000-fold range for wild type HeLa and HeLa transfectants. Interestingly, the I50 ratio for ouabagenin to ouabain in all mutants tested indicated a 19-24-fold lower affinity of the Na,K-ATPase for ouabagenin. This constant ratio among all mutations tested implies that the first transmembrane region and the first extracellular loop (H1-H2) do not participate in the binding of the sugar moiety of cardiac glycosides.
Amino Acid Sequence↗
Origin of differences of inhibitory potency of cardiac glycosides in Na+/K+-transporting ATPase from human cardiac muscle, human brain cortex and guinea-pig cardiac muscle.
The inhibitory potency of altogether 95 steroidal compounds (including cardenolides, bufadienolides and their glycosides) on the Na/K-ATPases (Na+/K+-transporting ATPases, EC 3.6.1.37) from human cardiac muscle, human brain cortex and guinea-pig cardiac muscle was compared to probe the complementary chemotopology of the inhibitor binding site areas on the three enzyme variants. The changes of potency, resulting from systematic variations of the geometry of steroid skeleton and the character as well as the structure of side chains at C3 or/and C17 of steroid backbone, allowed the following major conclusions. With the human cardiac and cerebral enzyme forms, the paired K0.5 (K'D) values for 77 steroid derivatives, covering seven orders of ten, were highly correlated. On an average, the total of compounds showed a 1.5-fold higher affinity to the cardiac enzyme. This tiny differentiation did not appear to be connected with an important difference in the chemotopology of the complementary subsites for steroid nucleus binding on the two enzyme forms. With the human and guinea-pig cardiac enzyme variants, the K0.5 values for 69 steroid derivatives, covering six orders of ten, were determined. For 41 5 beta, 14 beta-androstane derivatives only, the paired K0.5 values showed a close correlation. Here, the human enzyme variant exhibited 27-fold higher affinity. However, the paired K0.5 values determined on both enzymes for 28 steroid derivatives of differing structural features were but poorly correlated. Essentially, the geometries of the steroid nucleus determined the differential contributions of the side chains at C3 and C17 to the integral inhibitory potency on the two enzyme variants. Thus, the species differences in the potency of cardiac glycosides were traced to species differences in the complementarity of the steroid binding subsites. Hence, estimates of the potency of new steroidal compounds obtained on the guinea-pig cardiac enzyme can be neither quantitatively nor qualitatively easily extrapolated to the human cardiac enzyme. The extrathermodynamic analysis of the data opened major new insights in the structure-activity relationships concerning the role of C14 beta-OH, the character of the lead structure in cardioactive steroid lactones, and the significance of the configuration of A/B ring junction.
Animals↗
Kinetics of active sodium transport in rat proximal tubules and its variation by cardiac glycosides at zero net volume and ion fluxes. Evidence for a multisite sodium transport system.
1. Transepithelial Na concentration difference, deltaCNa, across proximal tubules of rat kidney was measured at varying intraluminal Na concentrations (CNainfinity) under conditions of zero net volume and Na flux. Simultaneous stopped-flow intratubular and artificial peritubular capillary perfusion techniques were used together with intratubular raffinose to achieve zero net fluxes. Under these conditions in rat proximal tubules, deltaCNa represents active transport, JactNa, factored by permeability, PNa, plus an electrical factor depending on transepithelial potential difference. 2. The relationship between CNainfinity and deltaCNa appeared sigmoidal with saturation being reached when intratubular Na was above 80 m-mole/kg. In the presence of ouabain (10(-2)M) and scilliroside (10(-3)M) the relationship remained the same. The maximum deltaCNa was reduced by approximately 50% by cardiac glycoside inhibition whereas the half-saturation constant was essentially unchanged. These changes from the control represent simple non-competitive inhibition by the cardiac glycosides. 3. Absence of potential difference (p.d.) measurements precludes exact description of the relation between true active transport and substrate concentration but much evidence indicates that the apparently sigmoid relation in the presence and absence of cardiac glycoside inhibition, would be retained if correction of deltaCNa values were possible. Such results could then be explained if there are at least three or more sites for Na on the pump system, of which at least two are not cardiac glycoside sensitive. They would also unequivocally exclude the presence of a single-site single-pump system or the simple algebraic addition of two such units since the kinetic curves for both would be hyperbolic rather than sigmoidal.
Animals↗