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PubMed1977

Anthroylouabain: a specific fluorescent probe for the cardiac glycoside receptor of the Na-K ATPase.

Anthroylouabain (AO) was synthesized by reaction of anthracene-9-carboxylic chloride with ouabain. Nuclear magnetic resonance spectroscopy of AO suggests that the anthracene is esterfied to the rhamnose in the glycoside. AO inhibits Na-K ATPase from human red cells, eel electroplax and rabbit and dog kidney with a KI less than 1muM. AO bound to rabbit or dog kidney Na-K ATPase shows enhanced fluorescence and characteristic spectral shifts. AO binding requires Mg and is optimum in the presence of Mg + Pi or MgATP + Na; ouabain prevents AO binding and fluorescence enhancement if added before AO or reverses it if added after AO is bound. Na inhibits AO binding in the presence of Mg + Pi and K inhibits it in the presence of MgATP + Na. AO binding and dissociation rate constants measured by fluorescence agree qualitatively with reported measurements for ouabain, using other methods, although AO shows faster kinetics than ouabain. Dissociation constants obtained from kinetic measurements are 1.5 X 10(-7) and 1.8 X 10(-7) M for the MgATP + Na complex and Mg + Pi complex, respectively. KD from fluorescence titrations is 2.3 X 10(-7) M for the latter. The enzyme has 2-2.5 nmol of AO binding sites/mg of protein. No differences in the fluorescence parameters of the Mg + Pi or MgATP + Na complexes were observed, suggesting that the same enzyme conformation binds AO under both ligand conditions. Comparison of the AO fluorescence parameters in the enzyme with those of model systems suggests that the binding site is hydrophobic and/or viscous and shielded from H2O. The results indicate that AO is a specific fluorescent probe of the cardiac glycoside receptor of the Na-K ATPase. Possible applications are discussed.

Adenosine Triphosphatases↗
PubMed2005

Endogenous cardiac glycosides: hormones using the sodium pump as signal transducer.

The search for an endogenous digitalis has led to the identification of the cardenolides ouabain and digoxin and the bufadienolide marinobufagenin in mammalian tissues and biological fluids. Ouabain's release from adrenal glands is under the control of epinephrine and angiotensin II; hence, its blood concentration changes rapidly on physical exercise. It also is controlled by brain areas sensing cerebrospinal Na+ concentration and apparently the body's K+ content because urinary K+ loss leads to an increase in its plasma concentration as well. Long-term treatment of rats with ouabain results in arterial hypertension, and 50% of Caucasians with low-renin hypertension have increased plasma concentrations of this cardenolide. Levels of digoxin, which is synthesized from acetate in adrenal glands, increase slightly in blood on prolonged exercise. It counteracts the hypertensinogenic action of ouabain in rats, as does the ouabain antagonist PST 2238. The plasma concentration of the bufadienolide marinobufagenin is increased after cardiac infarction. It may show natriuretic properties because it inhibits the alpha1 isoform of Na+/K+-adenosine triphosphatase (ATPase), the main sodium pump isoform of the kidney, much better than other sodium pump isoforms. These effects of endogenous cardiac glycosides are observed at concentrations that do not inhibit the sodium pump. Apparently, Na+/K+-ATPase is used by these steroids as a signal transducer to activate tissue proliferation, heart contractility, arterial hypertension, and natriuresis via various intracellular signaling pathways.

Animals↗
PubMed1996

The carbohydrate moieties of the beta-subunit of Na+, K(+)-ATPase: their lateral motions and proximity to the cardiac glycoside site.

The beta-subunit associated with the catalytic (alpha) subunit of the mammalian Na+, K(+) -ATPase is a transmembrane glycoprotein with three extracellularly located N-glycosylation sites. Although beta appears to be essential for a functional enzyme, the role of beta and its sugars remains unknown. In these studies, steady-state and dynamic fluorescence measurements of the fluorophore lucifer yellow (LY) covalently linked to the carbohydrate chains of beta have demonstrated that the bound probes are highly solvent exposed but restricted in their diffusional motions. Furthermore, the probes' environments on beta were not altered by Na+ or K+ or ouabain-induced enzyme conformational changes, but both divalent cation and oligomycin addition evoked modest changes in LY fluorescence. Frequency domain measurements reflecting the Förster fluorescence energy transfer (FET) occurring between anthroylouabain (AO) bound to the cardiac glycoside receptor site on alpha and the carbohydrate-linked LY demonstrated their close proximity (18 A). Additional FET determinations made between LY as donor and erythrosin-5-isothiocyanate, covalently bound at the enzyme's putative ATP binding site domain, indicated that a distance of about 85 A separates these two regions and that this distance is reduced upon divalent cation binding and increased upon the Na+E1-->K+E2 conformational transition. These data suggest a model for the localization of the terminal moieties of the oligosaccharides that places them, on average, about 18 A from the AO binding site and this distance or less from the extracellular membrane surface.

Adenosine Triphosphate↗
PubMed1983

Photoaffinity labeling of the sodium- and potassium-activated adenosinetriphosphatase with a cardiac glycoside containing the photoactive group on the C-17 side chain.

The synthesis and properties of a radiolabeled glycoside photoaffinity probe, [3H]-(3 beta,5 beta,14 beta, 20E)-24-azido-3-[(2,6-dideoxy-beta-D-ribo-hexopyranosyl) oxy]-14-hydroxy-21-norchol-20(22)-en-23-one, containing the photoactive group at the C-17 side chain of the steroid moiety are reported. The molecule binds to the sodium- and potassium-activated adenosinetriphosphatase from porcine kidney outer medulla under type II binding conditions [5 mM MgCl2, 3 mM phosphate, 2 mM ethylenediaminetetraacetic acid, 30 mM tris(hydroxymethyl)aminomethane, pH 7.2, 37 degrees C] in the dark with an equilibrium dissociation constant of (1.4 +/- 0.3) X 10(-7) M. Ultraviolet irradiation of a solution of enzyme plus 3H-labeled probe, followed by analysis of covalently incorporated radiolabel, shows ouabain-displaceable labeling exclusively of the alpha subunit of the sodium- and potassium-activated adenosinetriphosphatase. These data indicate that the binding site of the C-17 side group of cardiac glycosides is located on or near the alpha subunit of this enzyme.

Affinity Labels↗
PubMed1971

Plasma concentration, uptake by liver, and biliary excretion of tritiated cardiac glycosides in the isolated perfused guinea-pig liver.

1. Investigations were carried out on isolated perfused guinea-pig livers. Different doses of tritiated ouabain, digoxin, and digitoxin were added to the perfusion medium and the subsequent plasma elimination, hepatic uptake, and biliary excretion quantitatively measured. After the perfusion, extracts of liver, bile and plasma were subjected to thin layer chromatography in order to detect the radioactively labelled glycosides and their metabolites.2. The ouabain concentration in the plasma approached the equilibrium stage within 45 minutes. At this time 40% of the administered dose had been taken up by the liver, and no further elimination occurred. The elimination curve for ouabain followed a simple exponential function. After 1 h the tissue medium (T/M) ratio was approximately 3. In bile hardly any radioactivity could be detected. Ouabain was therefore not excreted by the liver.3. Up to 80% of the digitoxin was eliminated from the plasma within 4 hours. The elimination of radioactive material for the dose range studied could be described by a hyperbolic function. The T/M ratio in the liver varied with time. At the beginning it was as high as 10 and after 4 h reduced to approximately 3. After 45-60 min the concentration of radioactive material in the bile was 500 times as high as that in the plasma. Almost 70% of the administered radioactivity was excreted with the bile within 4 hours. At the end of the perfusion almost all the identifiable substances in plasma and bile were polar metabolites, as shown by thin layer radiochromatography.4. Digoxin behaved similarly to digitoxin.5. The findings led to the following hypothesis: uptake of cardiac glycosides into the liver cells occurs by a passive diffusion process and is related to their lipid solubility. On the other hand excretion in the bile occurs in general if polar metabolites are formed in the liver cells.

Animals↗
PubMedDate not supplied

[A disorder of myocardial contractile function in acute experimental coronary failure: the submolecular mechanisms and the action of cardiac glycosides].

Skinned and hybrid myocardial fibers were studied by methods of tensometry, determination of the ATP hydrolysis intensity, and resonance fluorescent energy transfer between highly selective labels bound to various amino acid residues. It was established that development of the early stage of heart failure in the case of acute myocardial ischemia caused by 15-min coronary artery occlusion (CAO) is related to a reversible damage or adaptive (functional) depression of the contractile protein system. As a result, the system features isolated submolecular post-translational variation in the properties of major proteins in a thin actin filament (myosin is not significantly damaged). This leads to a decrease in the force developed by the hybrid fibers (reconstructed using ghost myocardial fibers taken from ischemic area and normal myosin) and in the ATPase activity of actomyosin (ATP hydrolysis intensity) without any significant change in the Ca-sensitivity, cooperativity of the Ca-response of the actomyosin ensemble, and efficiency of the contractile process. In actin of the ischemic area, CAO results in a serious damage of the Lys61 and Cys374 regions and in a less pronounced damage of the Tyr69 and Cys10 regions. These results suggest that the Lys61 and, probably, Cys374-Lys61 regions are included in the actin monomer as a protomer, without adequate prepolymerization structural-conformational changes necessary to provide for the normal functioning of the filament. In the CAO-induced early stage of heart failure, cardiac glycosides (beta-acetyldigoxin, beta-methyldigoxin, and strophanthin K) produce a direct effect upon the intramolecular structure of myocardial actin, restore the generated force level, and increase the intensity of ATP hydrolysis by actomyosin ensemble. This is achieved by improving or normalizing the structural-conformational state and conformational mobility of the Lys61 and Cys374 region of actin.

Actins↗
PubMed1978

Inotropic and toxic effects of a polar cardiac glycoside derivative in the dog.

It has been suggested that central nervous system (CNS) neuroexcitation plays an important role in digitalis-induced cardiac arrhythmias. To elucidate further the role of the CNS in digitalis-induced arrhythmias, the inotropic and toxic effects of a highly polar semisynthetic cardiac glycoside, 3beta-O-(4 amino-4,6 dideoxy-beta-D-galactopyranosyl)-digitoxigenin (ASI-222) were compared to those of digoxin and correlated with plasma and cerebrospinal fluid (CSF) concentrations of each drug. Thirteen dogs anesthetized with sodium pentobarbital were given repeated intravenous doses of digoxin or ASI-222. Ventricular tachycardia was elicited at a mean dose of digoxin of 0.12 mg/kg, compared with 0.09 mg/kg for ASI-222 (not significant). Terminal ventricular fibrillation occurred after 0.18 mg/kg of digoxin, a value significantly larger than the ASI-222 dose (0.14 mg/kg, P less than 0.05) required to produce lethal arrhythmias. Digoxin produced a 21% increase in LV dP/dt at a plasma digoxin concentration of 20.0 +/- 2 ng/ml (mean +/- SEM) 30 minutes after 0.05 mg/kg; the CSF digoxin concentration at this time averaged 0.7 +/- 0.1 ng/ml. At death, the plasma digoxin concentration was 88 +/- 16 ng/ml and CSF digoxin concentration was 5.7 +/- 1.6 ng/ml. ASI-222 produced a similar 25% increase in LV dP/dt 30 minutes after administration of 0.05 mg/kg, with a plasma concentration of 18 +/- 2 ng/ml as determined by a newly developed radioimmunoassay. The plasma ASI-222 concentration at death, 95 +/- 18 ng/ml, was similar to that of digoxin. However, CSF samples at 30 minutes and at death showed no detectable levels of ASI-222. Thus, despite similar inotropic and toxic responses and similar plasma drug concentrations compared to digoxin, ASI-222 was demonstrated to have limited if any access to the CNS as judged by CSF concentrations. These findings suggest that direct CNS stimulation does not play a primary part in the genesis of digitalis-induced cardiac arrhythmias in this experimental model, or that CNS effects are mediated by an area or areas lacking an effective blood-brain barrier.

Aminoglycosides↗
PubMed2002

Effects of cardiac glycosides on sodium pump expression and function in LLC-PK1 and MDCK cells.

BACKGROUND: The decreases in proximal tubule sodium reabsorption seen with chronic renal failure and volume expansion have been ascribed to circulating digitalis-like substances (DLS). However, the circulating concentrations of DLS do not acutely inhibit the sodium pump to a degree consistent with the observed changes in proximal tubule sodium reabsorption. METHODS: We examined how cell lines that simulated proximal (LLC-PK1) and distal tubule (MDCK) cells responded to acute (30 min) and long-term (up to 12 hours) Na+,K+-ATPase inhibition with DLS. RESULTS: In LLC-PK1, but not MDCK cells, low concentrations of ouabain decreased 86Rb uptake profoundly in a time and dose dependent manner. In LLC-PK1 cells grown to confluence, transcellular 22Na flux was markedly reduced in concert with the decreases in 86Rb uptake. Similar findings were observed with marinobufagenin (MBG) and deproteinated extract of serum derived from patients with chronic renal failure. However, inhibition of the Na+,K+-ATPase with low extracellular potassium concentrations did not produce any of these effects. Western and Northern blots detected no change in alpha1 Na+,K+-ATPase protein and message RNA, respectively, in LLC-PK1 cells treated with ouabain for 12 hours. However, the decrease in enzymatic activity of Na+,K+-ATPase of these cells was comparable to observed decreases in 86Rb uptake. Differential centrifugation as well as biotinylation experiments demonstrated a shift of the Na+,K+-ATPase from the plasmalemma with prolonged ouabain treatment. CONCLUSIONS: The results show that binding of cardiac glycosides by proximal (but not distal) tubular cells results in internalization of Na+,K+-ATPase with the net effect to amplify inhibition of the Na+,K+-ATPase. As the circulating concentrations of DLS increase with chronic renal failure and volume expansion, we suggest that this phenomenon explains some of the decreased sodium reabsorption by the proximal tubule seen in these conditions.

Animals↗
PubMed1994

Identification of two cardiac glycosides as Na(+)-pump inhibitors in rat urine and diet.

Endogenous Na(+)-pump specific inhibitors are present in the plasma, urine, and tissues of humans and animals. To date, the source of these inhibitors has not been rigorously defined. In the present study, large amounts of several Na(+)-pump specific inhibitors have been demonstrated to exist in the urine of rats raised on a regular chow diet and tap water. All of the inhibitor levels have been found to increase 1.5-8-fold by the surgical preparation of reduced renal mass (RRM) and one-kidney, one-clip (IK, IC) hypertension. These urinary inhibitors, however, except for the ouabain-like inhibitor which eluted from a high performance liquid chromatography C18 column at the same retention time as [3H]ouabain, disappeared within a week after switching the diet from regular diet (number 5001, PMI Feeds, Inc.) to pure synthetic diet (number 5755). The urinary level of the ouabain-like inhibitor decreased to only one-half of the level in the control rat raised on a regular diet. Two of these inhibitors were purified from both urine and diet by a combination of Amberlite XAD-2 adsorption chromatography, reverse phase low pressure liquid chromatography, and several high performance liquid chromatographies. Reverse phase high performance liquid chromatography, liquid secondary ion and gas-liquid mass spectrometries, and proton nuclear magnetic resonance spectroscopy identified these inhibitors as a stereoisomer of convalloside, probably neoconvalloside, and a mono-rhamnoside of periplogenin or its stereoisomer. These cardiac glycosides exhibited inhibitory potencies comparable to ouabain against ouabain-displacement from Na+,K(+)-ATPase and against 86Rb uptake into human erythrocytes, and they also exhibited cross-reactivity to anti-ouabain antibodies and anti-digoxin antibodies. These results clearly demonstrate that the principal source of most of the inhibitors in rat urine is the diet. The results suggest that the ouabain-like inhibitor may be derived from an endogenous origin.

Analysis of Variance↗
PubMed1981

Techniques for studying the pharmacodynamic effects of cardiac glycosides on patients' own erythrocytes during glycoside therapy.

We have measured the effects of digoxin on the cation transport mechanisms of patients' erythrocytes during treatment with digoxin for atrial fibrillation and cardiac failure in sinus rhythm. The results show that during short-term treatment with digoxin there is occupation of erythrocytic cardiac glycoside receptors by digoxin with resultant inhibition of active cation transport. These effects correlate well with the patients' clinical responses to treatment. During long-term treatment, however, these effects are not seen, suggesting that there is pharmacological tolerance to the effects of digoxin. The clinical implications of these results are discussed.

Atrial Fibrillation↗