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At least 199 records · Page 11Linked to original sources
PubMed2001

Sanguinarine induces K+ outflow from yeast cells expressing mammalian sodium pumps.

Sanguinarine, an alkaloid from Sanguinaria canadensis, has no effect on the yeast Saccharomyces cerevisiae at concentrations of up to 225 microM. Yeast cells become sensitive to sanguinarine and lose cytosolic K+ in a time- and concentration-dependent manner when they express the mammalian Na+,K+-ATPase (sodium pump). Dose-response studies show that sanguinarine induces K+ outflow from cells expressing wild-type sodium pumps with an EC50 of 29.3+/-1.2 microM. A similar effect with a comparable EC50) of 26.8+/-1.3 microM is obtained with cells expressing an Asp369Ala mutant of the sodium pump alpha1 subunit. Since this sodium pump mutant does not hydrolyze ATP, it can be excluded that the observed sanguinarine-induced outflow of K+ is an active ion transport process. Ouabain inhibits the sanguinarine effect at concentrations higher than 1 mM. In contrast, proscillaridin A inhibits the sanguinarine-induced K+ outflow from cells expressing the wild-type sodium pump with an IC50 of 48.9+/-1.3 microM. A similar IC50 of 52.2+/-3.0 microM is obtained with cells expressing the Asp369Ala mutant. These data, together with the fact that sanguinarine inhibits the binding of [3H]ouabain to microsomes prepared from yeast cells expressing the sodium pump with an IC50 of 94.5+/-4.3 microM, all indicate that sanguinarine specifically targets the sodium pump, and that the observed K+ outflow is tightly associated with the presence of the enzyme.

Acrylamides↗
PubMed2004

Ouabain binding to Na+,K+-ATPase relaxes cell attachment and sends a specific signal (NACos) to the nucleus.

Abstract. In previous work we described a "P-->A mechanism" that transduces occupancy of the pump ( P) by ouabain into changes in phosphorylation, stimulation of mitogen-activated protein kinase (MAPK), and endocytosis of cell-cell- and cell-substrate-attaching molecules ( A), thereby causing a release of the cell from the monolayer. In the present work we try to understand the mechanism of this effect; whether, in order to trigger the P-->A mechanism, ouabain should block the pumping activity of Na(+),K(+)-ATPase as pump, or whether it would suffice that the drug occupies this enzyme as a receptor. We assay a series of drugs known to act on the pump, such as ouabain, digoxin, digitoxin, palytoxin, oligomycin, strophanthidin, neothyoside-A, proscillaridin-A, etc. We gauge their ability to block the pump by measuring the K(+) content in the cells, and their ability to detach the cells from the monolayer by determining the amount of protein remaining in the culturing well. None of the drugs tested was able to cause detachment without stopping the pump. Ouabain also enhances phosphorylation, yet pump inhibition and signal transduction do not seem to be intimately associated in a causal chain, but to occur simultaneously. To investigate the response of the site of cell attachment, we analyze the position of beta-catenin by fluorescence confocal microscopy, and find that this adherent junction-associated molecule is sent to the nucleus, where it is known to act as a transcriptional cofactor.

Animals↗
PubMed2005

A novel endogenous digitalis, telocinobufagin, exhibits elevated plasma levels in patients with terminal renal failure.

BACKGROUND AND OBJECTIVES: There are several potential endogenous digitalis-like factors (EDLF) in mammalian body fluids, and marinobufagenin (MBG) may be the most potent EDLF. Improved assays are needed to confirm the potency of these metabolites. In the present study, we have identified MBG and telocinobufagin (TCB) in human plasma by high-resolution mass spectrometry (MS) and nuclear magnetic resonance (NMR). METHODS AND RESULTS: The high-resolution MS analysis revealed the molecular masses of TCB and MBG to be the same as their respective theoretical values. Using a tandem mass spectrometer, the mass-charge ratio for TCB was determined to be 403.2 for the parent ion and 349.2 for the daughter ion. The mass-charge ratio for MBG was m/z 383.2 and m/z 401.2. The NMR study revealed that the signals for MBG and TCB were the same as those obtained by MS analysis. In human blood, MBG and TCB were also identified by liquid chromatography (LC) as well as MS. In the LC/MS assay, proscillaridin A was used as an internal standard. The plasma was pretreated with Sep-Pak C18, and then 50 microL was applied to the C8 high-performance liquid chromatography (HPLC) column. The mean plasma concentration of MBG in healthy volunteers (0.94 +/- 0.28 ng/mL) was significantly lower than that in patients undergoing regular hemodialysis (3.81 +/- 1.92 ng/mL). The concentration of TCB in the healthy volunteers (1.80 +/- 0.55 ng/mL) was also significantly lower than that in patients with terminal renal failure (6.86 +/- 4.30 ng/mL). CONCLUSION: These results indicate that the major EDLF is TCB because its plasma concentration is the highest among the reported endogenous digitalis candidates.

Bufanolides↗
PubMed2000

Selective inhibition of human erythrocyte Na+/K+ ATPase by cardiac glycosides and by a mammalian digitalis like factor.

Na+/K+ATPase is a transport membrane protein which contains the functional receptor for digitalis compounds. In this work we compare the inhibition curves of Na+/K+ATPase measured by the inhibition of 86Rb uptake in human red blood cells by cardiac glycosides and by an endogenous digitalis like factor (EDLF) extracted from human newborn cord blood. The curves of Na+/K+TPase inhibition show a monophasic shape for ouabain, strophantidin, digitoxin, proscillaridin and EDLF whereas a biphasic shape for ouabagenin, digoxin, digoxigenin and digitoxigenin. All the drugs are potent inhibitors of erythrocyte Na+/K+ATPase with an IC50 ranging from 1.8 x 10(-9) M to 1.4 x 10(-11) M for the higher affinity binding site and from 1.8 x 10(-6) M to 5.5 x 10(-9) M for the lower affinity site. Digitoxigenin is the most active showing the higher active site at 1.4 x 10(-11) M. Ouabain and digoxin have higher affinity compared with their corresponding genins, while digitoxigenin shows a binding site with higher affinity than the respective cardiac glycosides. The increased affinity of the drugs to Na+/K+ATPase may be related to a lipophilic region in correspondence of the carbons 10, 9, 11, 12, 13 of the steroid nucleus, situated in the opposite side with respect of the C-OH-14. The comparison of the inhibition curves and the HPLC profile of newborn EDLF and of the investigated cardenolides suggest that EDLF may be a compound identical or very similar to ouabain.

Cardiac Glycosides↗
PubMed2000

Scilla maderensis, TLC screening and positive inotropic effect of bulb extracts.

Scilla maderensis Menezes (Hyacinthaceae) is endemic to the Portuguese Archipelago of Madeira. The taxonomic proximity between Scilla L. and Urginea Steinh. genus, and also the knowledge that bulbs of Urginea maritima (L.) Baker (Scilla maritima L.) contain cardiac glycosides of the bufadienolide type, led us to a phytochemical and pharmacological study of S. maderensis. Extracts obtained from the bulbs were screened by TLC and tested in the isolated frog heart preparation. The TLC screening revealed spots with colours and R(f) values similar to those obtained for proscillaridin and scillaren A. In the frog heart preparation the extracts showed a positive inotropic effect and toxic doses induced the arrest of the heartbeat in systole. We can conclude that the bulbs of S. maderensis contain substances exerting pharmacological effects on the heart.

Animals↗
PubMed1998

A specific binding protein for cardiac glycosides exists in bovine serum.

Searching for a binding protein in blood, which may be involved in the specific transport of cardiac glycosides to their receptor sites on the sodium pump, we isolated a cardiac glycoside-binding protein (CGBG) of 26 kDa from the globulin fraction of bovine serum by affinity chromatography and on a ouabain-Sepharose 4B column by a purification factor of 5000. The cardiac glycoside-binding globulin was labeled specifically and covalently by the protein-reactive digoxigenin derivative HDMA (N-hydroxysuccimidyldigoxigenin-3-O-methylcarbonyl-epsilon-+ ++aminocapro ate). Even very high concentrations of other steroids, such as estrogen, testosterone, progesterone, and cortisone, did not prevent HDMA-labeling (at 5 and 100 nM) of CGBG, but the cardenolides ouabain and digoxin or the bufadienolide proscillaridin A did so. CGBG is a homodimer of two 26-kDa subunits forming disulfide bonds, since HDMA labeling of a protein of 53 kDa was observed in SDS-polyacrylamide gel electrophoresis when beta-mercaptoethanol was absent during SDS denaturation. The N-terminal amino acid sequence K-D-V-Y-R-A-P-D-G-T-Q-S-A showed no sequence similarity with proteins recorded in gene and protein sequence data banks. A 90-kDa cytosolic CGBG exists in bovine kidneys and reacts with antibodies against CGBG. Binding of ouabain to the cardiac glycoside-binding globulin was monitored by quenching of intrinsic tryptophan fluorescence. Such studies reveal two negatively cooperative ouabain binding sites with Kd' of 1.52 nM and Kd' = 75 nM and with an interaction factor of 50 using a Koshland-Némethy-Filmer model. The demonstration of a cardiac glycoside-binding globulin in plasma is consistent with the recent finding of endogenous cardiac glycosides in mammals.

Affinity Labels↗
PubMed1969

Effect of spironolactone and norbolethone on the toxicity of digitalis compounds in the rat.

1. In the rat, both spironolactone (an antimineralocorticoid) and norbolethone (an anabolic steroid) inhibit the characteristic neuromuscular disturbances and the mortality produced by digitoxin, gitalin, proscillaridin, digoxin and digitalin. The corresponding effects of strophanthin K, ouabain and digitoxigenin could not be prevented.2. It may be concluded that, in our experimental conditions, both spironolactone and norbolethone counteract the toxicity of some, but not all, digitalis compounds tested and that both the protective steroids affect the toxicity of the same digitalis derivatives.3. This antidigitalis effect is not merely a secondary consequence of either antimineralocorticoid or anabolic potency because spironolactone lacks anabolic and norbolethone lacks antimineralocorticoid properties. Indeed, it appears that the ability to antagonize the toxicity of digitalis compounds represents a pharmacological property independent of all known steroid hormone actions, since spironolactone is virtually devoid of these.

Anabolic Agents↗
PubMed1992

[Effects of bufadienolides and some kinds of cardiotonics on guinea pig hearts].

Effects of bufadienolides such as bufalin (BF) and cinobufagin (CB), the main components of Senso (Ch'an Su), on myocardial Na+,K(+)-ATPase activity, the cardiotonic activity in vivo and the action potential of isolated guinea pig papillary muscle cells were compared with those of other cardiotonic drugs. 1) The rank order of potency for inhibition of myocardial Na+,K(+)-ATPase activity was BF greater than digoxin (DG) greater than digitoxin (DT) greater than telocinobufagin greater than gamabufotalin greater than cinobufotalin greater than CB greater than g-strophanthin (GS) greater than digitoxigenin (DTG) greater than resibufogenin (RB) when compared at the 50% inhibitory concentration. 2) In isolated papillary muscle cells, CB shortened the action potential duration (APD) dose-dependently. The order of potency for shortening of APD was GS greater than CB greater than DTG much greater than DT. 3) In open-chest guinea pigs, intraduodenal administration of BF or CB increased the myocardial contractile force (MCF), but did not affect the heart rate. The order of potency for increase in MCF was as follows: methyldigoxin, proscillaridin greater than BF greater than CB greater than DG greater than Senso much greater than DT, DTG, RB. These results indicate that CB has a shortening effect on APD and an inhibitory effect on Na+,K(+)-ATPase activity along with its cardiotonic effect, like GS.

Action Potentials↗
PubMedDate not supplied

A comparative dose-effect study with cardiac glycosides assessing cardiac and extracardiac responses in normal subjects.

We tested the hypothesis that differences exist in the pharmacodynamic pattern of different cardiac glycosides. We conducted a randomized, placebo-controlled study in normal volunteers and evaluated the effects of weekly increased oral dosing of digoxin (n = 10; from 0.25 to 1.0 mg/day), meproscillarin (n = 10; from 0.5 to 2.0 mg/day), and placebo (n = 5). To determine the glycoside effects, corrected electromechanical systole (QS2c) was used to measure inotropy and the PQ interval to test dromotropy. Red-green discrimination and critical flicker fusion (CFF) assessed visual functions. Subjective complaints were collected using rating lists. Both glycosides dose dependently shortened QS2c and prolonged PQ interval. PQ prolongations over +20 ms occurred in seven of 10 digoxin subjects, in two of 10 meproscillarin, and in one of five placebo. Equi-inotropic response, identified at 12 ms mean QS2c shortening, revealed the relative potency of digoxin to be 2.4 times higher than meproscillarin; this ratio increased to sevenfold for equi-effective negative dromotropic effects at 12 ms mean PQ prolongation. Each drug was associated with a dominant subjective complaint: digoxin with anergy and meproscillarin with diarrhea. Red-green discrimination was better under meproscillarin and CFF was depressed by digoxin. The results indicate that pharmacodynamic differences exist between cardiac glycosides. A differential use of various glycosides should be considered and tested clinically.

Adult↗
PubMed1992

[Studies on cardiac ingredients of plants. X. Preparation of nitrates of tetrahydroproscillaridin and their pharmacological activities].

To reduce the vascular contracting effect of the hydrogenated cardiac glycosides, 20-(R)- and 20-(S)-tetrahydroproscillaridins (THPs, 1a, 1b), and to extend the concentration-dependent range, mono- and dinitrates of THPs were prepared. The pharmacological activities of the nitrates of THP were evaluated by use of isolated guinea-pig papillary muscle preparations and Na+,K(+)-adenosine triphosphatase preparations from dog kidney. Furthermore, the effect for smooth muscle was examined using the helical strips isolated from 13-week-old spontaneously hypertensive rat. The positive inotropic effects of mononitrates (11a, 11b, 2a, 2b, 8a, and 8b) were more potent than those of THPs. Nitration of the sugar moiety in THPs resulted in a vascular relaxing effect unobserved in the case of THPs.

Animals↗
PubMed1975

Multiclinical open studies on the effect of beta-methyldigoxin on congestive heart failure with atrial fibrillation.

Clinical open trials of beta-methyldigoxin were carried out in 15 institutions in order to examine the effect, usefulness and ease of its oral administration. In the case of oral digitalization with 0.2 mg, 3 times daily, an effect was obtained in all of 13 cases of congestive heart failure accompanied by atrial fibrillation or flutter. The average time and dose required for digitalization were about 50 hours and 1.27 mg respectively. In 9 of the 13 cases, the effect was achieved within 48 hours. The average maintenance does of beta-methyldigoxin in 102 cases of congestive heart failure with atrial fibrillation was 0.177 mg per day. About 75% of the cases were maintained with 0.15 to 0.2 mg. This range of dose of beta-methyldigoxin was much smaller than that of digoxin in our series. This can be ascribed to a higher absorption rate of beta-methyldigoxin from the digestive tract. Studies on the cases in which patients previously treated with other glycosides were switched over to beta-methyldigoxin revealed that 1 mg of beta-methyldigoxin is equivalent to 1.8 mg of digoxin or to 0.59 mg of digitoxin. The usefulness and ease of beta-methyldigoxin in maintenance was evaluated as being somewhat superior to other cardiac glycosides, according to the global judgement of the physicians. The observed side effects were similar to those of other glycosides in frequency and character.

Administration, Oral↗
PubMed1988

The bioavailability of methylepoxyproscillaridin (P35): a new semisynthetic cardiac glycoside.

The pharmacokinetic data of methylepoxyproscillaridin (3'-methyl-4'-5'-epoxyproscillaridin) (P35) after 1 mg i.v. or oral administration in two different galenic preparations (hard and soft gelatin capsules) in randomized succession were studied in 9 healthy volunteers, showing a bioavailability of 88 +/- 10.5% (soft gelatin capsule) and 81 +/- 12% (hard gelatin capsule). The half-life of P35 was calculated to be 80 +/- 13.3 h.

Adult↗