Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Digitalis-like immunoreactive factors (DLIF) are special types of steroids with lactone rings in their structures. Clinically, this type of compound can be used as medicine for heart failure; thus, the elevated endogenous DLIF found under certain pathological conditions are interferent substances in digoxin immunoassay. Endogenous DLIF with biological and immunological properties similar to cardiotonic drugs, such as digoxin, have been found in several tissues and body fluids of animals and humans. Since these endogenous Na+, K(+)-ATPase inhibitors can be considered hormones in nature, immunoassays must be selected detection of them to achieve the required sensitivity and specificity. In this study, we used three sets of in-house formulated immunoassays for DLIF and ouabain-like factors (OLF) detection. Using a polyclonal antibody-based ouabain enzyme immunoassay, the mean +/- S.E.M. of OLF in the sera of 10 healthy individuals were determined to be (9.1 +/- 0.9) x 10(-11) M. Using a monoclonal antibody-based ouabain enzyme immunoassay, the mean +/- S.E.M of OLF in the sera of 10 healthy individuals was (8.2 +/- 1.2) x 10(-11) M while using a antibody fragment Fab-based enzyme immunoassay for digoxin, the mean +/- S.E.M of DLIF in 11 healthy individuals was (4.0 +/- 1.2) x 10(-10) M. In conclusion, our immunological data indicate that DLIFs are normal constituents of human blood. Although DLIF is the major component, coexistence of OLF with DLIF in healthy individuals can not be excluded.
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PMID:Detection of endogenous digitalis-like immunoreactive factors in human blood. 977 2

Cardiac glycosides have played a prominent role in the therapy of congestive heart failure since William Withering codified their use in his late 18th century monograph on the efficacy of the leaves of the common foxglove plant (Digitalis purpurea). Despite their widespread acceptance into medical practice in the ensuing 200 years, both the efficacy and the safety of this class of drugs continue to be a topic of debate. Moreover, despite the fact that the molecular target for the cardiac glycosides, the alpha-subunit of sarcolemmal Na+K+-ATPase (or sodium pump) found on most eukaryotic cell membranes, has been known for several decades, it remains controversial whether the sympatholytic or positive inotropic effects of these agents is the mechanism most relevant to relief of heart failure symptoms in humans with systolic ventricular dysfunction. Herein, we review the molecular and clinical pharmacology of this venerable class of drugs, as well as the manifestations of digitalis toxicity and their treatment. We also review in some detail recent clinical trials designed to examine the efficacy of these drugs in heart failure, with a focus on the Digoxin Investigation Group data set. Although, in our opinion, the data on balance warrant the continued use of these drugs for the treatment of symptoms of heart failure in patients already receiving contemporary multidrug therapy for this disease, the use of digitalis preparations will inevitably decline with the maturation of newer pharmacotherapies.
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PMID:Digitalis. 1006 97

This issue of Hypertension Research contains the review and original articles presented at the International Symposium on Natriuretic and Digitalis-Like Factors held in Chitose, Hokkaido, Japan, on August 24, 1999. The symposium was the satellite meeting of the 9th International Conference on the Na/K-ATPase and Related ATPases, which was held in Sapporo, Hokkaido. At the symposium, it became clear that ouabain is the most promising candidate for a circulating hormone to regulate a number of physiological functions, including hypertension, and that other minor substances may also exist as endogenous digitalislike factors. Most of the symposium contributors submitted papers to this journal. I am going to summarize briefly the research history and current research results on endogenous digitalislike factors (EDLF).
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PMID:Endogenous digitalislike factor: an update. 1101 12

Digitalis-like compounds are recently identified steroids synthesized by the adrenal gland, which resemble the structure of plant cardiac glycosides. These compounds, like the plant steroids, bind to and inhibit the activity of the Na+, K+-ATPase. The possible function of the endogenous digitalis-like compounds has to be evaluated in view of the presence of different isoforms of the Na+, K+-ATPase, which differ in their sensitivity to digitalis. This review focuses on recent published data on the Na+, K+-ATPase inhibitors, the digitalis-like compounds, regarding their structure, biosynthesis and secretion from the adrenal gland, physiological role and pathological implications in diseases such as hypertension and depression. Emphasis is given to studies describing the involvement of these compounds in brain function.
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PMID:Endogenous digitalis-like Na+, K+-ATPase inhibitors, and brain function. 1169 49

Digitalis compounds are used in the treatment of congestive heart failure as positive inotropic agents; their action is mainly due to the inhibition of Na(+),K(+)-ATPase. A well-known drawback is their arrhythmogenic potential. Attempts to find safer digitalis-like compounds by means of molecular simplifications of the typical 5beta,14beta-steroidal skeleton, which appeared in the medicinal chemistry literature from 1990 until 2002, are briefly reviewed. Several novel achievements were obtained in order to better understand the requisites of the digitalis binding site on Na(+), K(+)-ATPase. Only minor simplification, such as cleavage of the D ring of the digitalis skeleton, could preserve the desired inotropic activity, while highly simplified digitalis-like compounds failed to give sufficiently high inotropic potency, even in the presence of a powerful pharmacophore, such as the O-aminoalkyloxime group.
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PMID:Simplified digitalis-like compounds acting on Na(+), K(+)-ATPase. 1456 42

Adrenal origin and ACTH-dependent secretion of endogenous digitalis-like factor(s) (EDLF) was investigated. Twelve normal weight normotensive subjects (normal group) and 10 patients with Addison's disease (Addison group) were subjected to prolonged ACTH stimulation with 1 mg tetracosactin-depot im. Blood sampling was at 0 and 240 min. Digitalis-like reactivity was monitored in plasma extracts (combined organic solvent solid phase method) by digoxin and ouabain radioimmunoassay (RIAD and RIAO, respectively). 3H-ouabain concentration on erythrocytes (OBS) was also determined. Na+, K+-ATPase inhibition by normal plasma extract was tested by measuring Vmax and Km of 86Rb+-transport into human erythrocytes. In the normal group basal median plasma concentrations RIAD (0.07 nmol/l) and RIAO (0.89 nmol/l) increased significantly after ACTH administration (median 0.31 and 1.83, respectively; Wilcoxon, p<0.01). In contrast, in the Addison group no plasma RIAD and RIAO reactivity was detected before or after ACTH administration with minor exceptions. The OBS remained unchanged in the Addison group at 0 and 240 min; in the normal group there was a significant decline at 240 min (Wilcoxon, p<0.05) implying increase in circulating EDLF after ACTH stimulation. In the 86Rb+-transport experiments, 2 nmol/l ouabain or 2 nmol/l plasma-extracted ouabain reactivity both significantly impaired substrate affinity equally increasing Km without affecting Vmax. In men, the adrenals may produce and secrete EDLF, whose secretion appears to be ACTH-dependent.
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PMID:Circulating endogenous digitalis-like factor(s) (EDLF) in man is derived from the adrenals and its secretion is ACTH-dependent. 1459 20

Despite controversy over their use and the potential for toxic side effects, cardiac glycosides have remained an important clinical component for the treatment for congestive heart failure (CHF) and supraventricular arrhythmias since the effects of Digitalis purpurea were first described in 1785. While there is a wealth of information available with regard to the effects of these drugs on their pharmacological receptor, the Na(+), K(+)-ATPase, the exact molecular mechanism of digitalis binding and inhibition of the enzyme has remained elusive. In particular, the absence of structural knowledge about Na(+), K(+)-ATPase has thwarted the development of improved therapeutic agents with larger therapeutic indices via rational drug design approaches. Here, we propose a binding mode for digoxin and several analogues to the Na(+), K(+)-ATPase. A 3D-structural model of the extracellular loop regions of the catalytic alpha1-subunit of the digitalis-sensitive sheep Na(+), K(+)-ATPase was constructed from the crystal structure of an E(1)Ca(2+) conformation of the SERCA1a and a consensus orientation for digitalis binding was inferred from the in silico docking of a series of steroid-based cardiotonic compounds. Analyses of species-specific enzyme affinities for ouabain were also used to validate the model and, for the first time, propose a detailed model of the digitalis binding site.
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PMID:Elucidation of the Na+, K+-ATPase digitalis binding site. 1588 34

Digitalis compounds are used in the treatment of congestive heart failure as positive inotropic agents; their action is mainly due to the inhibition of the Na(+),K(+)-ATPase. A well-known drawback is their arrhythmogenic potential together with a low therapeutic index. Digitalis compounds are characterized by a cis/trans/cis steroidal skeleton with an alpha,beta-unsaturated lactone (gamma-butyrolactone) in the 17beta-position, a 14beta-hydroxy group and a 3beta-hydroxy group, the latter usually linked to one or more sugar rings. The first three moieties are considered essential for inotropic activity, while the glycosides are responsible for the pharmacokinetics of the compounds. This review briefly reports on some of the replacements for the unsaturated gamma-butyrolactone moiety and then summarizes the work at Prassis that led to the discovery of the O-aminoalkyloxime group as a very powerful substitute. We also report on the development of new steroidal compounds which act as digitalis-like inhibitors of the Na(+),K(+)-ATPase, without any of the chemical features that are peculiar to naturally occurring digitalis glycosides.
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PMID:Digitalis-like compounds: the discovery of the O-aminoalkyloxime group as a very powerful substitute for the unsaturated gamma-butyrolactone moiety. 1618 Nov 36

In the HeLa tumor cell line, we studied the characteristics of the dual effect of digitalis compounds on cell growth (proliferation and death). In addition, we explored whether both effects occur by means of the same mechanism. HeLa cell cultures were exposed to increasing concentrations (0.01 nM-10 microM) of ouabain, strophantidin, digoxin, and digoxigenin at 24-96 h intervals. Cell growth in treated cultures was compared with cell growth under nontreated conditions. Additionally, we studied changes in nuclear morphology, as well as in genomic DNA degradation, cytochrome c release, and caspase-9 and -3 presence and processing induced by toxic concentrations of digitalis. Digitalis compounds increased HeLa cell number when exposed to concentrations <10 nM during a 48 h period. Ethacrynic acid (a nonsteroid inhibitor for Na+/K+-ATPase) did not induce cell growth at these concentrations. Digitalis concentrations >10 nM induced cell death in a concentration- and exposure period-dependent fashion. Changes in nuclear morphology, DNA fragmentation, mitochondrial cytochrome c release, and proteolytic processing of caspases-9 and -3, suggest apoptotic cell death. The IC50 for the inducing effect of apoptosis by ouabain at 96 h was 18 nM and corresponds with the IC50 for the Na+/K+-ATPase inhibition in HeLa cells. In conclusion, the dual effect of digitalis compounds on HeLa cells growth is concentration and time-dependent. The apoptosis-inducing effect correlates with inhibition of Na+/K+-ATPase. Proliferation does not appear to be mediated through this pathway. The apoptosis-induction pathway is possibly cytochrome c-dependent.
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PMID:Proliferation and apoptosis of HeLa cells induced by in vitro stimulation with digitalis. 1650 6

Digitalis-like compounds (DLC) are a family of steroid hormones synthesized in and released from the adrenal gland. DLC, the structure of which resembles that of plant cardiac glycosides, bind to and inhibit the activity of the ubiquitous cell surface enzyme Na(+), K(+)-ATPase. However, there is a large body of evidence suggesting that the regulation of ion transport by Na(+), K(+)-ATPase is not the only physiological role of DLC. The binding of DLC to Na(+), K(+)-ATPase induces the activation of various signal transduction cascades that activate changes in intracellular Ca(++) homeostasis, and in specific gene expression. These, in turn, stimulate endocytosis and affect cell growth and proliferation. At the systemic level, DLC were shown to be involved in the regulation of major physiological parameters including water and salt homeostasis, cardiac contractility and rhythm, systemic blood pressure and behavior. Furthermore, the DLC system has been implicated in several pathological conditions, including cardiac arrhythmias, hypertension, cancer and depressive disorders. This review evaluates the evidence for the different aspects of DLC action and delineates open questions in the field.
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PMID:The digitalis-like steroid hormones: new mechanisms of action and biological significance. 1749 13


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