In search of ideal inotropic steroids: Recent progress

Repke, K.; Sweadner, Kathleen J.; Weiland, Jürgen; Megges, R.; R, Schön

doi:10.1007/978-3-0348-8998-8_1

Cited by 19 publications

(37 citation statements)

References 119 publications

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“…As expected, corticosterone (100 nM), which lacks the lactone ring of CS, had no effect. On the other hand, proscillaridin A, digoxin, and digoxigenin induced changes in membrane traffic (Table 1) with a high correlation to their established ability to bind to and inhibit Na ϩ -K ϩ -ATPase activity (28,34). Astonishingly, the most established CS inhibitor of Na ϩ -K ϩ -ATPase activity, ouabain, even at 100 nM, had no effect on endocytosed membrane traffic.…”

Section: Resultsmentioning

confidence: 91%

“…It is well established that specific steroids, originally identified in plants and amphibians (e.g., digitalis, cardenolides, and bufadienolides), collectively termed here cardiac steroids (CS), bind to a specific site on the ␣-subunit and inhibit ATP hydrolysis and ion transport (4). The pharmacological profile of these steroids as Na ϩ -K ϩ -ATPase inhibitors has been extensively studied and well defined (28,34). In the past decade, several groups have identified CS-like compounds in animal and human tissues, and their synthesis in and release from the adrenal gland was proven (for reviews, see Refs.…”

mentioning

confidence: 99%

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Role of endosomal Na⁺-K⁺-ATPase and cardiac steroids in the regulation of endocytosis

Feldmann¹,

Glukmann²,

Medvenev³

et al. 2007

American Journal of Physiology-Cell Physiology

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Plasma membrane Na(+)-K(+)-ATPase, which drives potassium into and sodium out of the cell, has important roles in numerous physiological processes. Cardiac steroids (CS), such as ouabain and bufalin, specifically interact with the pump and affect ionic homeostasis, signal transduction, and endocytosed membrane traffic. CS-like compounds are present in mammalian tissues, synthesized in the adrenal gland, and considered to be new family of steroid hormones. In this study, the mechanism of Na(+)-K(+)-ATPase involvement in the regulation of endocytosis is explored. We show that the effects of various CS on changes in endosomal pH are mediated by the pump and correspond to their effects on endosomal membrane traffic. In addition, it was found that CS-induced changes in endocytosed membrane traffic were dependent on alterations in [Na(+)] and [H(+)] in the endosome. Furthermore, we show that various CS differentially regulate endosomal pH and membrane traffic. The results suggest that these differences are due to specific binding characteristics. Based on our observations, we propose that Na(+)-K(+)-ATPase is a key player in the regulation of endosomal pH and endocytosed membrane traffic. Furthermore, our results raise the possibility that CS-like hormones regulate differentially intracellular membrane traffic.

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Section: Resultsmentioning

confidence: 91%

mentioning

confidence: 99%

Role of endosomal Na⁺-K⁺-ATPase and cardiac steroids in the regulation of endocytosis

Feldmann¹,

Glukmann²,

Medvenev³

et al. 2007

American Journal of Physiology-Cell Physiology

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“…6 Side-chain/side-chain interactions between the two helical domains were initially energy minimized by molecular mechanics keeping constrained all the backbone atoms coordinates.…”

Section: (E)-21[(ez)-(2-aminoethoxy)imino]-5 -Pregn-17-ene-3 14 -Dmentioning

confidence: 99%

17β-O-Aminoalkyloximes of 5β-Androstane-3β,14β-diol with Digitalis-like Activity: Synthesis, Cardiotonic Activity, Structure−Activity Relationships, and Molecular Modeling of the Na⁺,K⁺-ATPase Receptor

et al. 2000

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A series of digitalis-like compounds with a 17-aminoalkoxyiminoalkyl or -alkenyl substituent was synthesized and evaluated for inhibition of Na(+),K(+)-ATPase and for inotropic activity. The highest inhibition was found with compounds having the substituent in configuration 17beta and the amino group at a distance of 6 or 7 bonds from C(17) of the digitoxigenin skeleton. The presence of the oxime function strengthens the interaction with the receptor, more if alpha,beta-unsaturated, thus mimicking the electronic situation of the unsaturated lactone in natural digitalis compounds. The most active compounds showed Na(+),K(+)-ATPase inhibitory potencies (IC(50)) 17-25 times higher than the standards digitoxigenin and digoxin and 3-11 times higher inotropic potencies (EC(50)) in isolated guinea pig left atria. These features are supported by a molecular model suggesting the possible interactions of the groups described above with particular amino acid residues in the H1-H2 domains of Na(+),K(+)-ATPase. Some interactions are the classical ones already described in the literature; a new, very strong interaction of the basic group with the Cys138 was found and adds new possibilities to design compounds interacting with this region of the receptor. The most interesting compounds were also studied in vivo in the anesthetized guinea pig for evaluating their inotropic effect versus the lethal dose. Compounds 9 and 12 showed a slightly higher safety ratio than digoxin and deserve further evaluation.

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“…These steroids can be used clinically to treat congestive heart failure because they have well documented inotropic effects on the heart (Akera and Brody, 1976;Repke et al, 1996). Although CTSs have been considered drugs since their discovery, recent studies have identified several of them, including ouabain and marinobufagenin, as endogenous steroids (Hamlyn et al, 1991;Bagrov and Fedorova, 1998).…”

mentioning

confidence: 99%

Identification of Hydroxyxanthones as Na/K-ATPase Ligands

Zhang¹,

Li²,

Tian³

et al. 2010

Mol Pharmacol

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In search of ideal inotropic steroids: Recent progress

Cited by 19 publications

References 119 publications

Role of endosomal Na⁺-K⁺-ATPase and cardiac steroids in the regulation of endocytosis

Role of endosomal Na⁺-K⁺-ATPase and cardiac steroids in the regulation of endocytosis

17β-O-Aminoalkyloximes of 5β-Androstane-3β,14β-diol with Digitalis-like Activity: Synthesis, Cardiotonic Activity, Structure−Activity Relationships, and Molecular Modeling of the Na⁺,K⁺-ATPase Receptor

Identification of Hydroxyxanthones as Na/K-ATPase Ligands

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In search of ideal inotropic steroids: Recent progress

Cited by 19 publications

References 119 publications

Role of endosomal Na+-K+-ATPase and cardiac steroids in the regulation of endocytosis

Role of endosomal Na+-K+-ATPase and cardiac steroids in the regulation of endocytosis

17β-O-Aminoalkyloximes of 5β-Androstane-3β,14β-diol with Digitalis-like Activity: Synthesis, Cardiotonic Activity, Structure−Activity Relationships, and Molecular Modeling of the Na+,K+-ATPase Receptor

Identification of Hydroxyxanthones as Na/K-ATPase Ligands

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Product

Resources

About

Role of endosomal Na⁺-K⁺-ATPase and cardiac steroids in the regulation of endocytosis

Role of endosomal Na⁺-K⁺-ATPase and cardiac steroids in the regulation of endocytosis

17β-O-Aminoalkyloximes of 5β-Androstane-3β,14β-diol with Digitalis-like Activity: Synthesis, Cardiotonic Activity, Structure−Activity Relationships, and Molecular Modeling of the Na⁺,K⁺-ATPase Receptor