Evidence for an intracellular site of action in the heart for two hydrophobic cardiac steroids

Núñez‐Durán, Harol; Fernández, Paola

doi:10.1016/j.lfs.2003.07.041

Cited by 7 publications

(4 citation statements)

References 12 publications

(11 reference statements)

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“…Thus, it can be postulated that CS exert their action on heart contractility and rhythm, partially by their effect on intracellular membrane traffic. This possibility is supported by recent findings that CS effects are inhibited by endocytosis inhibitors. , The effect of digoxin on the accumulation of transferrin in human neuronal NT2 cells is shown in Figure . In the absence of digoxin, no accumulation of transferrin was apparent (Figur 6a−c).…”

Section: Biological Activitysupporting

confidence: 76%

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4-(3‘α15‘β-Dihydroxy-5‘β-estran-17‘β-yl)furan-2-methyl Alcohol: An Anti-Digoxin Agent with a Novel Mechanism of Action

et al. 2005

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The synthesis and some pharmacological properties of 4-(3'alpha-15'beta-dihydroxy-5beta-estran-17'beta-yl)furan-2-methyl alcohol (16) have been described. The compound was synthesized by reacting a synthetic 3alpha- benzyloxy-5beta-estr-15-en-17-one with the ethylene acetal of 4-bromo-2-furancarboxyaldehyde, followed by hydrolysis of the ethylene acetal and reduction of the aldehyde. Despite its resemblance to the structure of cardiac steroids (CS), 16 does not bind to the CS receptor on Na(+),K(+)-ATPase and does not increase the force of contraction of heart muscle. However, 16 inhibited the digoxin-induced increase in the force of contraction and arrhythmias in guinea pig papillary muscle and human atrial appendages. The steroid also inhibited digoxin-induced alteration in endocytosed membrane traffic, indicating a novel mechanism of action.

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Section: Biological Activitysupporting

confidence: 76%

“…This possibility is supported by recent findings that CS effects are inhibited by endocytosis inhibitors. 32,33 The effect of digoxin on the accumulation of transferrin in human neuronal NT2 cells is shown in Figure 6. In the absence of digoxin, no accumulation of transferrin was apparent (Figur 6a-c).…”

Section: Biological Activitymentioning

confidence: 99%

4-(3‘α15‘β-Dihydroxy-5‘β-estran-17‘β-yl)furan-2-methyl Alcohol: An Anti-Digoxin Agent with a Novel Mechanism of Action

et al. 2005

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“…However, the predominant localization of the interaction at intracellular membranes (e.g., mitochondria, ER/perinuclear membrane) suggests potential alternative mechanisms of regulation. Although cardiac glycosides are reported to enter cells through either passive diffusion (for those compounds such as digoxin that are hydrophobic) or uptake by drug transporters (41,42), it is unclear how they would gain access to the extracellular domain of Na + ,K + -ATPase (which would be on the luminal side of intracellular membranous compartments). Therefore, it seems more likely that interactions between Na + ,K + -ATPase/Beclin 1 at the mitochondria and ER/perinuclear membrane are regulated indirectly via cardiac glycoside effects on ionic concentrations or signal transduction pathways.…”

Section: Discussionmentioning

confidence: 99%

Interaction between the autophagy protein Beclin 1 and Na+,K+-ATPase during starvation, exercise, and ischemia

et al. 2020

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“…32,33 Unlike ouabain, digoxin is able to pass through the cell membrane whereby it binds to ryanodine receptors. 34 Once bound, Ca 2 + is released from the sarcoplasmic reticulum. Digoxin is also capable of forming transmembrane calcium channels, resulting in increased intracellular Ca 2 + concentrations 35 that could potentially promote the collagen synthetic activity of chondrocytes and subsequently neotissue formation; especially considering the already approved clinical status of digoxin, the use of this agent in neocartilage tissue engineering merits investigation.…”

Section: Introductionmentioning

confidence: 99%

Digoxin and Adenosine Triphosphate Enhance the Functional Properties of Tissue-Engineered Cartilage

Makris

Huang

et al. 2015

Tissue Engineering Part A

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Toward developing engineered cartilage for the treatment of cartilage defects, achieving relevant functional properties before implantation remains a significant challenge. Various chemical and mechanical stimuli have been used to enhance the functional properties of engineered musculoskeletal tissues. Recently, Ca 2 + -modulating agents have been used to enhance matrix synthesis and biomechanical properties of engineered cartilage. The objective of this study was to determine whether other known Ca 2 + modulators, digoxin and adenosine triphosphate (ATP), can be employed as novel stimuli to increase collagen synthesis and functional properties of engineered cartilage. Neocartilage constructs were formed by scaffold-free self-assembling of primary bovine articular chondrocytes. Digoxin, ATP, or both agents were added to the culture medium for 1 h/ day on days 10-14. After 4 weeks of culture, neocartilage properties were assessed for gross morphology, biochemical composition, and biomechanical properties. Digoxin and ATP were found to increase neocartilage collagen content by 52-110% over untreated controls, while maintaining proteoglycan content near native tissue values. Furthermore, digoxin and ATP increased the tensile modulus by 280% and 180%, respectively, while the application of both agents increased the modulus by 380%. The trends in tensile properties were found to correlate with the amount of collagen cross-linking. Live Ca 2 + imaging experiments revealed that both digoxin and ATP were able to increase Ca 2 + oscillations in monolayer-cultured chondrocytes. This study provides a novel approach toward directing neocartilage maturation and enhancing its functional properties using novel Ca 2 + modulators.

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Evidence for an intracellular site of action in the heart for two hydrophobic cardiac steroids

Cited by 7 publications

References 12 publications

4-(3‘α15‘β-Dihydroxy-5‘β-estran-17‘β-yl)furan-2-methyl Alcohol: An Anti-Digoxin Agent with a Novel Mechanism of Action

4-(3‘α15‘β-Dihydroxy-5‘β-estran-17‘β-yl)furan-2-methyl Alcohol: An Anti-Digoxin Agent with a Novel Mechanism of Action

Interaction between the autophagy protein Beclin 1 and Na+,K+-ATPase during starvation, exercise, and ischemia

Digoxin and Adenosine Triphosphate Enhance the Functional Properties of Tissue-Engineered Cartilage

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