Letter to the editor: “Why isn't clinical experience with ouabain more widely accepted?”

Fürstenwerth, Hauke

doi:10.1152/ajpheart.00525.2014

American Journal of Physiology-Heart and Circulatory Physiology

2014

DOI: 10.1152/ajpheart.00525.2014

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Letter to the editor: “Why isn't clinical experience with ouabain more widely accepted?”

Hauke Fürstenwerth

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“…With dubious claims and even unfounded accusations ("edited their raw data", "scientific misconduct") he tries to discredit Vogeser's method. In addition Blaustein does not even mention the fact that ouabain has been used successfully in medical therapy of heart failure [20]. He ignores ideas and data that don't fit his preconceptions and neglects conflicting results that don't support his hypotheses.…”

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confidence: 99%

Ouabain - A gift from paradise

Fürstenwerth¹

2018

Cardiovasc Disord Med

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mentioning

confidence: 99%

Ouabain - A gift from paradise

Fürstenwerth¹

2018

Cardiovasc Disord Med

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Reply to “Letter to the editor: ‘Why isn't clinical experience with ouabain more widely accepted?'”

Blaustein

2014

American Journal of Physiology-Heart and Circulatory Physiology

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REPLY: Fürstenwerth (12a) notes that my "Perspectives" on endogenous ouabain (EO) (2) 1) didn't mention the use of ouabain as a therapeutic and antihypertensive agent (true; see last paragraph); 2) didn't consider the view that "(EO) is not 'ouabain'" (21) [I cited an earlier version (32) and the refutation (24); my article (2) was published online 4 days before Lewis and colleagues' (21); see our responses to Lewis et al. (2a, 14)]; and 3) called the 1993 discovery of ouabaindigoxin antagonism (27) "a surprise," despite the 2010 report that ouabain antagonizes acute digoxin and bufalin cardiotoxicity (31). Manunta et al. (26, 27) were, surely, the first to document that cardiotonic steroids (CTS) could antagonize one another and that all CTS do not have identical effects (e.g., ouabain, but not digoxin, causes hypertension). Thus this was "a surprise" in 1993. Nesher and colleagues (31) confirmed that ouabain and digoxin antagonize one another acutely but didn't address the mechanism (41). The mechanism for antagonizing the chronic effects of ouabain (26, 27), not studied by Nesher, is apparently more complex (47). Fürstenwerth cites the Lewis/Hilton/Nichols group (21) regarding "uncertainty on the identity of EO." The repeatedly verified analytical (HPLC plus mass spectroscopy, nuclear magnetic resonance, and UV) evidence that mammalian (including human) EO is, in fact, "ouabain" (13, 16-18, 39, 42) is not mentioned, although this contradicts the Lewis et al. view (21). The latter had already been refuted twice (23, 24). Moreover, much additional, independent, but generally overlooked evidence confirms that the endogenous substance is chemically very "ouabain-like." First, ouabain-resistant mutation of the ␣ 2 Na ϩ pump ouabain binding site abolishes the hypertensinogenic actions of ACTH and ouabain (10, 11, 22), proof that an EO-like ligand binds to this receptor. Second, prolonged subcutaneous administration of ouabain, but not digoxin, induces hypertension in rodents (15, 26, 44, 47). Ouabain's effect has been replicated in numerous laboratories in the United States, Brazil, Canada, China, and Italy. Third, ouabain, but not digoxin, also increases expression of Ca 2ϩ transporters, including Na ϩ /Ca 2ϩ exchanger-1 in arteries (47). Similar upregulation of these arterial transporters occurs in many forms of hypertension (4, 35, 36, 46). Fourth, digoxin blocks both the ouabain-induced protein upregulation (47) and hypertension (15, 26, 27). Fifth, complexation of EO with Fab fragments that bind digoxin and ouabain with high affinity (37, 38) abolishes several forms of hypertension (4), including those induced by ACTH (10), ouabain (10, 15), and high dietary salt (15). Sixth, reduced expression of ␣ 2 Na ϩ pumps (the EO receptors), equivalent to ␣ 2 Na ϩ pump inhibition by

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Influence of Endogenous Cardiac Glycosides, Digoxin, and Marinobufagenin in the Physiology of Epithelial Cells

Toro

Jimenez

Hinojosa

et al. 2019

Cardiology Research and Practice

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Cardiac glycosides are a group of compounds widely known for their action in cardiac tissue, some of which have been found to be endogenously produced (ECG). We have previously studied the effect of ouabain, an endogenous cardiac glycoside, on the physiology of epithelial cells, and we have shown that in concentrations in the nanomolar range, it affects key properties of epithelial cells, such as tight junction, apical basolateral polarization, gap junctional intercellular communication (GJIC), and adherent junctions. In this work, we study the influence of digoxin and marinobufagenin, two other endogenously expressed cardiac glycosides, on GJIC as well as the degree of transepithelial tightness due to tight junction integrity (TJ). We evaluated GJIC by dye transfer assays and tight junction integrity by transepithelial electrical resistance (TER) measurements, as well as immunohistochemistry and western blot assays of expression of claudins 2 and 4. We found that both digoxin and marinobufagenin improve GJIC and significantly enhance the tightness of the tight junctions, as evaluated from TER measurements. Immunofluorescence assays show that both compounds promote enhanced basolateral localization of claudin-4 but not claudin 2, while densitometric analysis of western blot assays indicate a significantly increased expression of claudin 4. These changes, induced by digoxin and marinobufagenin on GJIC and TER, were not observed on MDCK-R, a modified MDCK cell line that has a genetically induced insensitive α1 subunit, indicating that Na-K-ATPase acts as a receptor mediating the actions of both ECG. Plus, the fact that the effect of both cardiac glycosides was suppressed by incubation with PP2, an inhibitor of c-Src kinase, PD98059, an inhibitor of mitogen extracellular kinase-1 and Y-27632, a selective inhibitor of ROCK, and a Rho-associated protein kinase, indicate altogether that the signaling pathways involved include c-Src and ERK1/2, as well as Rho-ROCK. These results widen and strengthen our general hypothesis that a very important physiological role of ECG is the control of the epithelial phenotype and the regulation of cell-cell contacts.

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Letter to the editor: “Why isn't clinical experience with ouabain more widely accepted?”

Cited by 3 publications

References 33 publications

Ouabain - A gift from paradise

Ouabain - A gift from paradise

Reply to “Letter to the editor: ‘Why isn't clinical experience with ouabain more widely accepted?'”

Influence of Endogenous Cardiac Glycosides, Digoxin, and Marinobufagenin in the Physiology of Epithelial Cells

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