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

Abstract

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

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

“…It is very interesting that our results seem to support the hypothesis stating that a hormonal role of ECS is to influence renal function. Since decades ago, there has been evidence suggesting that ECS functions as natriuretic agents [90,91], although this hypothesis is still controversial [92][93][94][95][96][97]. Our findings, which have been made in epithelial cells, lead us to propose that the ECS modulates the epithelial phenotype because they influence the crucial properties of this type of tissue.…”