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Nephrology Dialysis Transplantation 2008 23(9):2723-2729; doi:10.1093/ndt/gfn325
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Role of endogenous cardiotonic steroids in sodium homeostasis

Wilhelm Schoner and Georgios Scheiner-Bobis

Institute of Biochemistry and Endocrinology, Justus-Liebig-University Giessen, Frankfurter Str. 100 D-35392 Giessen, Germany

Correspondence and offprint requests to: Wilhelm Schoner, Institute of Biochemistry and Endocrinology, Justus-Liebig-University Giessen, Frankfurter Str. 100, D-35392 Giessen, Germany. Tel: +49-641-99-38170; Fax: +49-641-99-38179; E-mail: wilhelm.schoner{at}vetmed.uni-giessen.de

Keywords: arterial hypertension; cardiomyopathy; endogenous cardiotonic steroids; marinobufagenin; ouabain



   Introduction
Top
 Introduction
Conclusions
 References
 
Consumption of an excess of salt over many years leads to arterial hypertension [1]. This process is accompanied by the activation of a great number of genes involved in the remodelling and hypertrophy of the heart, kidneys and the wall of the arteries. These sodium-induced alterations lead to a higher incidence of stroke, greater stiffness of conduit arteries and enhanced activity of resistance arteries [1–3]. Increased uptake of sodium from the diet may not, in some persons, affect the levels of circulating renin, angiotensin and norepinephrine in blood plasma and increase the urinary secretion of sodium, potassium and calcium [4]. Sodium sensors [5] and natriuretic hormones must be involved in the control of the body's sodium content [6,7]. Defects in this control mechanism induced by an altered gene expression pattern in different organs may explain why excess sodium consumption is toxic [2]. The recently discovered new class of endogenous cardiotonic steroid hormones involved in the control of heart function, vasoconstriction and kidney function seems to shed new light on the sodium toxic mechanisms that are more prominent in situations such as kidney failure and uraemic cardiomyopathy. The identification of new mechanisms inducing arterial hypertension may also open up the possibility of new therapeutic approaches [8,9].

The search for an additional natriuretic hormone involved in low-renin hypertension was initiated [6,10,11] because the existence of such an hormone was evident and not all of the Na+-related effects on the control of fluid volume and osmolality by the kidney, the circulatory system and the heart could be explained [7,12,13]. Hence, the idea evolved that a circulating inhibitor of the sodium pump of renal tubular cells might exist. Such a substance should act like an endogenous digitalis [13]. In fact, a close correlation between blood pressure and the concentration of a circulating inhibitor of the sodium pump in human blood plasma was demonstrated [14–16]. The intensive, international efforts to isolate an ‘endogenous digitalis’, which was postulated 50–100 years ago [17,18], finally led to the isolation and structural identification of a still increasing number of new steroid compounds in mammals (for recent reviews see [9,19–21]).

Mammalian endogenous cardiac steroids have their structural counterparts in plants and amphibians
Almost all of the newly detected mammalian steroid hormones were previously isolated as cardiotonic constituents and toxins from plants and amphibians. Cardiotonic steroids or cardiac glycosides are specific inhibitors of the sodium pump (Na+/K+-ATPase) [22]. Ouabain (g-Strophanthin) was identified in human blood plasma [23], bovine adrenal glands [24] and hypothalamus [25] (Figure 1). Digoxin was isolated from the urine of healthy human subjects [26]. In addition to these cardenolides, a number of bufadienolides were identified in mammals: marinobufagenin was identified in the urine of patients with acute myocardial infarction [27]. Marinobufotoxin—the C3-site arginine-suberoyl ester of marinobufagenin—was identified in the supernatant of the adrenocortical-derived cell line Y-1 [28]; telocinobufagin, the reduced form of marinobufagenin, was isolated from blood plasma of patients with terminal renal failure [29], and 19-norbufalin was isolated from human cataractous lenses [30]. A proscillaridin A immunoreactivity that increases with increasing blood pressure in human patients with essential hypertension has been detected as well [31]. There are indications that many more endogenous cardiotonic steroids may exist in mammals [24].


Figure 1
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  		Fig. 1 Cardiotonic steroids identified in mammalian tissues [9].

 
Biosynthesis of endogenous cardiotonic steroids
Endogenous cardiotonic steroids have been extracted from mammalian tissues such as hypothalamus [25], heart [32], cataractous lenses [30] and adrenal gland [24,28,33]. Even though there is indication that cardenolides might be synthesized in the heart [32] and the hypothalamus [34], most information points to the zona fasciculata and glomerulosa of the adrenal gland as the place of biosynthesis of cardenolides, especially endogenous ouabain [35]. Pregnenolone and progesterone are the precursors in the biosynthesis of endogenous ouabain and endogenous digoxin. Conversion of radioactive acetate and cholesterol into endogenous digoxin has been demonstrated [36]. In plants, conversion of the A/B trans rings of progesterone to the A/B cis ring conformation of 5β preganane-3,20-dione by progesterone 5β reductase is the key step of cardenolide biosynthesis [37]. This enzyme exists in mammals as well [38,39], but it has not been demonstrated thus far to be involved in mammalian cardenolide or bufadienolide biosynthesis.

Synthesis of bufadienolide-like marinobufagenin, marinobufotoxin and proscillaridine A also seems to occur in adrenocortical tumour cells [28,40]. Progesterone does not appear to be a precursor of marinobufagenin, and the cholesterol side chain cleavage as well as hydroxylation processes catalyzed by P450scc does not seem to be involved in the biosynthesis of this bufadienolide. However, mevastatin, an inhibitor of HMG-CoA reductase, reduced the biosynthesis of marinobufagenin, indicating that cholesterol is a precursor of bufadienolides in mammals as well [40]. There is evidence that the biosynthesis of the rare sugars found in many cardenolides of plant origin may occur in mammals [36].

Hence, both bufadienolides and cardenolides can be synthesized in the adrenal cortex (Figure 2). Cholesterol is a precursor of endogenous bufadienolides and cardenolides, but their biosynthetic pathways differ. As the concentration of endogenous cardiac glycosides is higher in the midbrain than in blood plasma, it is feasible that brain cells are also able to synthesize endogenous cardiotonic steroids as a neurotransmitter [21,41].


Figure 2
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  		Fig. 2 Synopsis on the probable secretory control and function of endogenous cardiotonic steroids in the mammalian cardiovascular system and volume control (for details see the text and reviews [8,9]). Synthesis of endogenous cardiotionic steroids in the adrenal cortex from cholesterol is under the control of catecholamines, ACTH and angiotensin II [35,42–48]. Increased NaCl in the midbrain cells may lead to its secretion as ouabain and stress do [9]. Digoxin probably lowers this release via internalization of sodium pumps in brain [80] and acts as an antihypertensive neurohormonal regulator [94,95]. Rostafuroxin decreases blood pressure as an ouabain antagonist [8]. The rapid effects on the heart, arterial wall and kidney are followed by a remodelling of the organs after prolonged exposition to endogenous cardiac glycosides [9,59,75,96–98].

 
Regulation of the release of endogenous cardiotonic steroids to the blood plasma
A synopsis of the current knowledge on the control of the concentration of cardiotonic steroids in blood plasma is given in Figure 2. From in vitro and in vivo studies, it is evident that adrenal cortical cells release endogenous ouabain and marinobufagenin [42–44] in response to epinephrine, angiotensin II and ACTH [35,42,45–48]. NaCl is recognized by Na+-sensing cells in the midbrain [5,41,49], which may cause, via the secretion of ouabain as a transmitter, renin-producing cells of the midbrain to release angiotensin II and to activate the sympathetic system. This assumption is supported by the observation that sodium effects can be mimicked by intrahippocampal microinjection of ouabain [50]. Adrenal cortical cells may then be activated via the β1-adrenergic receptor and the angiotensin II AT2 receptor to synthesize and release endogenous ouabain and marinobufagenin into the bloodstream [9]. Furthermore, physical exercise [51], hypoxia [52] and behavioural stress [53,54] may stimulate the release of endogenous cardiotonic steroids. Adrenalectomy results in a drop of the plasma concentration of endogenous ouabain in rats [55]. The extirpation of an ouabain-overproducing tumour (ouabainoma) from the adrenal gland in humans was shown to lower arterial hypertension [56,57]. The atrial natriuretic peptide, however, seems to suppress the liberation of endogenous ouabain in the brain [58]. It is not understood thus far how increased Na+ uptake may induce an intermediary rise of endogenous ouabain [44] but leads to a constant rise of endogenous marinobufagenin [59–61]. Uraemia due to partial nephrectomy leads to an increase of marinobufagenin in blood plasma [59,62], possibly via a rise of angiotensin II (Figure 2).

Why are so many cardiotonic steroids necessary?
Considering the still increasing number of endogenous cardiotonic steroids being identified (Figure 1), one may question the biological significance of this diversity. It is now clear that the cardiac glycoside receptor resides on the cell surface-oriented outer side of the four isoforms of the catalytic {alpha} subunit of Na+/K+-ATPase. These isozymes vary in their relative amounts in various tissues. The {alpha}1 subunit, considered to be the workhorse in cellular sodium export, is the major isozyme of the kidney tubule cells (Figure 2), and the {alpha}2 and {alpha}3 isozymes are considered to have regulatory functions in vasoconstriction [20] and cardiac inotropy [63]. Even though only minimal differences exist in the affinity of the various human sodium pump isozymes for the cations Na+ and K+ or for cardiac glycosides [64], the stability of the cardiac glycoside enzyme complex formed with the {alpha}2 isoform is much more labile [65,66]. This may be an important factor in considering cardiac glycosides acting as hormones at nanomolar concentrations, since the ouabain receptor site is important for the generation of arterial hypertension [67,68]. Consistent with the functioning of a hormone, low (nanomolar) concentrations of cardiac glycosides that do not inhibit the sodium pump may activate intracellular signalling cascades. This will lead to vasoconstriction, hypertension, natriuresis and, when such signals are of longer duration, also to tissue remodelling of the heart, arteries and kidneys [9,69] (Figure 2). Since kidney tubular cells contain exclusively the {alpha}1 isoform of Na+/K+-ATPase (which is responsible for the export of sodium from the renal tubular cells to the blood), differences in the target site specificity and biological action of the various cardiac glycosides are likely. For instance, marinobufagenin has been shown to have natriuretic properties due to its preference for the {alpha}1 isoform of Na+/K+-ATPase [70].

The functional pattern of the various endogenous cardiac steroids differs
It is now becoming evident that the various cardiac glycosides show overlapping specificities for various tasks. A similar phenomenon is known for other steroid hormones that have varying degrees of mineralocorticoid and/or glucocorticoid properties.

Ouabain as a blood pressure-raising steroid hormone
The plasma levels of water-soluble ouabain rapidly rise upon exercise in man and dogs [51]. Since ouabain leads to vasoconstriction and decreases the heart rate via the activation of the baroreceptor reflex, this steroid may be important for rapid adaptation of the haemodynamics in stress situations. Congestive heart failure is accompanied by increased concentrations of endogenous ouabain. Haemodynamics are altered by increased Na+ uptake as well as Ca2+ cycling in the heart, since ouabain induces oxidative changes of the sarcoplasmic reticulum Ca2+-ATPase and functions that lead to diastolic dysfunction of the heart [71]. Increased concentrations of endogenous ouabain have been reported to exist in 50% of Europeans with arterial hypertension. However, no direct correlation of this steroid hormone with the dietary Na+ uptake exists but with the urinary loss of K+ [43,72]. Ouabain was found to be kaliuretic [73]. Long-term exposure of rats to nanomolar concentrations of ouabain leads to hypertension. There is a high probability of children inheriting ouabain-induced hypertension when the parents suffered from this disease [74]. In patients who have hypertension with a high plasma ouabain concentration, any digitalis therapy is prognostically counter-indicated since this therapy may worsen the progression of heart failure [75]. Hence, any ouabain receptor antagonists should act therapeutically against the progression of heart failure by enhanced heart muscle remodelling and should lower arterial hypertension. Rostafuroxin is such a substance that is presently in Phase II of clinical evaluation [8]. Furthermore, infusion of FAB fragments against ouabain (Digibind®) may be useful to lower acute, untreatable arterial hypertension [76,77] in preeclampsia [78] and central haemorrhage-induced hypertension [79].

Digoxin, a hormone opposing endogenous ouabain?
This hormone is synthesized from cholesterol in the cortex of the adrenal gland. Higher concentrations of endogenous digoxin were found under conditions of renal failure and hypertensive pregnancy. As it is not possible to induce arterial hypertension in rats by long-term treatment with nanomolar concentrations of digoxin, which, in contrast, counteract ouabain-induced hypertension, it is probable that any rise in endogenous digoxin levels represents a counteractive baroreflex. It has been speculated that digoxin treatment leads to an internalization of the cardiac glycoside receptors in brain, and hence, to the inability of the Na+-induced neurotransmitter ouabain to activate the release of hypertensinogenic hormones [9,80]. The therapy for heart failure with digoxin may use this mechanism as well.

Marinobufagenin, a natriuretic and pressurizing hormone, is responsible for uraemic cardiomyopathy
The plasma concentration of the bufadienolide marinobufagenin (Figure 1) is raised acutely upon NaCl uptake and volume expansion, in preeclampsia, and upon myocardial infarction, but also after chronic loading with NaCl, in chronic heart failure, chronic renal failure and uraemic cardiomyopathy [27,53,59,81–83]. Levels of telocinobufagin, another bufadienolide, increase even more than other endogenous cardiac steroids in patients with terminal renal failure [29] (Figure 1). Long-term infusion of low nanomolar concentrations of marinobufagenin in animals raises arterial blood pressure and has been shown to lead to cardiomyopathy and increased collagen production in the heart, and may cause fibrosis as in uraemic cardiomyopathy [62]. Impressive changes in heart morphology and function observed after partial nephrectomy and marinobufagenin-induced alterations include the following: the left ventricular wall thickness measured by echocardiography was significantly elevated after subtotal nephrectomy; systolic and diastolic left ventricular volumes were reduced; fractional shortening was increased. Invasive measurements revealed increased maximal velocity of the rise in left ventricular pressure (dP/dt) and some evidence of impaired diastolic left ventricular function. As reported above, chronic renal failure leads to alterations in cardiac gene expression that in turn produce alterations in cardiac calcium cycling and contractile function, phenomena not explainable by the increase in blood pressure [84]. These findings concerning experimental uraemic cardiomyopathy were abrogated by preimmunization of the animals with marinobufagenin [59,62]. One should also note that the NaCl-dependent rise of blood pressure in pregnant rats can be reversed by antibodies against marinobufagenin [85,86].

One may ask how the natriuretic activity of marinobufagenin is accomplished. Marinobufagenin exhibits a greater affinity for the {alpha}1 isozyme of the sodium pump than for other isoforms [70]. The {alpha}1 isoform of Na+/K+-ATPase is the exclusive isozyme of the renal tubular cells. Hence, binding of marinobufagenin to it should promote natriuresis [70,82]. In fact, antibodies against marinobufagenin given to Sprague-Dawley rats kept on a high salt diet lowered urinary NaCl excretion by 60%, increased tubular 86Rb+ uptake and Na+/K+–ATPase activity and decreased significantly the content of the {alpha}1 subunit of the sodium pump in early and late endosomes [87]. Interaction of cardiac glycosides with the {alpha}1isozyme of Na+/K+-ATPase may activate intracellular signalling via Ca2+-dependent and -independent pathways. The latter mechanism perhaps leads, via a Src-EGFR-dependent signalling pathway, to ERK tyrosine phosphorylation and alteration of gene activity, but also to an alteration of the turnover of kidney tubular plasma membranes [8,9]. In LLC-PK1 cells, a model of proximal renal tubular cells, non-inhibitory nanomolar concentrations of ouabain and marinobufagenin lead to an internalization of the sodium pump and the Na+/H+ exchanger (NHE3), but in MDCK cells representing the distal tubule of kidney no such effects were observed [88]. In renal proximal tubules, salt loading not only depresses NHE3 expression but also induces Na+/K+-ATPase endocytosis in a marinobufagenin-dependent matter. NHE3 activity is also regulated by other processes like phosphorylation, trafficking and transcriptional regulation [88]. Additionally, inhibition of the {alpha}1 isoform of Na+/K+-ATPase by marinobufagenin may be enhanced by an ANP-induced stimulation of its phosphorylation. So, both hormones perhaps potentiate each other's natriuretic effect [89]. Hence, in proximal tubular epithelia, a cardiotonic steroid-induced internalization and phosphorylation of Na+ transporting proteins may enhance natriuresis (Figure 3). But, also another mechanism is likely to contribute to natriuresis: aldosteron is known to stimulate, in distal tubules and collecting duct, the sodium re-absorption [90]. This is achieved by the increased expression of the alpha subunit of the epithelial sodium channel (ENaC) as well as by the Na+/K+-ATPase [91,92]. Recently, it has been shown that marinobufagenin interferes in Cos-1 kidney cells with the functioning of the mineralocorticoid receptor (MR) by inhibiting the transcriptional activity of the receptor, and this is reflected in a reduced interaction between the SRC-3 coactivator and the mineralocorticoid receptor [93]. It may, hence, be possible that such a mechanism further increases natriuresis (Figure 3).


Figure 3
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  		Fig. 3 Probable mechanisms of marinobufagenin-induced natriuresis. Natriuresis may occur via internalization of sodium carriers in proximal kidney tubule epithelia [87,88] and interference with aldosterone in protein biosynthesis via the mineralocorticoid receptor in distal renal tubules and the collecting duct [93].

 


   Conclusions
Top
 Introduction
 Conclusions
References
 
It is evident now that long-term excessive sodium consumption stimulates, in addition to other known mechanisms, the generation of arterial hypertension via the release of various endogenous cardiac glycosides. A long-lasting rise of this new type of steroid hormone in blood plasma, and especially that of ouabain and marinobufagenin, leads to arterial hypertension, natriuresis and finally, via altered gene expression patterns, to remodelling of the heart, arterial wall and kidneys. In particular, a prolonged increased secretion of marinobufagenin, due to renal dysfunction, seems to be responsible for the alterations accompanying uraemic cardiomyopathy. Since 45% of hypertension cases are due to increased secretion of cardiac glycosides, it might be of diagnostic value to measure the plasma concentrations of endogenous cardiac glycosides to decide whether rostafuroxin, an ouabain antagonist and member of a new group of antihypertensives, might be the therapeutic agent of choice. The availability of an immunoassay for endogenous cardiac glycosides and knowledge of plasma concentrations of endogenous cardiac glycosides might also be of diagnostic value for the therapy of heart failure to avoid an iatrogenic progression of heart failure by treatment with digitalis compounds in those patients already suffering from elevated levels of plasma ouabain. In such patients, digitalis therapy would promote remodelling of the heart and increase fibrosis. Therapy with rostafuroxin, accompanied by other means of therapy (diuretics, β blockers, Ca2+ antagonists), would presumably be a better choice to lower the likelihood of cardiac remodelling, fibrosis and heart failure.

Conflict of interest statement. None declared.



   References
Top
 Introduction
 Conclusions
 References
 

  1. de Wardener HE, MacGregor GA. Sodium and blood pressure. Curr Opin Cardiol (2002) 17:360–367.[CrossRef][ISI][Medline]
  2. Ritz E, Dikow R, Morath C, et al. Salt—a potential ‘uremic toxin’? Blood Purif (2006) 24:63–66.[CrossRef][ISI][Medline]
  3. Frohlich ED. The Salt Conundrum: a hypothesis. Hypertension (2007) 50:161–166.[Free Full Text]
  4. Haddy F, Pamnani M. Role of dietary salt in hypertension. J Am Coll Nutr (1995) 14:428–438.[Abstract]
  5. Hiyama T, Watanabe E, Okado H, et al. The subfornical organ is the primary locus of sodium-level sensing by Nax sodium channels for the control of salt-intake behavior. J Neurosci (2004) 24:9276–9281.[Abstract/Free Full Text]
  6. Buckalew VM, Haddy FJ. Circulating natriuretic factors in hypertension. In: Hypertension: Pathophysiology, Diagnosis and Management—Laragh JH, Brenner EM, eds. (1990) New York: Raven Press. 939–954.
  7. DeWardener HE, Clarkson EM. Concept of natriuretic hormone. Physiol Rev (1985) 65:658–759.[Free Full Text]
  8. Ferrari P, Ferrandi M, Valentini G, et al. Rostafuroxin: an ouabain antagonist that corrects renal and vascular Na+-K+-ATPase alterations in ouabain and adducin-dependent hypertension. Am J Physiol Regul Integr Comp Physiol (2006) 290:R529–R535.[Abstract/Free Full Text]
  9. Schoner W, Scheiner-Bobis G. Endogenous and exogenous cardiac glycosides: their roles in hypertension, salt metabolism, and cell growth. Am J Physiol Cell Physiol (2007) 293:C509–C536.[Abstract/Free Full Text]
  10. Haddy FW, Overbeck HW. The role of humoral agents in volume expanded hypertension. Life Sci (1976) 19:935–948.[CrossRef][ISI][Medline]
  11. Blaustein MP. Sodium ions, calcium ions, blood pressure regulation and hypertension: a reassessment and a hypothesis. Am J Physiol (1977) 232:C167–C173.
  12. McGrath M, de Bold M, de Bold A. The endocrine function of the heart. Trends Endocrinol Metab (2005) 16:469–477.[CrossRef][ISI][Medline]
  13. Haddy FJ. Role of dietary salt in hypertension. Life Sci (2006) 79:1585–1592.[CrossRef][ISI][Medline]
  14. Hamlyn JM, Ringel R, Schaeffer J, et al. A circulating inhibitor of Na+ -K+-ATPase associated with essential hypertension. Nature (1982) 300:650–652.[CrossRef][ISI][Medline]
  15. Moreth K, Kuske R, Renner D, et al. Blood pressure in essential hypertension correlates with the concentration of a circulating inhibitor of the sodium pump. Klin Wochenschr (1986) 64:239–244.[CrossRef][ISI][Medline]
  16. Poston L, Sewell R, Wilkinson S, et al. Evidence for a circulating sodium transport inhibitor in essential hypertension. Brit Med J (1981) 282:847–849.[ISI][Medline]
  17. Ringer S. Regarding the influence of the organic constituents of the blood on the contractility of the ventricle. J Physiol (1885) 6:361–381.[Free Full Text]
  18. Szent-Györgyi A. Chemical Physiology of Contraction in Body and Heart Muscle (1953) New York: Academic Press. 86–91.
  19. Schoner W, Scheiner-Bobis G. Endogenous and exogenous cardiac glycosides and their mechanisms of action. Am J Cardiovasc Drugs (2007) 7:173–189.[CrossRef][ISI][Medline]
  20. Blaustein MP, Zhang J, Chen L, et al. How does salt retention raise blood pressure? Am J Physiol Regul Integr Physiol (2006) 290:514–523.
  21. Nesher M, Shpolansky U, Rosen H, et al. The digitalis-like steroid hormones: new mechanisms of action and biological significance. Life Sci (2007) 80:2093–2107.[CrossRef][ISI][Medline]
  22. Schatzmann HJ. Herzglykoside als Hemmstoffe für den aktiven Kalium- und Natriumtransport durch die Erythrocytenmembran. Helv Physiol Pharmacol Acta (1953) 11:346–354.[ISI][Medline]
  23. Hamlyn JM, Blaustein MP, Bova S, et al. Identification and characterization of a ouabain-like compound from human plasma. Proc Natl Acad Sci (1991) 88:6259–6263.[Abstract/Free Full Text]
  24. Schneider R, Wray V, Nimtz M, et al. Bovine adrenals contain, in addition to ouabain, a second inhibitor of the sodium pump. J Biol Chem (1998) 273:784–792.[Abstract/Free Full Text]
  25. Kawamura A, Guo J, Itagaki Y, et al. On the structure of endogenous ouabain. Proc Natl Acad Sci (1999) 96:6654–6659.[Abstract/Free Full Text]
  26. Goto A, Ishiguro T, Yamada K, et al. Isolation of an urinary digitalis-like factor indistinguishable from digoxin. Biochem Biophys Res Commun (1990) 173:1093–1101.[CrossRef][ISI][Medline]
  27. Bagrov AY, Fedorova OV, Dmitrieva RI, et al. Characterization of a urinary bufodienolide Na+, K+-ATPase inhibitor in patients after acute myocardial infarction. Hypertension (1998) 31:1097–1103.[Abstract/Free Full Text]
  28. Yoshika M, Komiyama Y, Konishi M, et al. Novel digitalis-like factor, marinobufotoxin, isolated from cultured Y-1 cells, and its hypertensive effect in rats. Hypertension (2007) 49:209–214.[Abstract/Free Full Text]
  29. Komiyama Y, Dong XH, Nishimura N, et al. A novel endogenous digitalis, telocinobufagin, exhibits elevated plasma levels in patients with terminal renal failure. Clin Biochem (2005) 38:36–45.[CrossRef][ISI][Medline]
  30. Lichtstein D, Gati I, Samuelov S, et al. Identification of digitalis-like compounds in human cataractous lenses. Eur J Biochem (1993) 216:261–268.[ISI][Medline]
  31. Sich B, Kirch U, Tepel M, et al. Pulse pressure correlates with a proscillaridin A immunoreactive compound. Hypertension (1996) 27:1073–1078.[Abstract/Free Full Text]
  32. D’Urso G, Frascarelli S, Balzan S, et al. Production of ouabain-like factor in normal and ischemic rat heart. J Cardiovasc Pharmacol (2004) 53:657–662.
  33. Komiyama Y, Nishimura N, Munakata M, et al. Identification of endogenous ouabain in culture supernatant of PC12 cells. J Hypertens (2001) 19:229–236.[CrossRef][ISI][Medline]
  34. Murrell JR, Randall JD, Rosoff J, et al. Endogenous ouabain. Upregulation of steroidogenic genes in hypertensive hypothalamus but not adrenal. Circulation (2005) 112:1301–1308.[CrossRef][ISI][Medline]
  35. Laredo J, Hamilton JP, Hamlyn JM. Secretion of endogenous ouabain from bovine adrenal cells. Role of zona glomerulosa and zona fasciculata. Biochem Biophys Res Commun (1995) 212:487–493.[CrossRef][ISI][Medline]
  36. Qazzaz HMAM, Cao Z, Bolanowski DD, et al. De novo biosynthesis and radiolabeling of mammalian digitalis-like factors. Clin Chem (2004) 50:612–620.[Abstract/Free Full Text]
  37. Gärtner DE, Keilholz W, Seitz H-U. Purification, characterization and partial peptide microsequencing of progesterone 5beta-reductase from shoot cultures of Digitalis purpurea. Eur J Biochem (1994) 225:1125–1132.[ISI][Medline]
  38. Charbonneau A, The V. Genomic organization of a human 5beta-reductase and its pseudogene and substrate selectivity of the expressed enzyme. Biochim Biophys Acta (2001) 1517:228–235.[Medline]
  39. Okuda A, Okuda K. Purification and characterization of D4-3-ketosteroid 5β-reductase. J Biol Chem (1984) 259:7519–7524.[Abstract/Free Full Text]
  40. Dmitrieva RI, Bagrov AY, Lalli E, et al. Mammalian bufadienolide is synthesized from cholesterol in the adrenal cortex by a pathway that is independent of cholesterol side-chain cleavage. Hypertension (2000) 36:442–448.[Abstract/Free Full Text]
  41. Huang BS, Amin MS, Leenen FHH. The central role of the brain in salt-sensitive hypertension. Curr Opin Cardiol (2006) 21:295–304.[ISI][Medline]
  42. Bagrov AY, Fedorova OV. Cardenolide and bufadienolide ligands of the sodium pump. How they work together in NaCl sensitive hypertension. Front Biosci (2005) 10:2250–2256.[Medline]
  43. Wang JG, Staessen JA, Messagio E, et al. Salt, endogenous ouabain and blood pressure interactions in the general population. J Hypertens (2003) 2003:1475–1481.
  44. Manunta P, Hamilton BP, Hamlyn JM. Salt intake and depletion increase circulating levels of endogenous ouabain in normal men. Am J Physiol Regul Integr Comp Physiol (2006) 290:R553–R559.[Abstract/Free Full Text]
  45. Laredo J, Hamilton BP, Hamlyn JM. Ouabain is secreted by bovine adrenocortical cells. Endocrinology (1994) 135:794–797.[CrossRef][ISI][Medline]
  46. Laredo J, Shah JR, Lu Z, et al. Angiotensin II stimulates secretion of endogenous ouabain from bovine adrenal cortical cells via angiotensin II receptors. Hypertension (1997) 29:401–407.[Abstract/Free Full Text]
  47. Laredo J, Shah JR, Hamilton BP, et al. Alpha-1 adrenergic receptors stimulate secretion of endogenous ouabain from human and bovine adrenocortical cells. In: Na/K-ATPase and Related ATPases—Taniguchi K, Kayas S, eds. (2000) Amsterdam: Elsevier. 671–679.
  48. Fedorova OV, Anderson DE, Bagrov AY. Plasma marinobufagenin-like and ouabain-like immunoreactivity in adrenocorticotropin-treated rats. Am J Hypertens (1998) 11:796–802.[CrossRef][ISI][Medline]
  49. Amin M, Wang H, Reza E, et al. Distribution of epithelial sodium channels and mineralocorticoid receptors in cardiovascular regulatory centers in rat brain. Am J Physiol Regul Integr Comp Physiol (2005) 289:R1787–R1797.[Abstract/Free Full Text]
  50. Fedorova OV, Zhuravin IA, Agalakova NI, et al. Intrahippocampal microinjection of an exquisitely low dose of ouabain mimics NaCl loading and stimulates a bufadienolide Na/K-ATPase inhibitor. J Hypertens (2007) 25:1834–1844.[CrossRef][ISI][Medline]
  51. Bauer N, Müller-Ehmsen J, Krämer U, et al. Ouabain-like compound changes rapidly upon physical exercise in man and dog—effects of b-blockade and ACE-inhibition. Hypertension (2005) 45:1024–1028.[Abstract/Free Full Text]
  52. De Angelis C, Haupert GT Jr. Hypoxia triggers release of an endogenous inhibitor of Na+-K+-ATPase from midbrain and adrenal. Am J Physiol (1998) 274:F182–F188.[ISI][Medline]
  53. Fedorova OV, Anderson DE, Lakatta EG, et al. Interaction of NaCl and behavioral stress on endogenous sodium pump ligands in rats. Am J Physiol Regul Integr Comp Physiol (2001) 281:R352–R358.[Abstract/Free Full Text]
  54. Weidemann H, Salomon N, Avnit-Sagi T, et al. Diverse effects of stress and additional adrenocorticotropic hormone on digitalis-like compounds in normal and nude mice. J Neuroendocrinol (2004) 16:1–6.[CrossRef][ISI][Medline]
  55. Hamlyn JM, Lu Z, Manunta P, et al. Observations on the nature, biosynthesis, secretion and significance of endogenous ouabain. Clin Exp Hypertens (1998) 20:523–533.[ISI][Medline]
  56. Komiyama Y, Nishimura N, Munakata M, et al. Increases in plasma ouabainlike immunoreactivity during surgical extirpation of pheochromocytoma. Hypertens Res (1999) 22:135–139.[ISI][Medline]
  57. Manunta P, Evans G, Hamilton BP, et al. A new syndrome with elevated plasma ouabain and hypertension secondary to an adrenocortical tumor. J Hypertens (1992) 10:S27.[CrossRef]
  58. Crabos M, Ausiello D, Haupert G Jr, et al. Atrial natriuretic peptide regulates release of Na+-K+-ATPase inhibitor from rat brain. Am J Physiol (1988) 254:F912–F917.[ISI][Medline]
  59. Kennedy DJ, Vetteth S, Periyasamy SM, et al. Central role for the cardiotonic steroid marinobufagenin in the pathogenesis of experimental uremic cardiomyopathy. Hypertension (2006) 47:488–495.[Abstract/Free Full Text]
  60. Fedorova OV, Lakatta EG, Bagrov AY. Endogenous Na,K pump ligands are differentially regulated during acute NaCl loading of DAHL rats. Circulation (2000) 102:3009–3014.[ISI][Medline]
  61. Kennedy D, Malhotra D, Shapiro J. Molecular insights into uremic cardiomyopathy: cardiotonic steroids and Na/K ATPase signaling. Cell Mol Biol (Noisy-le-grand) (2006) 52:3–14.
  62. Elkareh J, Kennedy DJ, Yashaswi B, et al. Marinobufagenin stimulates fibroblast collagen production and causes fibrosis in experimental uremic cardiomyopathy. Hypertension (2007) 49:215–224.[Abstract/Free Full Text]
  63. Dostanic I, Paul RJ, Lorenz JN, et al. The a2-isoform of Na-K-ATPase mediates ouabain-induced hypertension in mice and increased vascular contractility in vitro. Am J Physiol Heart Circ Physiol (2005) 288:H477–H485.[Abstract/Free Full Text]
  64. Blanco G, Mercer RW. Isozymes of the Na-K-ATPase: heterogeneity in structure, diversity in function. Am J Physiol (1998) 275:F633–F650.[ISI][Medline]
  65. Müller-Ehmsen J, Juvvadi P, Thompson CB, et al. Ouabain and substrate affinities of human Na+-K+-ATPase a1b1, a2b1, and a3b1 when expressed separately in yeast cells. Am J Physiol Cell Physiol (2001) 281:C1355–C1364.[Abstract/Free Full Text]
  66. Crambert G, Schaer D, Roy S, et al. New molecular determinants controlling the accessibility of ouabain to its binding site in human Na,K-ATPase a isoforms. Mol Pharmacol (2004) 65:335–341.[Abstract/Free Full Text]
  67. Dostanic-Larson I, Lorenz JN, Van Huysse JW, et al. Physiological role of the a1- and a2-isoforms of the Na+-K+-ATPase and biological significance of their cardiac glycoside binding site. Am J Physiol Regul Integr Comp Physiol (2006) 290:R524–R528.[Abstract/Free Full Text]
  68. Dostanic-Larson I, Van Huysse JW, Lorenz JN, et al. The highly conserved cardiac glycoside binding site of Na, K-ATPase plays a role in blood pressure regulation. PNAS (2005) 102:15845–15850.[Abstract/Free Full Text]
  69. Xie Z, Askari A. Na+/K+-ATPase as a signal inducer. Eur J Biochem (2002) 269:2434–2439.[ISI][Medline]
  70. Fedorova OV, Kolodkin NI, Agalakova NI, et al. Marinobufagenin, an endogenous a-1 sodium pump ligand, in hypertensive Dahl salt-sensitive rats. Hypertension (2001) 37:462–466.[Abstract/Free Full Text]
  71. Kennedy DJ, Vetteth S, Xie M, et al. Ouabain decreases sarcoplasmic reticulum calcium ATPase (SERCA2a) activity in rat hearts by a process involving protein oxidation. Am J Physiol Heart Circ Physiol (2006) 291:H3003–H3011.[Abstract/Free Full Text]
  72. Rossi GP, Manunta P, Hamlyn JM, et al. Immunoreactive endogenous ouabain in primary hyperaldosteronism and essential hypertension: relationship with plasma renin, aldosterone and blood pressure levels. J Hypertens (1995) 13:1181–1191.[CrossRef][ISI][Medline]
  73. Crabos M, Grichois M, Guicheney P, et al. Further biochemical characterization of an Na+ pump inhibitor purified from human urine. Eur J Biochem (1987) 162:129–135.[ISI][Medline]
  74. Manunta P, Iacoviello M, Forleo C, et al. High circulating levels of endogenous ouabain in the offspring of hypertensive and normotensive individuals. J Hypertens (2005) 23:1677–1681.[ISI][Medline]
  75. Pitzalis MV, Hamlyn JM, Messaggio E, et al. Independent and incremental prognostic value of endogenous ouabain in idiopathic dilated cardiomyopathy. Eur J Heart Fail (2006) 8:179–186.[CrossRef][ISI][Medline]
  76. Kaide JI, Ura N, Torii T, et al. Effect of digoxin-specific antibody fab fragment (Digibind) on blood pressure and renal water. Sodium metabolism in 5/6 reduced renal mass hypertensive rats. Am J Hypertens (1999) 12:611–619.[CrossRef][ISI][Medline]
  77. Pullen MA, Brooks DP, Edwards RM. Characterization of the neutralizing activity of digoxin-specific fab toward ouabain-like steroids. J Pharmacol Exp Ther (2004) 310:319–325.[Abstract/Free Full Text]
  78. Averina I, Tapilskaya N, Reznik V, et al. Endogenous Na/K-ATPase inhibitors in patients with preeclampsia. Cell Mol Biol (Noisy-le-grand) (2006) 52:19–23.
  79. Menezes JC, Dichtchekenian V. Digoxin antibody prevents cerebral hemorrhage-induced hypertension. Am J Hypertens (2003) 16:1062–1065.[CrossRef][ISI][Medline]
  80. Huang BS, Harmsen E, Yu H, et al. Brain ouabain-like activity and the sympathoexcitatory and pressor effects of central sodium in rats. Circ Res (1992) 71:1059–1066.[Abstract/Free Full Text]
  81. Fedorova OV, Doris PA, Bagrov AY. Endogenous marinobufagenin-like factor in acute volume expansion. Clin Exp Hypertens (1998) 20:581–591.[ISI][Medline]
  82. Bagrov AY, Feodorova OV, Dmitrieva RI, et al. Plasma marinobufagenin-like and ouabain-like immunoreactivity during saline volume expansion in anaesthetized dogs. Cardiovasc Res (1996) 31:296–305.[Abstract/Free Full Text]
  83. Vu H, Ianosi-Irimie M, Pridjian C, et al. Involvement of marinobufagenin in a rat model of human preeclampsia. Am J Nephrol (2005) 25:520–528.[CrossRef][ISI][Medline]
  84. Kennedy DJ, Omran E, Periyasamy SM, et al. Effect of chronic renal failure on cardiac contractile function, calcium cycling, and gene expression of proteins important for calcium homeostasis in the rat. J Am Soc Nephrol (2003) 14:90–97.[Abstract/Free Full Text]
  85. Fedorova OV, Talan MI, Agalakova NI, et al. Endogenous ligand of a sodium pump, marinobufagenin, is a novel mediator of sodium chloride dependent hypertension. Circulation (2002) 105:1122–1127.[CrossRef][ISI][Medline]
  86. Fedorova OV, Kolodkin NI, Agalakova NI, et al. Antibody to marinobufagenin lowers blood pressure in pregnant rats on a high NaCl intake. J Hypertens (2005) 23:835–842.[ISI][Medline]
  87. Periyasamy SM, Liu J, Tanta F, et al. Salt loading includes redistribution of the plasmalemmal Na/K-ATPase in proximal tubule cells. Kidney Int (2005) 67:1868–1877.[CrossRef][ISI][Medline]
  88. Liu J, Shapiro JI. Regulation of sodium pump endocytosis by cardiotonic steroids: molecular mechanisms and physiological implications. Pathophysiology (2007) 14:171–181.[CrossRef][Medline]
  89. Fedorova OV, Agalakova NI, Morrell CH, et al. ANP differentially modulates marinobufagenin-induced sodium pump inhibition in kidney and aorta. Hypertension (2006) 48:1160–1168.[Abstract/Free Full Text]
  90. Thomas W, McEneaney V, Harvey B. Aldosterone-induced signalling and cation transport in the distal nephron. Steroids (2008) 73:979–984.[CrossRef][Medline]
  91. Mick V, Itani O, Loftus R, et al. The alpha-subunit of the epithelial sodium channel is an aldosterone-induced transcript in mammalian collecting ducts, and this transcriptional response is mediated via distinct cis-elements in the 5'-flanking region of the gene. Mol Endocrinol (2001) 15:575–588.[Abstract/Free Full Text]
  92. Kolla V, Litwack G. Transcriptional regulation of the human Na/K ATPase via the human mineralocorticoid receptor. Mol Cell Biochem (2000) 204:35–40.[CrossRef][ISI][Medline]
  93. Smith C, He Q, Huang L, et al. Marinobufagenin interferes with the function of the mineralocorticoid receptor. Biochem Biophys Res Commun (2007) 356:930–934.[CrossRef][ISI][Medline]
  94. Gheorghiade M, Ferguson D. Digoxin: a neurohormone modulator in heart failure? Circulation (1991) 84:2181–2186.[ISI][Medline]
  95. Huang BS, Kudlac M, Kumarathasan R, et al. Digoxin prevents ouabain and high salt intake-induced hypertension in rats with sinoaortic denervation. Hypertension (1999) 34:733–738.[Abstract/Free Full Text]
  96. Kennedy D, Elkareh J, Shidyak A, et al. Partial nephrectomy as a model for uremic cardiomyopathy in the mouse. Am J Physiol Renal Physiol (2008) 294:F450–F454.[Abstract/Free Full Text]
  97. Gottlieb SS, Rogowski AC, Weinberg M, et al. Elevated concentrations of endogenous ouabain in patients with congestive heart failure. Circulation (1992) 86:420–425.[Medline]
  98. Manunta P, Hamilton J, Rogowski AC, et al. Chronic hypertension induced by ouabain but not digoxin in the rat: antihypertensive effect of digoxin and digitoxin. Hypertens Res (2000) 23:S77–S85.[CrossRef][ISI][Medline]
Received for publication: 11. 1.08
Accepted in revised form: 20. 5.08


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