Summary:
Ouabain has been isolated and identified as a constituent of human blood, bovine adrenal glands and hypothalamus. This water soluble inhibitor of the sodium pump (Na+/K+-ATPase) circulates in elevated concentrations in blood plasma of 50% of Caucasians with elevated blood pressure. It is released from adrenal cortical cells in tissue culture by angiotensin II. A ouabain antagonist, PST2238, lowers blood pressure in hypertensive rats. Hence, ouabain is most probably a new steroid hormone formed in adrenal glands and hypothalamus. Consistent therewith is the demonstration of a specific binding globulin for cardiac glycosides in blood plasma.
Key words:
Ouabain - endogenous digitalis - sodium pump - hypertension - cardiotonic steroids
References
-
1
Adair C D, Buckalew V, Taylor K, Ernest J M, Frye A H, Veille J C.
Elevated endoxin-like factor complicating a multifetal second trimester pregnancy: Treatment with digoxin-binding immunoglobulin.
Am J Nephrol.
16
529-531
1996;
-
2
Antolovic R, Bauer N, Mohadjerani M, Kost H, Neu H, Kirch U, Grünbaum E-G, Schoner W.
Endogenous ouabain and its binding globulin: Effect of physical exercise and study on its tissue distribution.
Hypertens Res.
23-S
2000 in press;
-
3
Antolovic R, Kost H, Mohadjerani M, Linder D, Linder M, Schoner W.
A specific binding protein for cardiac glycosides exists in bovine serum.
J Biol Chem.
273
16259-16264
1998;
-
4
Blaustein M P.
Physiological effects of endogenous ouabain: Control of intracellular Ca2+ stores and cell responsiveness.
Am J Physiol.
264
C1367-C1387
1993;
-
5
Bossuyt X, Müller M, Hagenbuch M, Meier P J.
Polyspecific druc and steroid clearance by an organic anion transporter of mammalian liver.
J Pharmacol Exptl Therapeut.
276
891-896
1996;
-
6
Boulanger B R, Lilly M P, Hamlyn J M, Laredo J, Shurtleff D, Gann D S.
Ouabain is secreted by the adrenal gland of the awake dogs.
Am J Physiol.
264
E413-E419
1993;
-
7
Budzikowski A S, Huang B S, Leenen F HH.
Brain “ouabain”, a neurosteroid mediates sympathetic hyperactivity in salt-sensitive hypertension.
Clin and Exper Hypertension.
20
119-140
1998;
-
8
Casari G, Barlassina C, Cusi D, Zagato I, Muirhead R, Righetti M, Nembri P, Amar K, Gati M, Macciacardi F, Binelli G, Bianchi G.
Association of the alpha-adducin locus with essential hypertension.
Hypertension.
25
320-326
1995;
-
9
Cusi D, Barlassina C, Azzani T, Casari G, Citterio L, Devoto M, Glorioso N, Lanzani C, Manunta P, Righetti M, Rivera R, Stella P, Troffa C, Zagato L, Bianchi G.
Polymorphism of α-adducin and salz-sensitivity in patients with essential hypertension.
Lancet.
349
1353-1357
1997;
-
10
De Angelis C, Haupert G T.
Hypoxia triggers release of an endogenous inhibitor of Na+-K+-ATPase from midbrain and adrenal.
Am J Physiol.
274
F182-F188
1998;
-
11
Doris P A, Hayward-Lester A, Bourne D, Stocco D M.
Ouabain production by cultured adrenal cells.
Endocrinol.
137
533-539
1996;
-
12
Ferrari P, Ferrandi M, Tripoldi G, Torielli L, Padoani G, Minotti E, Melloni E, Bianchi G.
PST 2238: A new antihypertensive compound that modulates Na,K-ATPase in genetic hypertension.
J Pharmacol Exptl Therapeut.
288
1074-1083
1999;
-
13
Ferrari P, Torielli L, Ferrandi M, Padoani G, Duzzi L, Florio M, Conti F, Melloni L, Vesci L, Corsico N, Bianchi G.
PST 2238: A new antihypertensive compound that antagonizes the long term pressor effect of ouabain.
J Pharmacol Exptl Therapeut.
285
83-94
1998;
-
14
Goodlin R C.
Antidigoxin antibodies in eclampsia.
New Engl J Med.
318
518-519
1988;
-
15
Goto A, Yamada K.
Ouabain-like factor.
Curr Opinion Nephrol Hypertens.
7
189-196
1998;
-
16
Goto A, Yamada K, Yaggi N, Yoshioka M, Sugimoto T.
Physiology and pharmacology of endogenous digitalis-like factors.
Pharmcol Rev.
44
377-399
1992;
-
17
Gottlieb S S, Rogowski A C, Weinberg M, Krichten C M, Hamilton B C, Hamlyn J M.
Elevated concentrations of endogenous ouabain in patients with congestive heart failure.
Circulation.
86
420-425
1992;
-
18 Greef K, Wirth K E. Pharmakokinetics of strophanthin glycosides. In: Greef K (ed.) Handbook of Experimental Pharmacology Springer Verlag. Berlin, Heidelberg, New York 56/II: 57-85 1981
-
19 Hamlyn J M. Discovery of endogenous ouabain - A new mammalian hormone. In: Bamberg E, Schoner W (eds.). The Sodium Pump Springer Verlag, New York 722-731 1994a
-
20
Hamlyn J M, Hamilton B P, Manunta P.
Endogenous ouabain, sodium balance and blood pressure: A review and a hypothesis.
J Hypertens.
14
151-167
1994b;
-
21
Hamlyn J M, Blaustein M P, Bova S, DuCharme D W, Mandel F, Mathews W R, Ludens J H.
Identification and characterization of a ouabain-like compound from human plasma.
Proc Natl Acad Sci US.
88
6259-6263
1991;
-
22
Hamlyn J M, Hamilton B P, Manunta P .
Endogenous ouabain, sodium balance and blood pressure: a review and a hypothesis.
J Hypertens.
14
151-167
1996;
-
23
Hamlyn J M, Lu Z, Manunta P, Ludens J H, Kimura K, Shah J R, Laredo J, Hamilton J P, Hamilton M J, Hamilton B P.
Observations on the nature, biosynthesis, secretion and significance of endogenous ouabain.
Clin & Exptl Hypertens.
20
523-533
1998;
-
25 Hamlyn J M, Manunta P, Hamilton B P. Endogenous ouabain in the pathogenesis of hypertensive and cardiovascular disorders. In: Laragh JH, Brenner BM (eds.). Hypertension: Pathophysiology, Diagnosis and Management. Raven Press, New York 1069-1081 1995
-
26
Hamlyn J M, Ringel R, Schaeffer J, Levinson P D, Hamilton B P, Kowarski A A, Blaustein M P.
A circulating inhibitor of (Na + K)-ATPase associated with essential hypertension.
Nature.
300
650-652
1982;
-
27
Hammond G L.
Molecular properties of corticosteroid-binding globulin and sex hormone binding proteins.
Endocr Rev.
11
65-79
1990;
-
28
Huang B S, Kudlac M, Kumarathasan R, Leenen F H.
Digoxin prevents ouabain and high salt intake-induced hypertension in rats with sinoaortic denervation.
Hypertension.
34
733-738
1999;
-
29
Hulthen U L, Bolli P, Kiowski W, Bühler F R.
Fore-arm vasoconstrictor response to ouabain: Studies in patients with mild and moderate essential hypertension.
J Cardiovasc Pharmacol.
6
75-81
1984;
-
30
Kaide J I, Ura N, Torii T, Nagakawa M, Takada T, Shimamoto K.
Effect of digoxin-specitic antibody Fab fragment (Digibind) on blood pressure and renal water. Sodium metabolism in 5/6 reduced renal mass hypertensive rats.
Am J Hypertens.
12
611-619
1999;
-
31
Kawamura A, Guo J, Itagaki Y, Bell C, Wang Y, Haupert J, Garner T, Magil S, Gallagher R T, Berova N, Nakanishi K.
On the structure of endogenous ouabain.
Proc Natl Acad Sci USA.
96
6654-6659
1999;
-
32
Kitano S, Morimoto S, Nishibe A, Fukuo K, Hirotani A, Nakahashi T, Ysuda O, Ogihara T.
Exogenous ouabain is accumulated in the adrenals and mimics the kinetics of endogenous digitalis-like factor in rats.
Hypertens Res.
21
47-56
1998;
-
33
Kometiani P, Li J, Gnudi L, Kahn B, Askari A, Xie Z.
Multiple signal transduction pathways link Na+/K+-ATPase to growth-related genes in cardiac myocytes. The roles of Ras and mitogen-activated protein kinases.
J Biol Chem.
273
15249-15256
1998;
-
34
Komiyama Y, Nishimura N, Munakata M, Okuda K, Nishino N, Kosaka C, Masuda M, Mori T, Matsuda T, Takahashi H.
Increases in plasma ouabainlike immunoreactivity during surgical extirpation of pheochromocytoma.
Hypertension Res.
22
135-139
1999;
-
35 Krieglstein J. Plasma protein binding of cardiac glycosides. In: Greef K (ed.). Handbook of Experimental Pharmacology. Springer Verlag. Berlin, Heidelberg, New York 8: 95-104 1981
-
36
Laredo J, Hamilton B P, Hamlyn J M.
Ouabain is secreted by bovine adrenocortical cells.
Endocrinol.
135
794-797
1994;
-
37
Laredo J, Hamilton J P, Hamlyn J M.
Secretion of endogenous ouabain from bovine adrenal cells. Role of zona glomerulosa and zona fasciculata.
Biochem Biophys Res Commun.
212
487-493
1995;
-
38
Laredo J, Shah J R, Lu Z, Hamilton B P, Hamlyn J M.
Angiotensin II stimulates secretion of endogenous ouabain from bovine adrenal cortical cells via angiotensin II receptors.
Hypertension.
29
401-107
1997;
-
39
Li S-Q, Eim C, Kirch U, Lang R E, Schoner W.
Bovine adrenals and hypothalamus are a major source of proscillaridin A- and ouabain-immunoreactivities.
Life Sci.
62
1023-1033
1998;
-
40
Lichtstein D, Steinitz M, Gati I, Samuelov S, Deutsch J, Orly J.
Biosynthesis of digitalis-compound in rat adrenal cells: hydroxycholesterol as a precursor.
Life Sci.
62
2109-2126
1998;
-
41
Ludens J H, Clark M A, Robinson G F, DuCharme D W.
Rat adrenal cortex is a source of a circulating ouabainlike compound.
Hypertension.
19
721-724
1992;
-
42
Mann J FE, Miemitz R, Ganten U, Ritz E.
Hemodynamic effects of intact digoxin antibodies and its Fab fragments in experimental hypertension.
J Hypertens.
5
543-549
1987;
-
43
Manunta P, Evans G, Hamilton B P, Gann D, Resau J, Hamlyn J M.
A new syndrome with elevated plasma ouabain and hypertension secondary to an adrenocortical tumor.
J Hypertens
10
((Supp. 4))
S27
1992;
-
44
Manunta P, Rogowski A C, Hamilton B C, Hamlyn J M.
Chronic hypertension induced by ouabain but not digoxin in the rat: Antihypertensive effect of digoxin. International Symposium on Natriuretic and Digitalis-like Factors, Chitose, Hokkaido Japan.
13
1999;
-
45
Manunta P, Rogowski A C, Hamilton B P, Hamlyn J M.
Ouabain-induced hypertension in the rat: Relationships among plasma and tissue ouabain and blood pressure.
J Hypertens.
12
549-560
1994;
-
46
Masugi F, Ogihara T, Hasegawa T, Sagakuchi K, Kumahara Y.
Normalization of high plasma level of ouabain-like immunoreactivity in primary aldosteronism after removal of adenoma.
J Hum Hypertens.
2
17-20
1988;
-
47
Mathews W R, DuCharme D W, Hamlyn J M, Harris D W, Mandel F, Clark M A, Ludens J A.
Mass spectral characterization of an endogenous digitalislike factor from human plasma.
Hypertension.
17
930-935
1991;
-
48
Nishibe A.
Exogenous ouabain in plasma and organs in spontaneously hypertensive rats.
Therapeutic Research.
16
63-66
1995;
-
49
Nishibe A.
Accumulation of exogenous ouabain in spontaneously hypertensive rats.
Therap Res.
17
134-137
1996;
-
50
Pamnani M B, Chen S, Yuan C M, Haddy F J.
Chronic blood pressure effects of bufalin, a sodium-potassium ATPase inhibitor in rats.
Hypertension
23
((Suppl. 1))
I106-I109
1994;
-
51
Peng M, Huang L, Xie Z, Huang W-H, Askari A.
Partial inhibition of Na+/K+-ATPase by ouabain induces the Ca2+-dependent expression of early response genes in cardiac myocytes.
J Biol Chem.
271
10372-10378
1996;
-
52
Perrin A, Brasmes B, Chambaz E M, Defaye G.
Bovine adrenocortical cells in culture synthesize an ouabain-like compound.
Molec Cell Endocrinol.
126
7-15
1997;
-
53 Rap Z M, Schoner W, Czerniki Z, Hildebrandt G, Mueller W, Hoffmann O. Changes in the endogenous ouabain-like substance in the brain and cerebrospinal fluid after cold-induced vasogenic brain edema. In: Bamberg E, Schoner W (eds.). The Sodium Pump Springer Verlag. New York 779-782 1994
-
54
Rodrígues-Barbero A, Martínez-Salgado C, Rodríguez-López A M, Ricote A M, Sancho J, López-Nova J M.
Effect of hypothalamic-hypophysary inhibitory factor on mesangial cell activation.
Hypertension.
26
905-911
1995;
-
55
Rosner W.
The function of corticosteroid-binding globulin and sex hormone binding: recent advances.
Endocr Rev.
11
80-91
1990;
-
56
Rosner W J, Hryb D J, Khan M S, Nakhla A M, Romas N A.
Sex hormone-binding globulin mediates steroid hormone signal transduction at the plasma membrane.
J Steroid Biochem Mol Biol.
69
481-485
1999;
-
57
Schneider R, Wray V, Nimtz M, Lehmann W-D, Kirch U, Antolovic R, Schoner W.
Bovine adrenals contain, in addition to ouabain, a second inhibitor of the sodium pump.
J Biol Chem.
273
784-792
1988;
-
58 Schoner W. Endogenous Cardiotonic Steroids: Facts and Open Questions. In: Taniguchi K (ed.). Na/K Pump and Related Pumps. Elsevier. Amsterdam 2000, in press
-
59 Szent-Györgyi A. Chemical physiology of contraction in body and heart muscle. Academic Press, New York 86-91 1953
-
60
Vasallo P F, Stefanon I, Rossoni L V, Franca A, Vasallo D V.
Small doses of canrenone block the effects of ouabain on the mechaniscal activity of the heart and vessels of the rat.
J Cardiovasc Pharmacol.
32
679-685
1998;
-
61
Westphal U.
Bindung von Progesteron und anderen Steroidhormonen an Proteine des Blutserums.
Hoppe-Seyler's Z Physiol Chem.
359
431-447
1978;
-
62 Withering W. An account on the foxglove, and some of its medical uses with practical remark on dropsy and other diseases. GGJ and J Robinson, London 1785
-
63
Woodcock G B, Rietbrock N.
Digitalis-quinidin interactions.
Trends Pharmacol Sci.
3
118-122
1982;
Prof. Dr. Wilhelm Schoner
Institut für Biochemie und Endokrinologie
Fachbereich Veterinärmedizin
Justus-Liebig-Universität Giessen
Frankfurter Str. 100
D-35392 Giessen
Phone: +49641-99 38 170
Fax: +49641-99 38 179
Email: wilhelm.schoner@vetmed.uni-giessen.de