Subscribe to RSS
DOI: 10.1055/s-2000-8140
© Johann Ambrosius Barth
Ouabain, a new steroid hormone of adrenal gland and hypothalamus
Publication History
Submitted March 23, 2000
Accepted June 9, 2000
Publication Date:
31 December 2000 (online)
![](https://www.thieme-connect.de/media/eced/200007/lookinside/thumbnails/10.1055-s-2000-8140-1.jpg)
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