„Endogenes Digitalis” – der lange Weg vom herzwirksamen pflanzlichen Toxin zum Hormon der Säuger

Zusammenfassung

Endogene Herzglykoside wurden kürzlich aus Blut, Urin, Nebennieren und Hypothalamus von Säugetieren isoliert und in ihrer Struktur aufgeklärt. Zu den endogenen Herzglykosiden zählen so gut bekannte Hemmstoffe der Natriumpumpe wie Ouabain (g-Strophanthin), Digoxin und Marinobufagenin. Endogenes Ouabain und Digoxin werden in der Nebennierenrinde der Säuger aus Progesteron und Pregnenolon synthetisiert. Ouabain wird bei Kreislaufbelastung rasch freigesetzt, seine Konzentration fällt bei Ruhe innerhalb weniger Minuten wieder ab. ACEInhibitoren und β-Blocker verhindern bei Hunden diesen Anstieg. Ouabain wird durch ACTH, Adrenalin und Angiotensin II aus Nebennierenrindenzellen in Kultur freigesetzt. Nanomolare Ouabain-Konzentrationen stimulieren die Proliferation von glatten Muskelzellen. An schwerer dilatativer Kardiomyopathie erkrankte Hunde haben im Vergleich zu gesunden Hunden signifikant erniedrigte Ouabain-Blutwerte. Beim Menschen und Ratten führt eine lang dauernde zu hohe NaCl-Zufuhr über die Nahrung zum Konzentrationsanstieg von endogenem Ouabain im Blut und zum Bluthochdruck. Eine über lange Zeit durchgeführte Infusion von Ouabain, aber nicht von Digoxin, erzeugt bei Ratten Bluthochdruck. Digoxin senkt den Ouabain-induzierten Bluthochdruck. Da bei ca. 50% der Hochdruckpatienten erhöhte Ouabain-Werte vorliegen, ist es von großer medizinischer Bedeutung, dass mit dem Ouabain-Antagonisten Rostafuroxin ein neues Prinzip und eine neue Gruppe von Blutdrucksenkern gefunden wurde. Marinobufagenin, dessen Konzentration bei Herzinfarkt akut ansteigt, hat auf die Niere eine natriuretische Wirkung. Im Gehirn wird Ouabain im Hypothalamus synthetisiert und bei einer erhöhten intrazellulären Natriumkonzentration freigesetzt.

Summary

Endogenous cardiac glycosides were recently identified in blood, urine, adrenal glands and hypothalamus of mammals. Such endogenous cardiac glycosides are ouabain, digoxin and marinobufagenin, all well known inhibitors of the sodium pump. The compounds are synthesized in the adrenal cortex from progesterone and pregnenolone as precursors. Physical exercise leads to a rapid increase of ouabain and it declines within minutes upon rest. However, treatment with ACE-inhibitors and β-blockers abolishes this rise. Adrenal cortical cells release ouabain rapidly upon treatment with ACTH, angiotensin II and epinephrine. Nanomolar concentrations of ouabain stimulate the proliferation of smooth muscle cells and the release of endothelin 1 from endothelial cells. Dogs suffering from dilatative cardiomyopathy have reduced plasma concentrations of endogenous ouabain as compared to healthy dogs. Increased dietary exposition of humans and rats to NaCl results in a parallel increase of endogenous ouabain and arterial blood pressure. Long-term infusion of rats with nanomomolar concentrations of ouabain– but not digoxin– results in the development of arterial hypertension. However, digoxin lowers ouabain-induced hypertension. About 50% of the European population suffering from arterial hypertension show elevated concentrations of endogenous ouabain in blood plasma. Hence it is of considerable importance that rostafuroxin– an ouabain antagonist – effectively lowers blood pressure. Marinobufagenin which rises in blood plasma of human patients with cardiac infarction induces natriuresis. Ouabain is synthesized in the hypothalamus as well. It is released quite certainly in some areas of the brain upon intracellular rise of sodium.

Schlüsselwörter

endogenes Digitalis - endogenes Ouabain - endogenes Marinobufagenin - Kardiomyopathie - arterieller Bluthochdruck - Ouabain-Antagonist Rostafuroxin

Key words

Endogenous digitalis - endogenous ouabain - endogenous marinobufagenin - cardiomyopathy - arterial hypertension - ouabain antagonist rostafuroxin

• Literatur

• 1 Abramowitz J, Dai C, Hirschi KK, Dmitrieva RI, Doris PA, Liu L, Allen JC. Ouabain- and marinobufagenin-induced proliferation of human umbilical vein smooth muscle cells and rat vascular smooth muscle cell line, A7r5. Circulation 2003; 108: 3048-53.
• 2 Adair CD, Buckalew V, Taylor K, Ernest JM, Frye AH, Veille JC. Elevated endoxin-like factor complicating a multifetal second trimester pregnancy: Treatment with digoxin-binding immunoglobulin. Am J Nephrol 1996; 16: 529-31.
• 3 Aizman O, Uhlén P, Lal M, Brismar H, Aperia A. Ouabain, a steroid hormone that signals with slow calcium oscillations. Proc Natl Acad Sci (USA) 2001; 98: 13420-4.
• 4 Aydemir-Koksoy A, Abramowitz J, Allen J. Ouabain-induced signaling and vascular smooth muscle cell proliferation. J Biol Chem 2001; 276: 46605-11.
• 5 Bagrov AY, Fedorova OV, Maslova MN, Roukoyatkina NI, Ukhanova MA, Zhabko EP. Endogenous plasma Na, K-ATPase inhibitory activity and digoxin-like immunoreactivity after acute myocardial infarction. Cardiovasc Res 1991; 25: 371-7.
• 6 Bagrov AY, Feodorova OV, Dmitrieva RI, French AW, Anderson DE. Plasma marinobufagenin-like and ouabain-like immunoreactivity during saline volume expansion in anaesthetized dogs. Cardiovasc Res 1996; 31: 296-305.
• 7 Bagrov AY, Fedorova OV, Dmitrieva RI, Howald WN, Hunter AP, Kuznetsova EA, Shpen VM. Characterization of a urinary bufodienolide Na+, K+-ATPase inhibitor in patients after acute myocardial infarction. Hypertension 1998; 31: 1097-103.
• 8 Bauer N, Müller-Ehmsen J, Krämer U, Hambarchian N, Zobel C, Schwinger RHG, Neu H, Kirch U, Grünbaum E-G, Schoner W. Ouabain-like compound changes rapidly upon physical exercise in man and dog– Effects of β-blockade and ACE-inhibition. Hypertension 2005; 45: 1024-8.
• 9 Bauer N, Schneider M, Neu H, Kirch U, Grünbaum E-G, Schoner W. “Endogenes Digitalis” bei gesunden und an dilatativer Kardiomyopathie oder Vorhofflimmern erkrankten Hunden. Tierärztl Prax 2004; 32 K 201-6.
• 10 Bers DM. Cardiac excitation-contraction coupling. Nature 2002; 415: 198-205.
• 11 Blaustein MP, Zhang J, Chen L, Hamilton BC. How does salt retention raise blood pressure?. Am J Physiol Regul Integr Physiol 2006; 290: 514-23.
• 12 Böhm M. Einleitung und Nosologie der Herzinsuffizienz. In: Herzinsuffizienz: Ursachen, Pathophysiologie und Therapie. Erdmann E. Hrsg Stuttgart: Wissenschaftliche Verlagsgesellschaft; 2000: 3-9.
• 13 Buckalew VM, Haddy FJ. Circulating natriuretic factors in hypertension. In: Hypertension: Pathophysiology, Diagnosis and Management. Laragh JH, Brenner EM. eds New York: Raven Press; 1990: 939-54.
• 14 Daniel D, Süsal C, Kopp B, Opelz G, Terness P. Apoptosis-mediated selective killing of malignant cells by cardiac steroids: maintenance of cytotoxixity and loss of cardiac activity of chemically modified derivatives. Int Immunopharmacol 2003; 03: 1791-801.
• 15 De Wardener HE. Kidney, salt intake and Na+, K+-ATPase inhibitors in hypertension: 1990 Cocoran lecture. Hypertension 1991; 17: 830-6.
• 16 Dostanic I, Paul RJ, Lorenz JN, Theriault S, Van Huysse JW, Lingrel JB. The α₂-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.
• 17 Dostanic-Larson I, Lorenz JN, Van Huysse JW, Neumann JC, Moseley AE, Lingrel JB. Physiological role of the α1– and α2-isoforms of the Na+-K+-AT-Pase and biological significance of their cardiac glycoside binding site. Am J Physiol Regul Integr Comp Physiol 2006; 290: R524-R528.
• 18 Erdmann E. Herzinsuffizienz, Ursachen. Pathophysiologie und Therapie, 2. Aufl. Stuttgart: Wissenschaftliche Verlagsgesellschaft; 2000
• 19 Erdmann E. Digitalis. In: Herzinsuffizienz: Ursachen, Pathophysiologie und Therapie, 2. Aufl. Erdmann E. Hrsg Stuttgart: Wissenschaftliche Verlagsgesellschaft; 2000: 205-17.
• 20 Fedorova OV, Bagrov AY. Inhibition of Na/K-ATPase from rat aorta by two endogenous Na/K pump inhibitors, ouabain and marinobufagenin. Evidence of interaction with different α-subunit isoforms. Am J Hypertens 1997; 10: 929-35.
• 21 Fedorova OV, Kolodkin NI, Agalakova NI, Lakatta EG, Bagrov AY. Marinobufagenin, an endogenous α-1 sodium pump ligand, in hypertensive Dahl salt-sensitive rats. Hypertension 2001; 37: 462-6.
• 22 Fedorova OV, Lakatta EG, Bagrov AY. Endogenous Na, K pump ligands are differentially regulated during acute NaCl loading of DAHL rats. Circulation 2000; 102: 3009-14.
• 23 Ferrari P, Ferrandi M, Valentini G, Bianchi G. 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.
• 24 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 Therap 1999; 288: 1074-83.
• 25 Ferrari P, Torielli L, Ferrandi M, Padoani G, Duzzi L, Florio M, Conti F, Melloni L, Vesci L, Corsico N. et al. PST 2238: A new antihypertensive compound that antagonizes the long term pressor effect of ouabain. J Pharmacol Exptl Therap 1998; 285: 83-94.
• 26 Fridman AI, Matveev SA, Agalakova NA, Fedorova OV, Lakatta EG, Bagrov AY. Marinobufagenin, an endogenous ligand of alpha-1 sodium pump, is a marker of congestive heart failure severity. J Hypertens 2002; 20: 1-6.
• 27 Garg R, Gorlin R, Smith T. The effect of digoxin mortality and morbidity in patients with heart failure. New Engl J Med 1997; 336: 525-33.
• 28 Gheorghiade M, Ferguson D. Digoxin: A neurohormone modulator in heart failure?. Circulation 1991; 84: 2181-6.
• 29 Goodlin RC. Antidigoxin antibodies in eclampsia. New Engl J Med 1988; 318: 518-9.
• 30 Goto A, Ishiguro T, Yamada K, Ishii M, Yoshioka M, Eguchi C, Shimura M, Sugimoto T. Isolation of an urinary digitalis-like factor indistinguishable from digoxin. Biochem Biophys Res Commun 1990; 173: 1093-101.
• 31 Goto A, Yamada K. Ouabain-like factor. Curr Opin Nephrol Hypertens 1998; 07: 189-96.
• 32 Goto A, Yamada K. Putative roles of ouabain-like compound in hypertension: Revisited. Hypertens Res 2000; (Suppl. 23) S7-S13.
• 33 Gottlieb SS, Rogowski AC, Weinberg M, Krichten CM, Hamilton BC, Hamlyn JM. Elevated concentrations of endogenous ouabain in patients with congestive heart failure. Circulation 1992; 86: 420-5.
• 34 Hamlyn JM, Ringel R, Schaeffer J, Levinson PD, Hamilton BP, Kowarski AA, Blaustein MP. A circulating inhibitor of (Na+K)-ATPase associated with essential hypertension. Nature 1982; 300: 650-2.
• 35 Huang BS, Harmsen E, Yu H, Leenen FHH. Brain ouabain-like activity and the sympathexcitatory and pressor effects of central sodium in rats. Circ Res 1992; 71: 1059-66.
• 36 Huang BS, Kudlac M, Kumarathasan R, Leenen FH. Digoxin prevents ouabain and high salt intake-induced hypertension in rats with sinoaortic denervation. Hypertension 1999; 34: 733-8.
• 37 Kawamura A, Guo J, Itagaki Y, Bell C, Wang Y, Haupert J, Garner T, Magil S, Gallagher RT, Berova N, Nakanishi K. On the structure of endogenous ouabain. Proc Natl Acad Sci USA 1999; 96: 6654-9.
• 38 Kimura K, Manunta P, Hamilton BP, Hamlyln JM. Different effects of in vivo ouabain and digoxin on renal artery function and blood pressure in rats. Hypertens Res 2000; (Suppl. 23) S67-S76.
• 39 Kochsiek K. Importance of serum glycoside concentrations. In: Cardiac Glycosides 1785–1985. Erdmann E, Greef K, Skou JC. eds New York: Springer; 1986: 407-16.
• 40 Kometiani P, Liu L, Askari A. Digitalis-induced signaling by Na+/K+-ATPase in human breast cancer cells. Mol Pharmacol 2005; 67: 929-36.
• 41 Komiyama Y, Dong XH, Nishimura N, Masaki H, Yoshika M, Masuda M, Takahashi H. A novel endogenous digitalis, telocinobufagin, exhibits elevated plasma levels in patients with terminal renal failure. Clini Biochem 2005; 38: 36-45.
• 42 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: 487-93.
• 43 Laredo J, Shah JR, Lu Z, Hamilton BP, Hamlyn JM. Angiotensin II stimulates secretion of endogenous ouabain from bovine adrenal cortical cells via angiotensin II receptors. Hypertension 1997; 29: 401-7.
• 44 Laredo J, Shah JR, Hamilton BP, Hamlyn JM. 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 Amsterdam: Elsevier; 2000: 671-9.
• 45 Lichtstein D, Gati I, Samuelov S, Berson D, Rozeman Y, Landau L, Deutsch J. Identification of digitalis-like compounds in human cataractous lenses. Eur J Biochem 1993; 216: 261-8.
• 46 Lin H, Juang J-L, Wang PS. Involvement of Cdk5/p25 in digoxin-triggered prostate cancer cell apoptosis. J Biol Chem 2004; 279: 29302-7.
• 47 Manunta P, Evans G, Hamilton BC, Gann D, Resau J, Hamlyn JM. A new syndrome with elevated plasma ouabain and hypertension secondary to an adrenocortical tumor. J Hypertens 1992; 10: S27 Abstr. P36.
• 48 Manunta P, Ferrandi M. Different effects of marinobufagenin and endogenous ouabain. J Hypertens 2004; 257: 257-9.
• 49 Manunta P, Hamilton J, Rogowski AC, Hamilton BP, Hamlyn JM. Chronic hypertension induced by ouabain but not digoxin in the rat: Antihypertensive effect of digoxin and digitoxin. Hypertens Res 2000; 23: S77-S85.
• 50 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.
• 51 Manunta P, Stella P, Rivera R, Ciurlino D, Cusi D, Ferrandi M, Hamlyn JM, Bianchi G. Left ventricular mass, stroke volume and ouabain-like factor in essential hypertension. Hypertension 1999; 34: 450-6.
• 52 Marbán E. Cardiac channelopathies. Nature 2002; 415: 213-8.
• 53 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 1988; 02: 17-20.
• 54 McConkey DJ, Lin Y, Nutt LK, Ozel HZ, Newman RA. Cardiac glycosides stimulate Ca²+ increases and apoptosis in androgen independent, metastatic human prostate adenocarcinoma cells. Cancer Res 2000; 60: 3807-12.
• 55 McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure. N Engl J Med 1971; 26: 1441-6.
• 56 Mijatovic T, Mathieu V, Lefranc F, Carnby I, Dewelle J, Van Quaquebeke E, Darra F, Kiss R. UNBS1450, a novel cardenolide, displays potent in vitro and in vivo activity in experimental human non-small-cell-Iung and prostate cancers and in glioblastomas. 4th World Congress of Cellular and Molecular Biology, Poities. France: Abstract Book; 2005: 107.
• 57 Miyakawa-Naito A, Uhlén P, Lal M, Aizman O, Mikoshiba K, Brismar H, Zelenin S, Aperia A. Cell signaling microdomain with Na, K-ATPase and Inositol 1, 4, 5-triphosphate receptor generates calcium oscillations. J Biol Chem 2003; 318: 50355-61.
• 58 Moreth K, Kuske R, Renner D, Schoner W. Blood pressure in essential hypertension correlates with the concentration of a circulating inhibitor of the sodium pump. Klin Wschr 1986; 64: 239-44.
• 59 Qazzaz HMAM, Goudy SL, Valdes RJ. Deglycosylated products of endogenous digoxin-like immunoreactive factor in mammalian tissue. J Biol Chem 1996; 271: 8731-7.
• 60 Qazzaz HM, El-Masri MA, Valdes RJ. Secretion of a lactone-hydrogenated ouabain-like effector of sodium, potassium-adenosine triphosphatase activity by adrenal cells. Endocrinology 2000; 141: 3200-9.
• 61 Rockman HA, Koch WJ, Lefkowitz RJ. Seven-transmembrane-spanning receptors and heart function. Nature 2002; 415: 206-12.
• 62 Ringer S. Regarding the influence of the organic constituents of the blood on the contractility of the ventricle. J Physiol 1885; 06: 361-81.
• 63 Saunders R, Scheiner-Bobis G. Ouabain stimulates endothelin release and expression in human endothelial cells without inhibiting the sodium pump. Eur J Biochem 2004; 271: 1054-62.
• 64 Schatzmann HJ. Herzglykoside als Hemmstoffe für den aktiven Kaliumund Natriumtransport durch die Erythrocytenmembran. Helv Physiol Pharmacol Acta 1953; 11: 346-54.
• 65 Scheiner-Bobis G, Schoner W. A fresh facet for ouabain action. Nat Med 2001; 07 (12) 1288-9.
• 66 Schoner W, Scheiner-Bobis G. Endogenous cardiac glycosides: Hormones using the sodium pump as signal transducer. Semin Nephrol 2005; 25: 343-51.
• 67 Smith TW, Butler VP, Haber E. Determination of therapeutic and toxic digoxin concentrations by radioimmunoassay. N Engl J Med 1969; 19: 1150-6.
• 68 Szent-Györgyi A. Chemical Physiology of Contraction in Body and Heart Muscle. New York: Academic Press; 1953: 86-91.
• 69 Terness P, Navolan D, Dufter C, Kopp B, Opelz G. The T-cell suppressiv effect of bufadienolides: structural requirements for their immunoregulatory activity. Int Immunopharmacol 2001; 01: 119-34.
• 70 Towbin JA, Bowles NE. The failing heart. Nature 2002; 415: 227-33.
• 71 Valdes Jr R. Endogenous digoxin-immunoactive factor in human subjects. Fed Proc 1985; 44: 2800-5.
• 72 Van Quaquebeke E, Simon G, Andre A, DeweIle J, EI MYazidi, Bruyneel F, Tuti J, Nacoulma O, Guissou P, Decaestecker C. et al. Identification of a novel cardenolide (2“-Oxovoruscharin) from Calotropis procera and the hemisynthesis of novel derivatives displaying potent in vitro antitumor activities and high in vivo tolerance: Structure-Activity relationship analyses. J Med Chem 2005; 48: 849-56.
• 73 Wang H, Haas M, Liang M, Cai T, Tian J, Li S, Xie Z. Ouabain assembles signaling cascades through the caveolar Na+/K+-ATPase. J Biol Chem 2004; 279: 17250-9.
• 74 Wang H, Huang BS, Leenen FHH. Brain sodium channel and ouabain-like compounds mediate central aldosterone-induced hypertension. Am J Heart Circ Physiol 2003; 285: H2516-H2523.
• 75 Wang H, Leenen FHH. Brain sodium channels mediate increases in brain “ouabain” and blood pressure in Dahl S rats. Hypertension 2002; 40: 96-100.
• 76 Weitkamp C. Warum zeigen die Herzglykoside Ouabain und Digoxin unterschiedliche Kreislaufwirkung? Charakterisierung eines mutmaßlichen Herzglykosid-Bindungsproteins im Serum und Analyse der Wirkung beider Steroide auf die Endothelin-1– und NO-Freisetzung aus arteriellen Endothelzellen. Dr. oec. troph., Fachbereich Agrarwissenschaften, Ökotrophologie und Umweltmanagement. Justus-Liebig-Universität Gießen. 2005
• 77 Withering W. An account on the foxglove, and some of its medical uses with practical remark on dropsy and other diseases. London: G. G. J. and J. Robinson; 1785
• 78 Xie Z, Askari A. Na+/K+-ATPase as a signal inducer. Eur J Biochem 2002; 269: 2434-9.
• 79 Yeh J-Y, Huang WJ, Kan S-F, Paulus SW. Inhibitory effects of digitalis on the proliferation of androgen dependent and independent prostate cancer cells. J Urol 2001; 166: 1937-42.
• 80 Yuan CM, Manunta P, Hamlyn JM, Chen S, Bohen E, Yeun J, Haddy FJ, Pamnani MB. Long-term ouabain administration produces hypertension in rats. Hypertension 1993; 22: 178-87.