Summary
The existence of an endogenous natriuretic hormone and ouabain-like factors (OLF) has been postulated for many years. This postulate was based on our original observation that a small M.W. fraction in the serum after acute expansion of the extracellular fluid volume (ECFV) not only exhibited natriuretic activity but also inhibited the Na-K-ATPase enzyme in vitro similar to ouabain. Since then, numerous studies confirmed the presence of OLFs in serum, urine, cerebrospinal fluid, and various organs including the heart and hypothalamus. Some of these OLFs are well-known endogenous compounds, such as free unsaturated fatty acids, which inhibit in vitro transmembranous sodium transport, Na-K-ATPase and3H-ouabain binding to its membrane receptor or crossreact with digoxin antibodies. Chemically yet undefined OLFs of potentially hypothalamic origin were detected in various models of experimental and clinical hypertension and are suggested to play a pathophysiological role especially in salt- and volume-dependent forms of hypertension. Our results show that OLFs isolated from the urine of salt-loaded healthy subjects strongly enhance basal and vasopressin-stimulated release of calcium in vascular smooth muscle cells and platelets similar to the effects we had observed with endothelin. This urine fraction also exhibits natriuretic activity which increases in parallel with sodium intake. Further chromatographic separation and amino acid analysis confirmed the peptidic nature (M.W.<1000) of the natriuretic factor(s). However, the two biological activities, namely natriuretic and ouabain-like activities, reside in distinct and chemically different compounds. In face of the previous discovery of the atrial natriuretic peptides (ANP) it is of special interest that very recent observations strongly suggest a natriuretic factor of non-cardiac origin to play an important role in the natriuresis that follows ECFV expansion. In addition, numerous experimental data point to an interaction between the ANP and OLF systems. They should stimulate once again the final identification of these yet unknown endogenous natriuretic and ouabain-like factors.
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Literatur
Kramer HJ, Gonick HC, Krück F (1972) Natriuretisches Hormon. Klin Wochenschr 50:893–897
Kramer HJ, Gonick HC, Paul W, Lu E (1969) Third factor: inhibitor of Na-K-ATPase? 4th Int Congr Nephrology, Abstracts I (Free communications), p 373
Haddy FJ, Pamnani MB, Clough DL (1980) Volume overload hypertension: a defect in the sodium-potassium pump? Cardiovasc Rev Rep 1:376–385
De Wardener HE, MacGregor GA (1980) Dahl's hypothesis that a saluretic substance may be responsible for a sustained rise in arterial pressure: its possible role in essential hypertension. Kidney Int 18:1–9
Carilli CT, Berne M, Cantley LC, Haupert GC Jr (1985) Hypothalamic factor inhibits the (Na,K)ATPase from the extracellular surface. Mechanism of inhibition. J Biol Chem 260:1027–1031
Cantiello HF, Chen E, Ray S, Haupert GT Jr (1988) Na+ pump in renal tubular cells is regulated by endogenous Na+-K+-ATPase inhibitor from hypothalamus. Am J Physiol 255:F574-F580
Klingmüller D, Weiler E, Kramer HJ (1982) Digoxin-like natriuretic activity in the urine of salt-loaded healthy subjects. Klin Wochenschr 60:1249–1253
Kramer HJ, Bäcker A, Weiler E, Liddiard C (1986) Studies on ouabain-like endogenous natriuretic factors in human urine. Inhibition of Na-K-ATPase and3H-ouabain binding. Klin Wochenschr 64:760–766
Gruber KA, Whitaker JM, Buckalew VM Jr (1980) Endogenous digitalis-like substance in plasma of volume-expanded dogs. Nature 287:743–745
Kramer HJ, Heppe M, Pennig J, Kipnowski J, Klingmüller D, Düsing R, Krück F (1985) Relation of endogenous digoxin-like immunoreacting activities to salt balance and renal function in man. Klin Wochenschr 63 (Suppl III):107–110
De Bold AJ, Borenstein HB, Veress AT, Sonnenberg H (1981) A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci 28:89–94
Sakata M, Greenwald JE, Needleman P (1988) Paradoxical relationship between atriopeptin plasma levels and diuresisnatriuresis induced by acute volume expansion. Proc Natl Acad Sci USA 85:3155–3159
Kramer HJ, Heppe M, Weiler E, Bäcker A, Liddiard C, Klingmüller D (1985) Further characterization of the endogenous natriuretic and digoxin-like immunoreacting activities in human urine: effects of changes in sodium intake. Renal Physiol 8:80–89
Akagawa K, Hara N, Tsukada Y (1984) Partial purification and properties of the inhibitor of Na,K-ATPase and ouabain-binding in bovine central nervous system. J Neurochemistry 42:775–780
Halperin JA, Riordan JF, Tosteson DC (1988) Characteristics of an inhibitor of the Na+/K+ pump in human cerebrospinal fluid. J Biol Chem 263:646–651
Morgan K, Lewis MD, Spurlock G, Collins PA, Ford SM, Southgate K, Scanlon MF, Mir MA (1985) Characterization and partial purification of the sodium-potassium-ATPase inhibitor release from cultured rat hypothalamic cells. J Biol Chem 260:13595–13600
Goto A, Yamada K, Ishii M, Yoshioka M, Ishiguro T, Eguchi C, Sugimoto T (1988) Presence of digitalis-like factor in mammalian plasma. Biochem Biophys Res Comm 152:322–327
Hamlyn JH, Harris DW, Ludens JH (1989) Digitalis-like activity in human plasma. Purification, affinity and mechanism. J Biol Chem 264:7395–7404
Haupert GT Jr, Sancho JM (1979) Sodium transport inhibitor from bovine hypothalamus. Proc Natl Acad Sci USA 76:4658–4660
Millett JA, Holland SM, Alaghband-Zadeh J, de Wardener HE (1987) Extraction and characterization of a cytochemically assayable Na+/K+-ATPase inhibitor/glucose-6-phosphate dehydrogenase stimulator in the hypothalamus and plasma of man and rat. J Endocr 112:299–303
Cloix JF, Crabos M, Wainer IW, Ruegg U, Seiler M, Meyer P (1985) High yield-purification of a urinary Na pump inhibitor. Biochem Biophys Res Comm 131:1234–1240
Lichtstein D, Kachalsky S, Deutsch J (1986) Identification of a ouabain-like compound in toad skin and plasma as a bufodienolide derivative. Life Sci 38:1261–1270
Kelly RA, O'Hara DS, Mitch WE, Smith TW (1986) Identification of NaK-ATPase inhibitors in human plasma as nonesterified fatty acids and lysophospholipids. J Biol Chem 261:11704–11711
Tamura M, Kuwano H, Kinoshita T, Inagami T (1985) Identification of linoleic and oleic acids as endogenous NaK-ATPase inhibitors from acute volume-expanded hog plasma. J Biol Chem 260:9672–9677
Rauch AL, Buckalew VM Jr (1988) Plasma volume expansion increases lysophosphatidylcholine and digitalis-like activity in rat plasma. Life Sci 42:1189–1197
Tamura M, Inagami T, Kinoshita T, Kuwano H (1987) A search for endogenous Na+,K+-ATPAse inhibitor in acutely volume-expanded hog plasma led to lysophosphatidylcholineγ-stearoyl. J Hypertension 5:219–225
Masugi F, Ogihara T, Sakaguchi K, Tomii A, Hasegawa T, Chen Y, Azuma M, Kumahara Y (1988) Partial purification and properties of a plasma ouabain-like inhibitor of Na+,K+-ATPase in patients with essential hypertension. J Hypertension 6 (suppl 4):S351-S353
Rauch AL, Buckalew VM Jr (1988) Lysophospholipids are natriuretic and diuretic in rats. Am J Physiol 254:F824-F827
Weiler E, Tuck M, Gonick HC (1985) Observations on the “cascade” of Na — K-ATPase inhibitory and digoxin-like immunoreactive material in urine: possible relevance to essential hypertension. Clin Exp Hypertension A7:809–836
Meyer-Lehnert H, Wanning C, Bäcker A, Michel H, Kramer HJ (1989) Distinct effects of an endogenous Na-K-ATPase inhibitor and of ouabain on cytosolic calcium (Ca2+)i in vascular smooth muscle cells (VSMC) (abstract). Am J Hypertension 2 (No 5, part 2):13A
Meyer-Lehnert H, Wanning C, Predel HG, Bäcker A, Stelkens H, Kramer HJ (1989) Effects of endothelin on sodium transport mechanisms: Potential role in cellular Ca2+ mobilization. Biochem Biophys Res Comm 163:458–465
Wanning C, Meyer-Lehnert H, Michel H, Kramer HJ (1990) Endogenous ouabain-like factor (OLF) stimulates Na+/H+-antiport in rat vascular smooth muscle cells (VSMC): effects on Ca2+ mobilization (abstract). Kidney Int 35:337
Kramer HJ (1981) Natriuretic Hormone — a circulating inhibitor of sodium- and potassium-activated adenosine triphosphatase. Its potential role in body fluid and blood pressure regulation. Klin Wochenschr 59:1225–1230
Kramer HJ, Lichardus B, de Wardener HE (1989) Natriuretic hormones and disorders of sodium homeostasis. Curr Nephrol 12:39–86
Kramer HJ, Bäcker A, Krück F (1977) Antinatriferic activity in human plasma following acute and chronic salt loading. Kidney Int 12:214–222
Valdes R Jr (1985) Endogenous digoxin-like immunoreactive factors: impact on digoxin measurements and potential physiological implications (Review). Clin Chem 31:1525–1532
Kramer HJ, Pennig J, Klingmüller D, Kipnowski J, Glänzer K, Düsing R (1985) Digoxin-like immunoreacting substance(s) in the serum of patients with chronic uremia. Nephron 40:297–302
Kramer HJ, Meyer-Lehnert H, Michel H, Predel HG (1990) Endogenous natriuretic and ouabain-like factors: Their roles in body fluid volume and blood pressure regulation. Am J Hypertension 3:(im Druck)
Clough DL, Huot SJ, Pamnani MB, Haddy FJ (1985) Decreased myocardial Na+ K+-ATPase activity in rats with reduced renal mass-saline hypertension. J Hypertension 3:583–589
Whitmer KR, Lee JH, Martin AF, Lane LK, Lee SW, Schwartz A, Overbeck HW, Wallick ET (1986) Myocardial Na,K-ATPase in one-kidney, one-clip hypertensive rats. J Mol Cell Cardiol 18:1085–1095
Songu-Mize E, Bealer SL, Caldwell RW (1987) Effect of DOCA-salt treatment duration and anteroventral third ventricle lesions on a plasma-borne sodium pump inhibitor in rats. J Hypertension 5:461–467
Hu J, Harsdorf RV, Lang RE (1988) Inhibition of cardiac Na,K-ATPase stimulates atrial natriuretic factor release. J Hypertension 6 (Suppl 4):S712
Bloch KD, Zamir N, Lichtstein D, Seidman CE, Seidman JG (1988) Ouabain induces secretion of proatrial natriuretic factor by rat atrial cardiocytes. Am J Physiol 255:E383-E387
Morris MJ, Pernollet MG, Meyer P, Devynck MA (1988) Is there a relationship between the stimulation of atrial natriuretic factor by acute volume expansion and the plasma digitalis-like activity? J Hypertension 6 (Suppl 4):S718
Crabos M, Ausiello DA, Haupert GT Jr, Cantiello HF (1988) Atrial natriuretic peptide regulates release of Na+-K+-ATPase inhibitor from rat brain. Am J Physiol 254:F912-F917
Songu-Mize E, Bealer SL, Hassid AI (1990) Centrally administered ANF promotes appearance of a circulating sodium pump inhibitor. Am J Physiol 258:H1655-H1659
Goetz KL, Wang BC, Geer PG, Leadley RJ Jr, Reinhardt HW (1986) Atrial stretch increases sodium excretion independently of release of atrial peptides. Am J Physiol 250:R946-R950
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Die in dieser übersicht zitierten eigenen Untersuchungen wurden von der Deutschen Forschungsgemeinschaft, Bonn, dem Ministerium für Wissenschaft und Forschung des Landes Nordrhein-Westfalen (FA-2914, FA-8871, IVA6-402-046-87), Düsseldorf, und der Konrad-Adenauer-Stiftung, Bonn, unterstützt
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Kramer, H.J., Bäcker, A., Krampitz, G. et al. Endogene Natriuretische und Ouabain-ähnliche Faktoren. Klin Wochenschr 68, 1112–1118 (1990). https://doi.org/10.1007/BF01798061
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DOI: https://doi.org/10.1007/BF01798061