Abstract
The plasma membrane sodium-potassium pumps that regulate intracellular sodium in most animal cells have specific, high-affinity receptors for the digitalis glycosides and their aglycones. This has fostered speculation that there is an endogenous ligand. We have purified and structurally identified by mass spectroscopy an endogenous substance from human plasma that binds with high affinity to this receptor and that is indistinguishable from the cardenolide ouabain. This human ouabain-like compound (OLC) displaces [3H]ouabain from its receptor, inhibits Na,K-ATPase and ouabain-sensitive 86Rb+ uptake, and has cardiotonic actions quantitatively similar to commercial ouabain. Immunoreactive OLC was detected in the plasma of many mammals, and high concentrations were found in the adrenals. The circulating OLC may modulate intracellular Na+ and affect numerous Na+ gradient-dependent processes including intracellular Ca2+ and pH homeostasis in many tissues. Furthermore, altered circulating levels of OLC may be associated with the pathogenesis of certain forms of hypertension.
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- Blanco G., Berberian G., Beaugé L. Detection of a highly ouabain sensitive isoform of rat brainstem Na,K-ATPase. Biochim Biophys Acta. 1990 Aug 10;1027(1):1–7. doi: 10.1016/0005-2736(90)90039-q. [DOI] [PubMed] [Google Scholar]
- Brown L., Erdmann E. Binding of digitalis derivatives to beef, cat and human cardiac (Na+ + K+)-ATPase. Affinity and kinetic constants. Arch Int Pharmacodyn Ther. 1984 Oct;271(2):229–240. [PubMed] [Google Scholar]
- Buckalew V. M., Jr, Martinez F. J., Green W. E. The effect of dialysates and ultrafiltrates of plasma of saline-loaded dogs on toad bladder sodium transport. J Clin Invest. 1970 May;49(5):926–935. doi: 10.1172/JCI106312. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Churchill P. C. Possible mechanism of the inhibitory effect of ouabain on renin secretion from rat renal cortical slices. J Physiol. 1979 Sep;294:123–134. doi: 10.1113/jphysiol.1979.sp012919. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Flier J., Edwards M. W., Daly J. W., Myers C. W. Widespread occurrence in frogs and toads of skin compounds interacting with the ouabain site of Na+, K+-ATPase. Science. 1980 May 2;208(4443):503–505. doi: 10.1126/science.6245447. [DOI] [PubMed] [Google Scholar]
- Goto A., Ishiguro T., Yamada K., Ishii M., Yoshioka M., Eguchi C., Shimora M., Sugimoto T. Isolation of a urinary digitalis-like factor indistinguishable from digoxin. Biochem Biophys Res Commun. 1990 Dec 31;173(3):1093–1101. doi: 10.1016/s0006-291x(05)80898-8. [DOI] [PubMed] [Google Scholar]
- Graves S. W. Endogenous digitalis-like factors. Crit Rev Clin Lab Sci. 1986;23(3):177–200. doi: 10.3109/10408368609165799. [DOI] [PubMed] [Google Scholar]
- Haddy F. J., Pamnani M. B. The role of a humoral sodium-potassium pump inhibitor in low-renin hypertension. Fed Proc. 1983 Jul;42(10):2673–2680. [PubMed] [Google Scholar]
- Hamlyn J. M., Ashen M. D., Forrest B., Rogowski A. C., White R. J. Species sensitivity of the sodium pump to a circulating ouabain-like inhibitor in acute hypervolemia and DOCA hypertension: comparison with ouabain. Prog Biochem Pharmacol. 1988;23:22–34. [PubMed] [Google Scholar]
- Hamlyn J. M., Harris D. W., Clark M. A., Rogowski A. C., White R. J., Ludens J. H. Isolation and characterization of a sodium pump inhibitor from human plasma. Hypertension. 1989 Jun;13(6 Pt 2):681–689. doi: 10.1161/01.hyp.13.6.681. [DOI] [PubMed] [Google Scholar]
- Hamlyn J. M., Harris D. W., Ludens J. H. Digitalis-like activity in human plasma. Purification, affinity, and mechanism. J Biol Chem. 1989 May 5;264(13):7395–7404. [PubMed] [Google Scholar]
- Hamlyn J. M. Increased levels of a humoral digitalis-like factor in deoxycorticosterone acetate-induced hypertension in the pig. J Endocrinol. 1989 Jul;122(1):409–420. doi: 10.1677/joe.0.1220409. [DOI] [PubMed] [Google Scholar]
- 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. 1982 Dec 16;300(5893):650–652. doi: 10.1038/300650a0. [DOI] [PubMed] [Google Scholar]
- Harris D. W., Clark M. A., Fisher J. F., Hamlyn J. M., Kolbasa K. P., Ludens J. H., DuCharme D. W. Development of an immunoassay for endogenous digitalislike factor. Hypertension. 1991 Jun;17(6 Pt 2):936–943. doi: 10.1161/01.hyp.17.6.936. [DOI] [PubMed] [Google Scholar]
- Kelly R. A., O'Hara D. S., Mitch W. E., Smith T. W. Identification of NaK-ATPase inhibitors in human plasma as nonesterified fatty acids and lysophospholipids. J Biol Chem. 1986 Sep 5;261(25):11704–11711. [PubMed] [Google Scholar]
- Lane L. K., Potter J. D., Collins J. H. Large-scale purification of Na,K-ATPase and its protein subunits from lamb kidney medulla. Prep Biochem. 1979;9(2):157–170. doi: 10.1080/00327487908061681. [DOI] [PubMed] [Google Scholar]
- Lichtstein D., Samuelov S., Deutsch J., Xu H., Lutz R. A., Chernick S. S., Chernick S. S. The ouabain receptor in animal tissues and its endogenous ligand. Klin Wochenschr. 1987;65 (Suppl 8):40–48. [PubMed] [Google Scholar]
- Masugi F., Ogihara T., Hasegawa T., Kumahara Y. Ouabain-like and non-ouabain-like factors in plasma of patients with essential hypertension. Clin Exp Hypertens A. 1987;9(7):1233–1242. doi: 10.3109/10641968709160046. [DOI] [PubMed] [Google Scholar]
- Masugi F., Ogihara T., Hasegawa T., Tomii A., Nagano M., Higashimori K., Kumahara K., Terano Y. Circulating factor with ouabain-like immunoreactivity in patients with primary aldosteronism. Biochem Biophys Res Commun. 1986 Feb 26;135(1):41–45. doi: 10.1016/0006-291x(86)90939-3. [DOI] [PubMed] [Google Scholar]
- 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 Wochenschr. 1986 Mar 3;64(5):239–244. doi: 10.1007/BF01711656. [DOI] [PubMed] [Google Scholar]
- Nutbourne D. M., Howse J. D., Schrier R. W., Talner L. B., Ventom M. G., Verroust P. J., De Wardener H. E. The effect of expanding the blood volume of a dog on the short-circuit current across an isolated frog skin incorporated in the dog's circulation. Clin Sci. 1970 Jun;38(6):629–648. doi: 10.1042/cs0380629. [DOI] [PubMed] [Google Scholar]
- Pamnani M. B., Burris J. F., Jemionek J. F., Huot S. J., Price M., Freis E. D., Haddy F. J. Humoral Na+-K+ pump inhibitory activity in essential hypertension and in normotensive subjects after acute volume expansion. Am J Hypertens. 1989 Jul;2(7):524–531. doi: 10.1093/ajh/2.7.524. [DOI] [PubMed] [Google Scholar]
- Repke K., Est M., Portius H. J. Uber die Ursache der Speciesunterschiede in der Digitalisempfindlichkeit. Biochem Pharmacol. 1965 Dec;14(12):1785–1802. doi: 10.1016/0006-2952(65)90269-8. [DOI] [PubMed] [Google Scholar]
- SCHATZMANN H. J. Herzglykoside als Hemmstoffe für den aktiven Kalium- und Natriumtransport durch die Erythrocytenmembran. Helv Physiol Pharmacol Acta. 1953;11(4):346–354. [PubMed] [Google Scholar]
- SIPERSTEIN M. D., MURRAY A. W., TITUS E. Biosynthesis of cardiotonic sterols from cholesterol in the toad, Bufo marinus. Arch Biochem Biophys. 1957 Mar;67(1):154–160. doi: 10.1016/0003-9861(57)90254-0. [DOI] [PubMed] [Google Scholar]
- Shoback D. M., Thatcher J., Leombruno R., Brown E. M. Relationship between parathyroid hormone secretion and cytosolic calcium concentration in dispersed bovine parathyroid cells. Proc Natl Acad Sci U S A. 1984 May;81(10):3113–3117. doi: 10.1073/pnas.81.10.3113. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Songu-Mize E., Bealer S. L., Caldwell R. W. Effect of DOCA-salt treatment duration and anteroventral third ventricle lesions on a plasma-borne sodium pump inhibitor in rats. J Hypertens. 1987 Aug;5(4):461–467. [PubMed] [Google Scholar]
- Tamura M., Kuwano H., Kinoshita T., Inagami T. Identification of linoleic and oleic acids as endogenous Na+,K+-ATPase inhibitors from acute volume-expanded hog plasma. J Biol Chem. 1985 Aug 15;260(17):9672–9677. [PubMed] [Google Scholar]
- Topol E. J., Traill T. A., Fortuin N. J. Hypertensive hypertrophic cardiomyopathy of the elderly. N Engl J Med. 1985 Jan 31;312(5):277–283. doi: 10.1056/NEJM198501313120504. [DOI] [PubMed] [Google Scholar]
- Van Winkle W. B., Allen J. C., Schwartz A. The nature of the transport ATPase-digitalis complex. 3. Rapid binding studies and effects of ligands on the formation and stability of magnesium plus phosphate-induced glycoside-enzyme complex. Arch Biochem Biophys. 1972 Jul;151(1):85–92. doi: 10.1016/0003-9861(72)90476-6. [DOI] [PubMed] [Google Scholar]