Endogenous Sodium-Transport Inhibitors as Physiological Regulators of the Sodium Pump

  • Garner T. HaupertJr.
Part of the Clinical Physiology Series book series (CLINPHY)


since the discovery of endogenous analogues of opium, the endorphins and enkephalins (16, 27), it has been tempting to postulate that parallel situations might obtain for other pharmacologically potent substances from the plant kingdom that exert their effects through specific receptors in animal tissues. Thus the Nat and Ktactivated ATPase (Na+-K+-ATPase) in animal species might have an endogenous analogue to the cardiac glycosides. Several “endogenous factors” that either inhibit active sodium transport, inhibit Na+-K+ATPase activity in vitro, or prevent ouabain binding to the Na+-K+-ATPase have been extracted from amphibian and mammalian sources (for a review, see ref. 12). Such an endogenous sodium-transport inhibitor has been implicated in many important physiological and pathophysiological processes. De Wardener et al. (30) suggested that the natriuresis of intravascular volume expansion was mediated in part by a humoral substance distinct from known regulators of renal hemodynamics and tubular cation transport. Hillyard et al. (15) recognized the ouabainlike effects of such a substance during their attempts to characterize a natriuretic principle extracted from renal tissue of volume-expanded rats. At about the same time Overbeck et al. (21) showed that volume expansion was associated with the elaboration of a heat-stable substance in plasma that inhibited cell membrane sodium transport in vascular muscle, and Haddy and Overbeck (9) postulated that the unknown compound might be responsible for the sequence of physiological events characterizing the development of experimental volume-expanded hypertension in animals. A decrease in sodium-pump activity was documented in uremia (7, 31), and a natriuretic factor was found in the urine of uremic patients with intravascular volume expansion but not in that of nephrotic uremics who demonstrate the physiology of intravascular volume depletion (2). It was hypothesized that this factor might be important in the adaptive response to progressive nephron loss whereby an enhanced fractional excretion of sodium permits maintenance of normal sodium balance in patients with nonnephrotic chronic renal failure (23). It also seems that patients with essential hypertension have an elevated concentration of a circulating pump inhibitor (6, 11, 22), raising the provocative possibility that an abnormality in regulation of Na+-K+-ATPase plays a role in a prevalent human disease.


ATPase Activity Cardiac Glycoside Sodium Transport Sodium Pump Renal Tubular Epithelial Cell 
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  1. 1.
    Bidard, J.-N., B. RossI, J.-F. Renaud, And M. Lazdunski. A search for an “ouabain-like” substance from the electric organ of Electrophorus electricus which led to arachidonic acid and related fatty acids. Biochim. Biophys. Acta 769: 245–252, 1984.PubMedCrossRefGoogle Scholar
  2. 2.
    Bourgoignie, J. J., K. H. Hwang, E. Ipakchi, And N. S. Bricker. The presence of a natriuretic factor in urine of patients with chronic uremia. The absence of the factor in nephrotic uremic patients. J. Clin. Invest. 53: 1559–1567, 1974.PubMedCrossRefGoogle Scholar
  3. 3.
    Cantley, L. C. Structure and mechanism of the Na,K-Atpase. Curr. Top. Bioenerg. 11: 20 1237, 1981.Google Scholar
  4. 4.
    Carilli, C. T., M. Berne, L. C. Cantley, And G. T. Haupert, JR. Hypothalamic factor inhibits the (Na,K)Atpase from the extracellular surface. Mechanism of inhibition. J. Biol. Chem. 260: 1027–1031, 1985.PubMedGoogle Scholar
  5. 5.
    Carilli, C. T., R. A. Farley, D. M. Perlman, And L. C. Cantley. The active site structure of Na+- and K+-stimulated Atpase. Location of a specific fluorescein isothiocyanate reactive site. J. Biol. Chem. 257: 5601–5606, 1982.PubMedGoogle Scholar
  6. 6.
    Edmondson, R. P. S., R. D. Thomas, P. J. Hilton, J. Patrick, And N. F. Jones. Abnormal leucocyte composition and sodium transport in essential hypertension. Lancet 1: 1003–1005, 1975.PubMedCrossRefGoogle Scholar
  7. 7.
    Fine, L. G., J. J. Bourgoignie, K. H. Hwang, And N. S. Bricker. On the influence of the natriuretic factor from patients with chronic uremia on the bioelectric properties and sodium transport of the isolated mammalian collecting tubule. J. Clin. Invest. 58: 590–597, 1976.Google Scholar
  8. 8.
    Flier, J., M. W. Edwards, J. W. Daly, And C. W. Myers. Widespread occurrence in frogs and toads of skin compounds interacting with the ouabain site of Na+,K+-Atpase. Science Wash. DC 208: 503–505, 1980.CrossRefGoogle Scholar
  9. 9.
    Haddy, F. J., And H. W. Overbeck. The role of humoral agents in volume expanded hypertension. Life Sci. 19: 935–947, 1976.PubMedCrossRefGoogle Scholar
  10. 10.
    Haddy, F. J., M. B. Pamnani, And D. L. Clough. The sodium-potassium pump in volume expanded hypertension. Clin. Exp. Hypertens. 1: 295–336, 1978.PubMedCrossRefGoogle Scholar
  11. 11.
    Hamlyn, J. M., R. Ringel, J. Schaeffer, P. D. Levinson, B. P. Hamilton, A. A. Kowarski, And M. P. Blaustein. A circulating inhibitor of (Na+ + K+)Atpase associated with essential hypertension. Nature Lond. 300: 650–652, 1982.PubMedCrossRefGoogle Scholar
  12. 12.
    Haupert, G. T., JR. Endogenous glycoside-like substances. In: Current Topics in Membranes and Transport, edited by J. F. Hoffmann and B. Forbush. New York: Academic, 1983, vol. 19, p. 843–855.Google Scholar
  13. 13.
    Haupert, G. T., JR., C. T. Carilli, And L. C. Cantley. Hypothalamic sodium-transport inhibitor is a high-affinity reversible inhibitor of Na+-K+-Atpase. Am. J. Physiol. 247 (Renal Fluid Electrolyte Physiol. 16 ): F919 - F924, 1984.Google Scholar
  14. a.HAuPert, G. T., JR., C. T. Carilli, And L. C. Cantley. Hypothalamic NattransportGoogle Scholar
  15. inhibitor: mechanism of inhibition. In: The Sodium Pump, edited by I. Glynn and C. Ellory. Cambridge, UK: Company of Biologists, 1985, p. 641–647.Google Scholar
  16. b.HAuPert, G. T., JR., E. Chen, S. Ray, And H. F. Cantiello. Hypothalamic factor regulates sodium pump activity in cultured renal tubular epithelial cells. Ann. NY Acad. Sci. In press.Google Scholar
  17. 14.
    Haupert, G. T., JR., And J. M. Sancho. Sodium transport inhibitor from bovine hypothalamus. Proc. Natl. Acad. Sci. Usa 76: 4658–4660, 1979.PubMedCrossRefGoogle Scholar
  18. 15.
    Hillyard, S. D., E. Lu, And H. C. Gonick. Further characterization of the natriuretic factor derived from kidney tissue of volume-expanded rats. Effects on short-circuit current and sodium-potassium-adenosine triphosphatase activity. Circ. Res. 38: 250–255, 1976.PubMedCrossRefGoogle Scholar
  19. 16.
    Hughes, J., T. W. Smith, H. W. Kosterlitz, L. A. Fothergill, B. A. Morgan, And H. R. Morris. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature Lond. 258: 577–579, 1975.PubMedCrossRefGoogle Scholar
  20. 17.
    Jorgensen, P. L. Purification and characterization of (Na+ + K+)-Atpase. 3. Purification from the outer medulla of mammalian kidney after selective removal of membrane components by sodium dodecylsulphate. Biochim. Biophys. Acta 356: 36–52, 1974.PubMedCrossRefGoogle Scholar
  21. 18.
    Josephson, L., And L. C. Cantley, JR. Isolation of a potent (Na+-K+)Atpase inhibitor from striated muscle. Biochemistry 16: 4572–4578, 1977.PubMedCrossRefGoogle Scholar
  22. 19.
    Karlish, S. J., L. A. BeaugÉ, And I. M. Glynn. Vanadate inhibits (Na+ + K+)Atpase by blocking a conformational change of the unphosphorylated form. Nature Lond. 282: 333–335, 1979.PubMedCrossRefGoogle Scholar
  23. 20.
    Maclennan, D. H. Purification and properties of an adenosine triphosphatase from sarcoplasmic reticulum. J. Biol. Chem. 245: 4508–4518, 1970.PubMedGoogle Scholar
  24. 21.
    Overbeck, H. W., M. B. Pamnani, T. Akera, T. M. Brody, And F. J. Haddy. Depressed function of a ouabain-sensitive sodium-potassium pump in blood vessels from renal hypertensive dogs. Circ. Res. 38, Suppl. 2: 48–52, 1976.PubMedCrossRefGoogle Scholar
  25. 22.
    Poston, L., R. B. Sewell, S. P. Wilkinson, P. J. Richardson, R. Williams, E. M. Clarkson, G. A. Macgregor, And H. E. DE Wardener. Evidence for a circulating sodium transport inhibitor in essential hypertension. Br. Med. J. 282: 847–849, 1981.CrossRefGoogle Scholar
  26. 23.
    Schmidt, R. W., J. J. Bourgoignie, And N. S. Bricker. On the adaptation in sodium excretion in chronic uremia. The effects of “proportional reduction” of sodium intake. J. Clin. Invest. 53: 1736–1741, 1974.PubMedCrossRefGoogle Scholar
  27. 24.
    Schwartz, A., K. Whitmer, G. Grupp, I. Grupp, R. J. Adams, And S. W. Lee Mechanism of action of digitalis: is the Na,K-Atpase the pharmacological receptor ? Ann. NY Acad. Sci. 402: 253–271, 1982.PubMedCrossRefGoogle Scholar
  28. 25.
    Shimoni, Y., M. Gotsman, J. Deutsch, S. Kachalsky, And D. Lichtstein. Endogenous ouabain-like compound increases heart muscle contractility. Nature Lond. 307: 369–371, 1984.PubMedCrossRefGoogle Scholar
  29. 26.
    Shull, G. E., A. Schwartz, And J. B. Lingrel. Amino-acid sequence of the catalytic subunit of the (Na+ + K+)Atpase deduced from a complementary Dna. Nature Lond. 316: 691–695, 1985.PubMedCrossRefGoogle Scholar
  30. 27.
    Simantov, R., And S. H. Snyder. Morphine-like peptides in mammalian brain: isolation, structure elucidation, and interactions with the opiate receptor. Proc. Natl. Acad. Sci. Usa 73: 2515–2519, 1976.PubMedCrossRefGoogle Scholar
  31. 28.
    Steck, T., And J. Kant. Preparation of impermeable ghosts and inside-out vesicles from human erythrocyte membranes. Methods Enzymol. 31: 172–180, 1974.PubMedCrossRefGoogle Scholar
  32. 29.
    Tamura, M., H. Kuwano, T. Kinoshita, And T. Inagami. Identification of linoleic and oleic acids as endogenous Na+,K+-Atpase inhibitors from acute volume-expanded hog plasma. J. Biol. Chem. 260: 9672–9677, 1985.PubMedGoogle Scholar
  33. 30.
    Wardener, H. E. DE, I. H. Mills, W. F. Clapham, And C. J. Hayter. Studies on the efferent mechanism of the sodium diuresis which follows the administration of intravenous saline in the dog. Clin. Sci. Lond. 21: 249–258, 1961.Google Scholar
  34. 31.
    Welt, L. G., J. R. Sachs, And T. J. Manus. An ion transport defect in erythrocytes from uremic patients. Trans. Assoc. Am. Physicians 77: 169–181, 1964.PubMedGoogle Scholar

Copyright information

© American Physiological Society 1987

Authors and Affiliations

  • Garner T. HaupertJr.
    • 1
  1. 1.Renal UnitMassachusetts General Hospital, Harvard Medical SchoolBostonUSA

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