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Circulating digitalis-like factors

Abstract

The ability of extracts of mammalian plasma and tissue to mimic the biologic activities of the digitalis glycosides has suggested the existence of endogenous regulators for Na, K ATPase. Purification of plasma extracts has identified several classes of circulating lipids with digitalis-like activity including free fatty acids, lysophospholipids, and arachidonic acid metabolites of the lipoxygenase pathway. Circulating steroids with digitalis-like activity include dehydroepiandrosterone sulfate and hydrocortisone. Evidence for other, more unique compounds has also been puplished although their structure has not yet been determined. Analysis of tissue suggests that hypothalamus contains a unique, low molecular digitalis-like factor (DLF) which also circulates in plasma. Some studies suggest that the hypothalamic factor is also present in other parts of the brain and in the adrenal. Some of these endogenous DLF may function as modulators of cardiovascular function by regulating renal sodium excretion and peripheral vascular resistance in both physiological and pathophysiological situations.

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References

  1. 1.

    Sharpey-Schafer EA (1924) The endocrine organs: an introduction to the study of internal secretion, 2nd edn, vol 1. Longman, London

  2. 2.

    Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Morgan BA, Morris HR (1975) Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 258:577–579

  3. 3.

    Kosterlitz HW (1978) Endogenous opioid peptides: historcal aspects. In: Hughes J (ed) Centrally acting peptides. University Park Press, Baltimore, pp 157–159

  4. 4.

    Gruber KA (1982) Endogenous druglike substances: implications and approaches to their study. Perspect Biol Med 26:51–61

  5. 5.

    Asano T, Spector S (1979) Identification of inosine and hypoxanthine as endogenous ligands for the brain benzodiazepine-binding sites. Proc Natl Acad Sci USA 76: 977–981

  6. 6.

    Atlas D, Burstein Y (1984) Isolation and partial purification of a clonidine-displacing endogenous brain substance. Eur J Biochem 144:287–293

  7. 7.

    Wardener HE de, Clarkson EM (1985) Concept of natriuretic hormone. Physiol Rev 65:658–759

  8. 8.

    Buckalew VM Jr (1988) Natriuretic hormone. In: Epstein M (ed) The kidney in liver disease. Williams and Wilkins, Baltimore (in press)

  9. 9.

    Ahmed K, Thomas BS (1971) The effects of long chain fatty acids on sodiumplus potassium ion-stimulated adenosine triphosphatase of rat brain. J Biol Chem 246: 103–109

  10. 10.

    Karli JN, Karikas GA, Hatzipavlou PK, Levis GM, Moulopoulos SN (1979) The inhibition of Na+ and K+ stimulated ATPase activity of rabbit and dog heart sarcolemma by lysophosphatidyl choline. Life Sci 24:1869–1875

  11. 11.

    Schmalzing G, Kutschera P (1982) Modulation of ATPase activities of human erythrocyte membranes by free fatty acids or phospholipase A2 J Membr Biol 69:65–76

  12. 12.

    Tamura M, Kuwano H, Kinoshita T, Inagami T (1985) Identification of linoleic and oleic acids as endogenous Na+, K+-ATPase inhibitors from acute volume-expanded hog plasma. J Biol Chem. 260:9672–9677

  13. 13.

    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

  14. 14.

    Buckalew VM Jr, Morris M, Campbell WG, Rauch AL (1987) Plasma inhibitors of Na, K-ATPase: relation to salt balance and hypertension. Klin Wochenschr 65 [Suppl VIII]:133–138

  15. 15.

    Kashiwamata S, Goto S, Semba RK, Suzuki FN (1979) Inhibition by bilirubin of (Na++K+)-activated adenosine triphosphatase and K+-activated p-nitrophenylphosphatase activities of NaI-treated microsomes from young rat cerebrum. J Biol Chem 254:4577–4584

  16. 16.

    Vasdev SC, Longerich LL, Ittel TH, Johnson E, Barrowman JA, Gault MH (1986) Bile salts as endogenous digitalis like factors. Clin Invest Med 9:201–208

  17. 17.

    Vasdev S, Longerich L, Johnson E, Brent D, Gault MH (1985) Dehydroepiandrosterone sulfate as a digitalislike factor in plasma of healthy human adults. Res Commun Chem Pathol Pharmacol 49:387–399

  18. 18.

    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

  19. 19.

    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 Commun 131:1234–1240

  20. 20.

    Tamura M, Lam T-T, Inagami T (1987) Further characterization of the endogenous ouabain-like Na+, K+-ATPase inhibitor. Circulation 4:345

  21. 21.

    Buckalew VM Jr, Gruber KA (1984) Natriuretic hormone Annu Rev Physiol 46:343–358

  22. 22.

    Morgan K, Lewis MD, Spurlock G, Collins PA, Foord SM, Southgate K, Scanlon MF, Mir MA (1985) Characterization and partial purification of the sodium-potassium-ATPase inhibitor released from cultured rat hypothalamic cells. J Biol Chem 260:13595–13600

  23. 23.

    English LH, Cantlly LC (1986) Delta endotoxin is a potent inhibitor of the (Na,K)-ATPase. J Biol Chem 261: 1170–1173

  24. 24.

    Matsukawa R, Terao N, Hayakawa M, Takiguchi H (1981) Effects of prostaglandin A2 and Na+,K+-ATPase activity in basolateral plasma membrane of rat intestine in vitro. Biochem Biophys Res Commun 101:1305–1310

  25. 25.

    Schwartzman M, Ferreri NR, Carroll MA, Songu-Mize E, McGiff JC (1985) Renal cytochrome P450-related arachidonate metabolite inhibits (Na++K+)ATPase. Nature 314:620–622

  26. 26.

    Marver D, Schmitz JM (1987) The influence of various lipoxygenase pathway metabolites of arachidonic acid (HPETEs/HETEs) on NaK ATPase activity Kidney Int. 31:278

  27. 27.

    Haupert GT Jr, Carilli CT, Cantley LC (1984) Hypothalamic sodium-transport inhibitor is a high-affinity reversible inhibitor of Na+-K+-ATPase. Am J Physiol 247: F919-F924

  28. 28.

    Alaghband-Zadeh J, Fenton S, Hancock K, Millett J, Wardener HE de (1983) Evidence that the hypothalamus may be a source of a circulating Na+-K+-ATPase inhibitor. J Endocrinol 98:221–226

  29. 29.

    Rauch AL, Buckalew VM (1987) Tissue distribution of an endogenous ligand of the digitalis receptor. Fed Proc 46: 1407

  30. 30.

    Rauch AL, Buckalew VM (1987) Characterization of a circulating inhibitor of Na,K ATPase. Kidney Int 31:307

  31. 31.

    Pollock DM, Mullins MM, Banks RO (1983) Failure of atrial myocardial extract to inhibit renal Na+,K+-ATPase. Renal Physiol 6:295–299

  32. 32.

    Trippodo NC, Cole FE, MacPhee AA (1984) Atrial natriuretic factor: sodium transport in human erythrocytes. Clin Sci 67:403–405

  33. 33.

    Sagnella GA, Nolan DA, Shore AC, MacGregor GA (1985) Effects of synthetic atrial natriuretic peptides on sodium-potassium transport in human erythrocytes. Clin Sci 69:223–226

  34. 34.

    Matsui K, Kimura T, Ota K, Shoji M, Inoue M, Iitake K, Yoshinaga K (1987) A rapid bioassay for quantification of atrial natriuretic polypeptides. Am J Physiol 252: R1009-R1014

  35. 35.

    Portman OW, Soltys P, Alexander M, Osuga T (1970) Metabolism of lysolecithin in vivo: effects of hyperlipemia and atherosclerosis in squirrel monkeys. J Lipid Res 11: 596–604

  36. 36.

    Weltzien HU (1979) Cytolytic and membrane-perturbing properties of lysophosphatidylcholine. Biochim Biophys Acta 559:259–287

  37. 37.

    Corr PB, Snyder DW, Cain ME, Crafford WA Jr, Gross RW, Sobel BE (1981) Electrophysiological effects of amphiphiles on canine Purkinje fibers. Implications for dysrhythmia secondary to ischemia. Circ Res 49:354–363

  38. 38.

    Hamlyn JM, Schenden JA, Zyren J, Baczynskyj L (1987) Purification and characterization of digitalislike factors from human plasma. Hypertension 10:171–177

  39. 39.

    Rauch AL, Buckalew VM Jr (1988) Lysophosphatidylcholine is natriuretic and its plasma level is increased by acute volume expansion. Am J Physiol 254 (in press)

  40. 40.

    Gow A, Winzor DJ, Smith R (1987) Equilibrium binding of myristollysophosphatidylcholine to bovine myelin basic protein: an example of ligand-mediated acceptor association. Biochemistry 26:982–987

  41. 41.

    Williamson HE (1965) Natriuretic action of certain adrenocortical androgens. Steroids 6:365–369

  42. 42.

    Crabos M, Grichois M, Wainer I, Cloix JF (1987) Chemistry and biochemistry of sodium transport inhibitors in plasma and urine. In: Puschett JB, Greenberg A. (eds) Diuretics II: chemistry, pharmacology and clinical applications. Proceeding of the Second International Conference on Diuretics, June 1986, Cascais, Portugal. Amsterdam Elsevier, New York, pp 756–762

  43. 43.

    Wardener HE de, Millett J, Holland S, MacGregor GA, Alaghband-Zadeh J (1987) Ouabainlike Na+,K+-ATPase inhibitor in the plasma of normotensive and hypertensive humans and rats. Hypertension 10 [Suppl]: 152–156

  44. 44.

    Guyton AC, Granger HJ, Coleman TG (1971) Autoregulation of the total systemic circulation and its relation to control of cardiac output and arterial pressure. Circ Res 28 [Suppl I]:193–197

  45. 45.

    Haddy FJ, Overbeck HW (1976) The role of humoral agents in volume expanded hypertension. Life Sci 19: 935–948

  46. 46.

    Buckalew VM Jr, Haddy FJ (1988) The role of digitalis-like factor in the pathology of hypertension. In: Laragh JH, Brenner B (eds) Endocrine mechanisms in hypertension, vol II. Raven Press, New York (in press)

  47. 47.

    Haddy FJ, Pamnani MB (1987) Natriuretic hormones in low renin hypertension. Klin Wochnschr 65:154–160

  48. 48.

    Bianchi G, Carafoli E, Scarpa A (eds) (1986) Membrane pathology. New York Academy of Sciences, New York

  49. 49.

    Blaustein MP (1977) Sodium ions, calcium ions, blood pressure regulation and hypertension: a reassessment and a hypothesis. Am J Physiol 232:C165-C173

  50. 50.

    Guthrie GP Jr (1984) Effects of digoxin on responsiveness to the pressor actions of angiotensin and norepinephrine in man. J Clin Endocrinol Metab 58:76–80

  51. 51.

    Portman OW, Illingworth DR (1974) Factors determining the concentrations of lysolecithin in plasma and tissues. Scand J Clin Lab Invest 33 [Suppl 137]:49–55

  52. 52.

    Postnov YV, Orlov SN (1985) Ion transport across plasma membrane in primary hypertension. Physiol Rev 65: 904–945

  53. 53.

    Tarazi RC (1976) Hemodynamic role of extracellular fluid in hypertension. Circ Res 38 [Suppl II]:II73-II83

  54. 54.

    Hamlyn JM, Blaustein MP (1986) Sodium chloride, extracellular fluid volume, and blood pressure regulation. Am J Physiol 251:F563-F575

  55. 55.

    London GM, Safar ME, Weiss YA, Corvol PL, Lehner JP, Menard JM, Simon AC, Miliez PL (1977) Volume-dependent parameters in essential hypertension. Kidney Int 11:204–208

  56. 56.

    Hamlyn JM, Levinson PD, Ringel R, Levin PA, Hamilton BP, Blaustein MP, Kowarski AA (1985) Relationships among endogenous digitalis-like factors in essential hypertension. Fed Proc 44:2782–2788

  57. 57.

    Edmondson RPS, MacGregor GA (1981) Leukocyte cation transport in essential hypertension: its relation to the renin-angiotensin system. Br Med J 282:1267–1269

  58. 58.

    MacGregor GA, Fenton S, Alghband-Zadeh J, Markandu N, Roulston JE, Wardener HE de (1981) Evidence for a raised concentration of a circulating sodium transport inhibitor in essential hypertension. Br Med J 283: 1355–1357

  59. 59.

    Deray G, Pernollet MG, Devynck MA, Zingraff J, Touam A, Rosenfeld J, Meyer P (1986) Plasma digitalis like activity in essential hypertension or end-stage renal disease. Hypertension 8:632–638

  60. 60.

    Weder AB (1986) Red-cell lithium-sodium countertransport and renal lithium clearance in hypertension. N Engl J Med 314:198–201

  61. 61.

    Graves SW, Valdes R Jr, Brown BA, Knight AB, Craig HR (1984) Endogenous digoxin-immunoreactive substance in human pregnancies. J Clin Endocrinol Metab 58:748–751

  62. 62.

    Valdes R Jr, Graves SW, Brown BA, Landt M (1983) Endogenous substance in newborn infants causing false positive digoxin measurements. J Pediatr 102:947–950

  63. 63.

    Graves SW (1987) The possible role of digitalislike factors in pregnancy-induced hypertension. Hypertension 10 [Suppl]:I84-I86

  64. 64.

    Gusdon JP Jr, Buckalew VM Jr, Hennessy JF (1984) A digoxin-like immunoreactive substance in preeclampsia. Am J Obstet Gynecol 150:83–85

  65. 65.

    Kelly RA, O'Hara DS, Mitch WE, Steinman TI, Goldszer RC, Solomon HS, Smith TW (1986) Endogenous digitalis-like factors in hypertension and chronic renal insufficiency. Kidney Int 30:723–729

  66. 66.

    Vasdev S, Johnson E, Longerich L, Prabhakaran VM, Gault MH (1987) Plasma endogenous digitalis-like factors in healthy individuals and in dialysis dependent and kidney transplant patients. Clin Nephrol 27:169–174

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Buckalew, V.M. Circulating digitalis-like factors. Pediatr Nephrol 2, 264–270 (1988). https://doi.org/10.1007/BF00862603

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Key words

  • Digitalis-like factor
  • Natriuretic hormone
  • Hypertension