Na,K-ATPase expression in normal and failing human left ventricle

  • Paul D. Allen
  • T. A. Schmidt
  • J. D. Marsh
  • K. Kjeldsen

Summary

The expression of the Na,K-ATPase was studied in both normal and failing human myocardium which was collected within 5 min of cardiac explanation in preparation for orthotopic transplantation or at the time of organ harvest. Abundance of mRNA for all three catalytic α subunits of the Na,K-ATPase was analyzed in samples from patients with end-stage heart failure due to either ischemic or dilated cardiomyopathy, as well as from normal controls. Vanadate facilitated 3H-oubain binding before and after a Digibind wash was analyzed on tissue from a subset of these patients. mRNA analysis demonstrated that all three catalytic Na,K-ATPase α subunits were expressed in human heart and that there was no evidence for change in relative expression or abundance induced by disease. The specific digitalis receptor concentration was 760 ± 58 and 614 ± 47 pmol/g wet weight in the samples from normal and failing hearts, respectively (p = NS). From these studies it can be concluded that, whereas there is a tendency for a decrease in the number of oubain receptors in heart failure, there is no significant alteration in the expression of Na,K-ATPase message or protein caused by chronic heart failure.

Key words

Heart failure myocardium Na,K-ATPase; 3H-oubain binding heart mRNA 

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References

  1. 1.
    Aalkjaer C, Kjeldsen K, Norgaard A, Clausen T, Mulvany MJ (1985) Oubain binding and Na + content in resistance vessels and skeletal muscles of SHR and K + -depleted rats. Hypertension 7: 277–286PubMedGoogle Scholar
  2. 2.
    Azuma KK, Hensley CB, Putnam DS, McDonough A A (1990) Differential regulation of Na,K-ATPase α1, α2, and β in heart, muscle and brain of hypokalemic rats. J Gen Physiol 96: 87aGoogle Scholar
  3. 3.
    Bluschke V, Bonn R, GreeffK (1976) Increase in the (Na+ + K +)-ATPase activity in heart muscle after chronic treatment with digitoxin or potassium deficient diet. Eur J Pharmacol 37: 189–191PubMedCrossRefGoogle Scholar
  4. 4.
    Boheler KR, Carrier L, Bastie D, Allen PD, Komajda M, Mercadier JJ, Schwartz K (1991) Skeletal actin mRNA increases in the human heart during ontogenic development and is the major isoform of control and failing adult hearts. J. Clin Invest 88: 323–330PubMedCrossRefGoogle Scholar
  5. 5.
    Bonn R, GreeffK (1978) The effect of chronic administration of digitoxin on the activity of the myocardial (na + K)-ATPase in guinea-pigs. Arch Int Pharmacodyn Ther 233: 53–64PubMedGoogle Scholar
  6. 6.
    Bohm M, Ungerer M, Erdmann E (1990) Beta adrenoceptors and m-cholinoceptors in myocardium of hearts with coronary artery disease or idiopathic dilated cardiomyopathy removed at cardiac transplantation. Am J Cardiol 66: 880–882PubMedCrossRefGoogle Scholar
  7. 7.
    Brodie C, Sampson SR (1985) Effects of chronic oubain treatment on [3H] oubain binding sites and electrogenic component of membrane potential in cultured rat myotubes. Brain Res 247: 121–123CrossRefGoogle Scholar
  8. 8.
    Chirgwin JM, Przybyla AE, MacDonald RJ, Rutter WJ (1979). Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry (Wash) 18: 5294–5299.CrossRefGoogle Scholar
  9. 9.
    Cutler CP, Cramb G (1990) The isoforms of Na,K-ATPase in myocardial tissues of the Milan hypertensive rat. J Gen Physiol 96: 63aGoogle Scholar
  10. 10.
    DePover A, Godfraind T: Interaction of oubain with (Na+ + K+) ATPase from human heart and from guinea-pig heart. Biochem Pharmacol 28: 3051–3056Google Scholar
  11. 11.
    DePover A, Grupp G, Schwartz A, Grupp IL (1991) Coupling of contraction through effects on Na,K-ATPase: changes in Na,K-ATPase isoforms in heart disease? Heart Failure 1: 201–258Google Scholar
  12. 12.
    Erdmann E, Hasse W (1975) Quantitative aspects of oubain binding to human erythrocyte and cardiac membranes. J Physiol (Lond) 251: 617–682Google Scholar
  13. 13.
    Erdmann E, Werdan K, Krawietz W (1984) Influence of digitalis and diuretics on oubain binding sites on human erythrocytes. Klin Wochenschr 62: 87–92PubMedCrossRefGoogle Scholar
  14. 14.
    Ford AR, Aronson JK, Grahame-Smith DG, Carver JG (1979) Changes in cardiac glycoside receptor sites, 86 rubidium uptake and intracellular sodium concentrations in the erythrocytes of patients receiving digoxin during the early phases of treatment of cardiac failure in regular rhythm and of atrial fibrillation. Br J Clin Pharmacol 8: 125–134PubMedGoogle Scholar
  15. 15.
    Grupp G, Grupp IL, Melvin DB, Schwartz A (1988) Functional evidence in diseased human heart fibers for multiple sensitivities of the inotropic oubain receptor Na,K-ATPase, in Membrane Biophysics III: Biological Transport. New York, Alan R Liss, pp. 215–222.Google Scholar
  16. 16.
    Hansen O, Skou JC (1973) A study on the influence of the concentration of Mg2+, Pi, K1+, Na+, and Tris on (Mg2+ + Pi)-supported g-strophanthin binding to (Na+ — K+) activated ATPase from ox brain. Biochim Biophys Acta 311: 51–66PubMedCrossRefGoogle Scholar
  17. 17.
    Herrera VL, Chobanian AV, Opazo NR: Isoform specific modulation of Na+, K+-ATPase alpha-subunit gene expression in hypertension. Science 241: 221–223Google Scholar
  18. 18.
    Herrera YLM, Ruiz-Opazo N (1990) Alteration of al Na,K-ATPase 86Rb+ influx by a single amino acid substitution. Science 249: 1023PubMedCrossRefGoogle Scholar
  19. 19.
    Kim D, Marsh JD, Barry WH, Smith TW (1984) Effects of growth in low potassium medium or oubain on membrane Na,K-ATPase, cation transport, and contractility in cultured chick heart cells. Circ Res 55: 39–48PubMedGoogle Scholar
  20. 20.
    Lee SW, Schwartz A, Adams RJ et al (1983) Decrease in Na,K-ATPase activity and [3H]oubain binding sites in sarcolemma from hearts of spontaneously hypertensive rats. Hypertension 5: 683Google Scholar
  21. 21.
    Ligrel JB, Orlowski J, Shull MM, Price EM (1990) Molecular genetics of Na,K-ATPase. Prog Nucleic Acid Res Mol Biol 38: 37–89CrossRefGoogle Scholar
  22. 22.
    Maixent JM, Lelievre L (1987) Differential inactivation of inotropic and toxic digitalisre- ceptors in ischemic dog hearts. Molecular basis for the deleterious effects of digitalis. J Biol Chem 262: 12458Google Scholar
  23. 23.
    Nojima H, Yagawa Y, Kawakami K (1989) The Na,K-ATPase alpha 2 subunit gene displays restriction fragment length polymorphisms between the genomes of normotensive and hypertensive rats. J Hypertension 7: 937CrossRefGoogle Scholar
  24. 24.
    Norgaard A, Kjeldsen K, Hansen O, Clausen T, Larsen CG, Larsen FG (1986) Quantification of the 3H-oubain binding site concentration in human myocardium: a postmortem study. Cardiovasc Res 30: 428–435CrossRefGoogle Scholar
  25. 25.
    Norgaard A, Bagger JP, Bjerregaard P, Baandrup U, Kjeldsen K, Thomsen PEB (1988) Relation of left ventricular function and Na,K-pump concentration in suspected idiopathic dilated cardiomyopathy. Am J Cardiol 61: 1312–1315PubMedCrossRefGoogle Scholar
  26. 26.
    Norgaard A, Kjeldsen K (1989) Human myocardial Na,K-pumps in relation to heart disease. J Appl Cardiol 4: 239–245Google Scholar
  27. 27.
    Rayson BM (1989) Rates of synthesis and degradation of Na+ — K+-ATPase during chronic oubain treatment. Am J Physiol 356: C75–C80Google Scholar
  28. 28.
    Schmidt TA, Kjeldsen K (1991) Enhanced clearance of specifically bound digoxin from human myocardial and skeletal muscle samples by specific digoxin antibody fragments. Subsequent complete digitalis glycoside receptor ( Na,K-ATPase) quantification. J Cardiovasc Pharmacol 17: 670–677Google Scholar
  29. 29.
    Schwinger RH, Böhm M, Erdmann E (1990) Effectivness of cardiac glycosides in human myocardium with the without “downregulated” beta-adrenoceptors. J Cardiovas. Pharmacol 15: 692–697Google Scholar
  30. 30.
    Smith TW, Antman EM, Friedman PL (1984) Digitalis glycosides: mechanisms and manifestations of toxicity. Progr Cardiovasc Dis 1984; 26–413Google Scholar
  31. 31.
    Smith TW (1988) Digitalis. Mechanisms of action and clinical use. N Engl J Med 318: 358–365PubMedCrossRefGoogle Scholar
  32. 32.
    Sweadner KJ (1979) Two molecular forms of (Na+ + K+) simulated ATPase in brain separation, and difference in affinity for strophanthidin. J Biol Chem 254: 6060–6067PubMedGoogle Scholar

Copyright information

© Dr. Dietrich Steinkopff Verlag GmbH & Co.KG, Darmstadt 1992

Authors and Affiliations

  • Paul D. Allen
    • 1
    • 4
  • T. A. Schmidt
    • 2
  • J. D. Marsh
    • 3
  • K. Kjeldsen
    • 2
  1. 1.Department of AnesthesiaBrigham and Women’s HospitalBostonUSA
  2. 2.Department of Medicine B, Division of CardiologyRigshospitalet, Copenhagen University School of MedicineDenmark
  3. 3.Department of Medicine, Cardiovascular DivisionBrigham and Women’s HospitalUSA
  4. 4.Department of AnesthesiaBrigham and Women’s HospitalBostonUSA

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