Structure of the Enzyme and Mechanism of Action of Digitalis
  • Arnold Schwartz
  • John H. Collins


There seems to be no doubt that the Na+/K+-ATPase is the enzyme that represents the machinery of active transport of sodium and potassium across cell membranes. Very early in evolution, critical ion gradients must have been established; movement involving the expenditure of energy across membrane barriers must also have represented an early development, for without this mechanism, important biological processes could not exist. These include nerve excitability, motility, maintenance and possible regulation of cell volume, excretion, and reabsorption, a variety of sodium-dependent or -coupled transport processes, and electrical and mechanical activity of muscle. While an ATP-dependent process for transport was recognized for many years, it was not until the work of J. C. Skou (1957, 1960) that a specific enzyme system was recognized. Among the criteria for recognition of this enzyme is the very potent inhibition of ATP hydrolysis by cardiac glycosides. Thousands of papers have been published using ouabain, a water-soluble glycoside, as a marker for this important enzyme. When we examine the structure of a typical cardiac glycoside, we are struck with its apparent similarity to hormonal steroids. The geometrical configuration, however, is quite different Like the steroids, the glycosides are used in very low concentrations to produce their effects. The primary effect on the intact organism is an increased force of contraction of heart muscle, a discovery made by William Withering more than 200 years ago. This class of drugs is still the most widely used in the treatment of heart failure. The fascination with this drug also arises from its very potent inhibitory effect on Na+/K+-ATPase, so it is not illogical that it is employed as a “chemical tool” to, on the one hand, dissect the mechanism of action of the Na+/K+-ATPase and on the other hand to search for the mechanism of its action on the heart.


Cardiac Glycoside Positive Inotropic Effect Hormonal Steroid Ouabain Binding Positive Inotropic Action 
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  1. Akera, T. (1977). Science 198, 569–574.CrossRefGoogle Scholar
  2. Akera, T., and Brody, T. M. (1978). Pharmacol. Rev. 29, 187–220.Google Scholar
  3. Albers, R. W., Koval, G. J., and Seigel, G. J. (1968). Mol. Pharmacol. 4, 324–336.Google Scholar
  4. Allen, G. (1980). Biochem. J. 187, 545–563.Google Scholar
  5. Blostein, R., Pershadsingh, M. A., Drapeau, P., and Chu, L. (1979). In Na,K-ATPase: Structure and Kinetics (J. C. Skou and J. B. Norby, eds.), Academic Press, New York.Google Scholar
  6. Bodeman, H. H., and Hoffman, J. F. (1976). J. Gen. Physiol. 67, 497–525.CrossRefGoogle Scholar
  7. Castro, J., and Farley, R. A. (1979). J. Biol. Chem. 254, 2221–2228.Google Scholar
  8. Churchill, L., Peterson, G. L., and Hokin, L. E. (1979). Biochem. Biophys. Res. Commun. 90, 488–490.CrossRefGoogle Scholar
  9. Collins, J. H., and Lane, L. K. (1978). Fed. Proc. 37, 1301.Google Scholar
  10. Craig, W. S., and Kyte, J. (1980). J. Biol. Chem. 255, 6262–6269.Google Scholar
  11. Dowd, F., Pitts, B., and Schwartz, A. (1976). Arch. Biochem. Bophys. 175, 321–331.CrossRefGoogle Scholar
  12. Farley, R. A., Goldman, D. W., and Bayley, H. (1980). J. Biol. Chem. 255, 860–864.Google Scholar
  13. Forbush, B., and Hoffman, J. F. (1979). Biochim. Biophys. Acta 555, 299–306.CrossRefGoogle Scholar
  14. Forbush, B., Kaplan, J. H., and Hoffman, J. F. (1978). Biochemistry 17, 3667–3676.CrossRefGoogle Scholar
  15. Hall, C., and Ruoho, A. (1980). Proc. Natl. Acad. Sci. USA 77, 4529–4533.CrossRefGoogle Scholar
  16. Hopkins, B. L., Wagner, H. W., Jr., and Smith, T. W. (1976). J. Biol. Chem. 251, 4365–4371.Google Scholar
  17. Kyte, J. (1972). J. Biol. Chem. 247, 7642–7649.Google Scholar
  18. Lane, L. K., Potter, J. D., and Collins, J. H. (1979). Prep. Biochem. 9, 157–170.CrossRefGoogle Scholar
  19. Lindenmayer, G. E., and Schwartz, A. (1973). J. Biol. Chem. 248, 1291–1300.Google Scholar
  20. Lüllman, H., and Peters, T. (1977). Clin. Exp. Pharmacol. Physiol. 4, 49–57.CrossRefGoogle Scholar
  21. Matsui, H., and Schwartz, A. (1966a). Biochem. Biophys. Res. Commun. 25, 147–150.CrossRefGoogle Scholar
  22. Matsui, H., and Schwartz, A. (1966b). Biochim. Biophys. Acta 128, 380–390.Google Scholar
  23. Matsui, H., and Schwartz, A. (1968). Biochim. Biophys. Acta 151, 655–663.Google Scholar
  24. Noble, D. (1980). Cardiovasc. Res. 14, 495–514.CrossRefGoogle Scholar
  25. Perrone, J. R., Hackney, J. F., Dixon, J. F., and Hokin, L. C. (1975). J. Biol. Chem. 250, 4178–4184.Google Scholar
  26. Peterson, G. L., and Hokin, L. E. (1980). Biochem. J. 192, 107–118.Google Scholar
  27. Racker, E. (1976). Trends Biochem. Sci. 1, 244.Google Scholar
  28. Reeves, A. S., Collins, J. H., and Schwartz, A. (1980). Biochem. Bophys. Res. Commun. 95, 1591–1598.CrossRefGoogle Scholar
  29. Repke, K. R. H. (1963). In New Aspects of Cardiac Glycosides (W. Wilbrandt, ed.), Vol. III, pp. 47–73, Pergamon Press, Elmsford, N.Y.Google Scholar
  30. Rivas, E., Lew, V., and De Robertis, E. (1972). Biochim. Biophys. Acta 290, 419–423.CrossRefGoogle Scholar
  31. Robinson, J. D. (1980). Biochem. Pharmacol. 29, 1995–2000.CrossRefGoogle Scholar
  32. Rogers, T. B., and Lazdunski, M. (1979). FEBS Lett. 98, 373–376.CrossRefGoogle Scholar
  33. Rossi, B., Viulleumier, P., Gache, C., Balema, M., and Lazdunski, M. (1980). J. Biol. Chem. 255, 9936–9941.Google Scholar
  34. Schwartz, A., and Adams, R. (1980). Circ. Res. 46 (Suppl. I), 154–160.Google Scholar
  35. Schwartz, A., Matsui, H., and Laughter, A. H. (1968). Science 159, 323–325.CrossRefGoogle Scholar
  36. Schwartz, A., Lindenmayer, G. E., and Allen, J. C. (1975). Pharmacol. Rev. 27, 3–134.Google Scholar
  37. Skou, J. C. (1957). Biochim. Biophys. Acta 23, 394–401.CrossRefGoogle Scholar
  38. Skou, J. C. (1960). Biochim. Biophys. Acta 42, 6–23.CrossRefGoogle Scholar
  39. Solomon, A. K., Gill, T. J., 3rd, and Lennard, G. (1956). J. Gen. Physiol. 40, 327–350.CrossRefGoogle Scholar
  40. Thorp, R. H., and Cobbin, L. B. (1967). In Cardiac Stimulant Substances, pp. 263–268, Academic Press, New York.Google Scholar
  41. Wallick, E. T., Lane, L. K., and Schwartz, A. (1979). Annu. Rev. Physiol. 41, 397–411.CrossRefGoogle Scholar
  42. Wellsmith, N. V., and Lindenmayer, G. E. (1980). Circ. Res. 47, 710–720.Google Scholar

Copyright information

© Plenum Press, New York 1982

Authors and Affiliations

  • Arnold Schwartz
    • 1
  • John H. Collins
    • 1
  1. 1.Department of Pharmacology and Cell BiophysicsUniversity of Cincinnati College of MedicineCincinnatiUSA

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