Effects of Cardiac Glycosides on Na+, K+-ATPase

  • T. Akera
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 56 / 1)

Abstract

The inhibitory action of cardiac glycosides on active Na + and K + transport across the cell membrane had been demonstrated in the early 1950 s (Schatzmann, 1953; see Hajdu and Leonard, 1959). Thus, with the discovery of Na +, K+-ATPase (Skou, 1957; Hess and Pope, 1957), the effect of these glycosides on the enzyme activity was examined and a specific inhibition was observed (Post et al., 1960; Skou, 1960; see Fig. 1). The interaction of cardiac glycosides with the enzyme, and its possible relationship to the pharmacologic or toxic actions of these agents have been extensively studied during the last two decades (see the following review articles: Glynn, 1964; Repke, 1964, 1965; Skou, 1965; Langer, 1971, 1972a; Lee and Klaus, 1971; Smith and Haber, 1973; Schwartz et al., 1975; Akera and Brody, 1976, 1977; Akera, 1977; Brody and Akera, 1977; Langer, 1977; Okita, 1977; Wallick et al., 1977).

Keywords

Ischemia Ghost Nash Lactone Phosphatidyl Ethanolamine 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ahmed, K., Judah, J.D.: On the action of strophanthin G. Can. J. Biochem. 43, 877–880 (1965)Google Scholar
  2. Akera, T.: Quantitative aspects of the interaction between ouabain and (Na ++K+)-activated ATPase in vitro. Biochim. Biophys. Acta (Amst.) 249, 53–62 (1971)Google Scholar
  3. Akera, T.: Membrane adenosinetriphosphatase: A digitalis receptor? Science 198, 569–574 (1977)PubMedGoogle Scholar
  4. Akera, T., Brody, T.M.: Membrane adenosine triphosphatase: The effect of potassium on the formation and dissociation of the ouabain-enzyme complex. J. Pharmacol. Exp. Ther. 176, 545–557 (1971)PubMedGoogle Scholar
  5. Akera, T., Brody, T.M.: Inotropic action of digitalis and ion transport. Life Sci. 18, 135–142 (1976)PubMedGoogle Scholar
  6. Akera, T., Brody, T.M.: The role of Na+, K+-ATPase in the inotropic action of digitalis. Pharmacol. Rev. 29, 187–220 (1977)Google Scholar
  7. Akera, T., Cheng, V.-J.K.: A simple method for the determination of affinity and binding site concentration in receptor binding studies. Biochim. Biophys. Acta (Amst.) 470, 412423 (1977)Google Scholar
  8. Akera, T., Larsen, F.S., Brody, T.M.: The effect of ouabain on sodium-and potassium-activated adenosine triphosphatase from the hearts of several mammalian species. J. Pharmacol. Exp. Ther. 170, 17–26 (1969)PubMedGoogle Scholar
  9. Akera, T., Larsen, F.S., Brody, T.M.: Correlation of cardiac sodium-and potassium-activated adenosine triphosphatase activity with ouabain-induced inotropic stimulation. J. Pharmacol. Exp. Ther. 173, 145–151 (1970)PubMedGoogle Scholar
  10. Akera, T., Hook, J.B., Tobin, T., Brody, T.M.: Cardiac glycoside sensitivity of (Na + K+)-activated ATPase in new-born rats. Res. Commun. Chem. Pathol. Pharmacol. 4, 699–706 (1972)PubMedGoogle Scholar
  11. Akera, T., Baskin, S.I., Tobin, T., Brody, T.M.: Ouabain: Temporal relationship between the inotropic effect and the in vitrobinding to, and dissociation from, (Na ++K+)-activated ATPase. Naunyn-Schmiedebergs Arch. Pharmacol. 277, 151–162 (1973)Google Scholar
  12. Akera, T., Brody, T.M., So, R.H.-M., Tobin, T., Baskin, S.I.: Factors and agents that in-fluence cardiac glycoside-Na+, K +-ATPase interaction. Ann. N.Y. Acad. Sci. 242, 617–634 (1974a)Google Scholar
  13. Akera, T., Tobin, T., Gatti, A., Shieh, I.-S., Brody, T.M.: Effect of potassium on the conformational state of the complex of ouabain with sodium-and potassium-dependent adenosine triphosphatase. Mol. Pharmacol. 10, 509–518 (1974b)Google Scholar
  14. Akera, T., Bennet, R.T., Olgaard, M.K., Brody, T.M.: Cardiac Na+, K+-adenosine triphosphatase inhibition by ouabain and myocardial sodium: A computer simulation. J. Pharmacol. Exp. Ther. 199, 287–297 (1976a)Google Scholar
  15. Akera, T., Ku, D., Tobin, T., Brody, T.M.: The complexes of ouabain with sodium and potassium activated adenosine triphosphatase formed with various ligands: Relationship to the complex formed in the beating heart. Mol. Pharmacol. 12, 101–114 (1976b)Google Scholar
  16. Akera, T., Ku, D., Brody, T.M.: Lack of effect on brain stem and cerebral cortex Na+, K+-ATPase during heart block produced by chronic digoxin treatment. Eur. J. Pharmacol. 45, 243–249 (1977a)Google Scholar
  17. Akera, T., Olgaard, M.K., Temma, K., Brody, T.M.: Development of the positive inotropic action of ouabain: Effects of transmembrane sodium movement. J. Pharmacol. Exp. Ther. 203, 675–684 (1977b)Google Scholar
  18. Akera, T., Temma, K., Wiest, S.A., Brody, T.M.: Reduction of the equilibrium binding of cardiac glycosides and related compounds to Na+, K+-ATPase as a possible mechanism for the potassium-induced reversal of their toxicity. Naunyn-Schmiedebergs Arch. Pharmacol. 304, 157–165 (1978)Google Scholar
  19. Akera, T., Brody, T.M., Wiest, S.A.: Saturable adenosine 5’-triphosphate-independent binding of (3H)-ouabain to brain and cardiac tissue in vitro. Brit. J. Pharmacol. 65, 403–409 (1979a)Google Scholar
  20. Akera, T., Choi, Y.R., Yamamoto, S.: Potassium-induced changes in Na, K-ATPase: Influences on the interaction between cardiac glycosides and enzyme. In: Na, K-ATPase: Structure and Kinetics. Skou, J.C., Nerby, J.G. (eds.), pp. 405–420. London: Academic Press 1979bGoogle Scholar
  21. Akera, T., Wiest, S.A., Brody, T.M.: Differential effect of potassium on the action of di- goxin and digoxigenin in guinea-pig heart. Eur. J. Pharmacol. 57, 343–351 (1979c)Google Scholar
  22. Akera, T., Yamamoto, S., Chubb, J., McNish, R., Brody, T.M.: Biochemical basis for the low sensitivity of the rat heart to digitalis. Naunyn-Schmiedebergs Arch. Pharmacol. 308, 81–88 (1979d)Google Scholar
  23. Albers, R.W., Koval, G.J., Siegel, G.J.: Studies on the interaction of ouabain and other cardioactive steroids with sodium-potassium-activated adenosine triphosphatase. Mol. Pharmacol. 4, 324–336 (1968)Google Scholar
  24. Allen, D.G., Blinks, J R • Calcium transients in aequorin-injected frog cardiac muscle. Nature (Lond.) 273, 509–513 (1978)Google Scholar
  25. Allen, J.C., Schwartz, A.: A possible biochemical explanation for the insensitivity of the rat to cardiac glycosides. J. Pharmacol. Exp. Ther. 168, 42–46 (1969)PubMedGoogle Scholar
  26. Allen, J.C., Schwartz, A.: Effects of potassium, temperature, and time on ouabain interaction with the cardiac Na+, K+-ATPase: Further evidence supporting an allosteric site. J. Mol. Cell. Cardiol. 1, 39–45 (1970)PubMedGoogle Scholar
  27. Allen, J.C., Schwartz, A.: Human cardiac Na+, K+-ATPase: A pharmacologic receptor for cardiac glycosides. Cardiovasc. Res. Center Bull. 10, 133–141 (1972)Google Scholar
  28. Allen, J.C., Besch, H.R. Jr., Glick, G., Schwartz, A.: The binding of tritiated ouabain to sodium-and potassium-activated adenosine triphosphatase and cardiac relaxing system of perfused dog heart. Mol. Pharmacol. 6, 441–443 (1970a)Google Scholar
  29. Allen, J.C., Lindenmayer, G.E., Schwartz, A.: An allosteric explanation for ouabain-induced time-dependent inhibition of sodium, potassium-adenosine triphosphatase. Arch. Biochem. Biophys. 141, 322–328 (1970b)Google Scholar
  30. Allen, J.C., Harris, R.A., Schwartz, A.: The nature of the transport ATPase-digitalis complex. I. Formation and reversibility in the presence and absence of a phosphorylated enzyme. Biochem. Biophys. Res. Commun. 42, 366–370 (1971a)Google Scholar
  31. Allen, J.C., Harris, R.A., Schwartz, A.: The nature of the transport ATPase-digitalis complex. II. Some species differences and ouabain “exchange” characteristics. J. Mol. Cell. Cardiol. 3, 297–300 (1971b)Google Scholar
  32. Allen, J.C., Martines-Maldonado, M., Eknoyan, G., Suki, W.N., Schwartz, A.: Relation between digitalis binding in vivo and inhibition of sodium, potassium-adenosine triphosphatase in canine kidney. Biochem. Pharmacol. 20, 73–80 (1971c)Google Scholar
  33. Allen, J.C., Entman, M.L., Schwartz, A.: The nature of the transport adenosine triphos-phatase-digitalis complex. VIII. The relationship between in vivo-formed (3H-ouabainNa+, K +-adenosine triphosphatase) complex and ouabain-induced positive inotropism. J. Pharmacol. Exp. Ther. 192, 105–112 (1975)PubMedGoogle Scholar
  34. Asano, Y., Liberman, U.A., Edelman, I.S.: Thyroid thermogenesis: Relationships between Na+-dependent respiration and Na +K+-adenosine triphosphatase activity in rat skeletal muscle. J. Clin. Invest. 57, 368–379 (1976)PubMedGoogle Scholar
  35. Ash, A.S.F., Schwartz, A.: Sodium-plus-potassium ion-activated adenosine triphosphatase in a heavy-membrane fraction isolated from rat skeletal muscle. Biochem. J. 118, 20P–21P (1970)Google Scholar
  36. Baker, P.F., Willis, J.S.: On the number of sodium pumping sites in cell membranes. Biochim. Biophys. Acta (Amst.) 183, 646–649 (1969)Google Scholar
  37. Baker, P.F., Willis, J.S.: Potassium ions and the binding of cardiac glycosides to mammalian cells. Nature (Lond.) 226, 521–523 (1970)Google Scholar
  38. Baker, P.F., Willis, J S • Inhibition of the sodium pump in squid giant axons by cardiac glycosides: The dependence on extracellular ions and metabolism. J. Physiol. (Lond.) 224, 463–475 (1972)Google Scholar
  39. Balasubramanian, V., McNamara, D.B., Singh, J.N., Dhalla, N.S.: Biochemical basis of heart function. X. Reduction in the Na+-K+-stimulated ATPase activity in failing rat heart due to hypoxia. Can. J. Physiol. Pharmacol. 51, 504–510 (1973)PubMedGoogle Scholar
  40. Barnett, R.E.: Effect of monovalent cations on the ouabain inhibition of the sodium and potassium ion activated adenosine triphosphatase. Biochemistry 9, 4644–4648 (1970)PubMedGoogle Scholar
  41. Baskin, S.I., Akera, T., Puckett, C.R., Brody, S.L., Brody, T.M.: Effect of potassium canrenoate on cardiac functions and (Na+ + K +)-activated ATPase. Proc. Soc. Exp. Biol. Med. 143, 495–498 (1973)PubMedGoogle Scholar
  42. Beauge, L.A., Adragna, N.: The kinetics of ouabain inhibition and the partition of rubidium influx in human red blood cells. J. Gen. Physiol. 57, 576–592 (1971)PubMedGoogle Scholar
  43. Beard, N.A., Rouse, W., Somerville, A.R.: Cardiotonic steroids: Correlation of sodium-potassium adenosine triphosphate inhibition and ion transport in vitro with inotropic activity and toxicity in dogs. Br. J. Pharmacol. 54, 65–74 (1975)PubMedGoogle Scholar
  44. Beller, G.A., Conroy, J., Smith, T.W.: Ischemia-induced alterations in myocardial (Na++K+)-ATPase and cardiac glycoside binding. J. Clin. Invest. 57, 341–350 (1976)PubMedGoogle Scholar
  45. Bentfeld, M., Lüllmann, H., Peters, T., Proppe, D.: Interdependence of ion transport and the action of ouabain in heart muscle. Brit. J. Pharmacol. 61, 19–27 (1977)Google Scholar
  46. Bergelson, L.D., Barsukov, L.I.: Topological asymmetry of phospholipids in membranes. Science 197, 224–230 (1977)PubMedGoogle Scholar
  47. Besch, H.R. Jr., Schwartz, A.: On the mechanism of action of digitalis. J. Mol. Cell. Cardiol. 1, 195–199 (1970)Google Scholar
  48. Besch, H.R. Jr., Allen, J.C., Glick, G., Schwartz, A.: Correlation between the inotropic action of ouabain and its effects on subcellular enzyme systems from canine myocardium. J. Pharmacol. Exp. Ther. 171, 1–12 (1970)PubMedGoogle Scholar
  49. Besch, H.R. Jr., Jones, L.R., Watanabe, A.M.: Intact vesicles of canine cardiac sarcolemma: Evidence from vectorial properties of Na+, K+-ATPase. Circ. Res. 39, 586–595 (1976)Google Scholar
  50. Blaustein, M.P.: Sodium-calcium exchange and the regulation of cell calcium in muscle fi-bers. Physiologist 19, 525–540 (1976)PubMedGoogle Scholar
  51. Blood, B.E., Noble, D.: Glycoside induced inotropism of the heart — more than one mechanism? J. Physiol. (Lond.) 266, 76P–78P (1977)Google Scholar
  52. Bluschke, V., Bonn, R., Greeff, K.: Increase in the (Na+ + K +)-ATPase activity in heart muscle after chronic treatment with digitoxin or potassium defficient diet. Europ. J. Pharmacol. 37, 189–191 (1976)Google Scholar
  53. Bodemann, H.H., Hoffman, J.F.: Side-dependent effects of internal versus external Na and K on ouabain binding to reconstituted human red blood cell ghosts. J. Gen. Physiol. 67, 497–525 (1976a)Google Scholar
  54. Bodemann, H.H., Hoffman, J.F.: Comparison of the side-dependent effects of Na and K on orthophosphate-, UTP-, and ATP-promoted ouabain binding to reconstituted human red blood cell ghosts. J. Gen. Physiol. 67, 527–545 (1976b)Google Scholar
  55. Bonn, R., Greeff, K.: The effect of chronic administration of digitoxin on the activity of the myocardial (Na + K)-ATPase in guinea-pigs. Arch. Int. Pharmacodyn. 233, 53–64 (1978)Google Scholar
  56. Borsch-Galetke, E., Dransfeld, H., Greeff, K.: Specific activity and sensitivity of strophanthin of the Na++K+-activated ATPase in rats and guinea-pigs with hypoadrenalism. Naunyn-Schmiedebergs Arch. Pharmacol. 274, 74–80 (1972)Google Scholar
  57. Böttcher, H., Fischer, K., Proppe, D.: Untersuchungen über die Wirkung von Digoxigeninmono-, -bis-and -tridigitoxosid am Herz-Lungen-Präparat der Katze. Basic. Res. Cardiol. 70, 279–291 (1975)Google Scholar
  58. Boutagy, J., Gelbart, A., Thomas, R.: Cardenolide analogues. IV. Inhibition of Na+, K+-ATPase. Aust. J. Pharmaceut. Sci. NS2, 41–46 (1973)Google Scholar
  59. Brennan, F.J., McCans, J.L., Chiong, M.A., Parker, J.O.: Effects of ouabain on myocardial potassium and sodium balance in man. Circulation 45, 107–113 (1972)PubMedGoogle Scholar
  60. Brody, T.M., Akera, T.: Relations among Na+, K+-ATPase activity, sodium pump activity, transmembrane sodium movement, and cardiac contractility. Fed. Proc. 36, 2219–2224 (1977)Google Scholar
  61. Brown, T.E., Acheson, G.H., Grupp, G.: The saturated-lactone glycoside dihydro-ouabain: Effects on potassium balance of the dog heart. J. Pharmacol. Exp. Ther. 136, 107–113 (1962)PubMedGoogle Scholar
  62. Byrne, J.E., Dresel, P.E.: The effect of temperature and calcium concentration on the action of ouabain in quiescent rabbit atria. J. Pharmacol. Exp. Ther. 166, 354–363 (1969)PubMedGoogle Scholar
  63. Caldwell, R.W., Nash, C.B.: Comparison of effects of aminosugar cardiac glycosides with ouabain and digoxin on Na+, K +-adenosine triphosphatase and cardiac contractile force. J. Pharmacol. Exp. Ther. 204, 141–148 (1977)Google Scholar
  64. Chang, C.C., Trosko, J.E., Akera, T.: Characterization of ultraviolet light-induced ouabainresistant mutations in Chinese hamster cells. Mutation Res. 51, 85–98 (1978)PubMedGoogle Scholar
  65. Charnock, J.S., Potter, H.A.: The effect of Mg’ and ouabain on the incorporation of P32 from ATV’ into Na+- and K+-activated adenosine triphosphatase. Arch. Biochem. Biophys. 134, 42–47 (1969)Google Scholar
  66. Charnock, J.S., Rosenthal, A.S., Post, R.L.: Studies of the mechanism of cation transport. II. A phosphorylated intermediate in the cation stimulated enzymic hydrolysis of adenosine triphosphate. Aust. J. Exp. Biol. 41, 675–686 (1963)Google Scholar
  67. Charnock, J.S., Almeida, A.F., To, R.: Temperature-activity relationships of cation activation and ouabain inhibition of (Na+ +K+)-ATPase. Arch. Biochem. Biophys. 167, 480487 (1975)Google Scholar
  68. Charnock, J.S., Simonson, L.P., Almeida, A.F.: Variation in sensitivity of the cardiac glycoside receptor characteristics of (Na + + K+)-ATPase to lipolysis and temperature. Biochim. Biophys. Acta (Amst.) 465, 77–92 (1977)Google Scholar
  69. Choi, Y.R., Akera, T.: Kinetic studies on the interaction between ouabain and (Na +, K+)-ATPase. Biochim. Biophys. Acta (Amst.) 481, 648–659 (1977)Google Scholar
  70. Choi, Y.R., Akera, T.: Membrane (Na + + K +)-ATPase of canine brain, heart, and kidney: Tissue dependent differences in kinetic properties and the influence of purification procedures. Biochim Biophys. Acta (Amst.) 508, 313–327 (1978)Google Scholar
  71. Clark, A.F., Swanson, P.D., Stahl, W.L.: Increase in dissociation rate constants of cardiotonic steroid-brain (Na + + K+)-ATPase complexes by reduction of unsaturated lactone. J. Biol. Chem. 250, 9355–9359 (1975)PubMedGoogle Scholar
  72. Clausen, T., Hansen, O.: Ouabain binding and Na + -K + transport in rat muscle cells and adipocytes. Biochim. Biophys. Acta (Amst.) 345, 387–404 (1974)Google Scholar
  73. Cohen, I., Daut, J., Noble, D.: An analysis of the actions of low concentrations of ouabain on membrane currents in Purkinje fibres. J. Physiol. (Lond.) 260, 75–103 (1976)Google Scholar
  74. Curfman, G.D., Crowley, T.J., Smith, T.W.: Thyroid-induced alterations in myocardial sodium-and potassium-activated adenosine triphosphatase, monovalent cation active transport, and cardiac glycoside binding. J. Clin. Invest. 59, 586–590 (1977)PubMedGoogle Scholar
  75. DePont, J.J.H.H.M., Bonting, S.L.: The role of phospholipids in Na-K-ATPase. In: Bazan, N.G., Brenner, R.R., Guisto, N.M. (eds.). Function and biosynthesis of lipids, pp. 219224. New York: Plenum Publ. Corp. 1977Google Scholar
  76. DePover, A., Godfraind, T.: Sensitivity to cardiac glycosides of (Na + K) ATPase prepared from human heart, guinea-pig heart, and guinea-pig brain. Arch. Int. Pharmacodyn. Ther. 221, 339–341 (1976)Google Scholar
  77. Dhalla, N.S., Singh, J.N., Fedelesova, M., Balasubramanian, V., McNamara, D.B.: Biochemical basis of heart function. XII. Sodium-potassium stimulated adenosine triphosphatase activity in the perfused heart made to fail by substrate-lack. Cardiovasc. Res. 8, 227–236 (1974)Google Scholar
  78. Dransfeld, H., Greeff, K., Berger, H., Cautius, V.: Die verschiedene Empfindlichkeit der Na++K+-aktivierten ATPase des Herz-and Skeletmuskels gegen k-Strophanthin. Naunyn-Schmiedebergs Arch. Pharmacol. 254, 225–234 (1966)Google Scholar
  79. Dransfeld, H., Greeff, K., Schorn, A., Ting, B.T.: Calcium uptake in mitochondria and vesicles of heart and skeletal muscle in presence of potassium, sodium, k-strophanthin, and pentobarbital. Biochem. Pharmacol. 18, 1335–1345 (1969)Google Scholar
  80. Dudding, W.F., Winter, C.G.: On the reaction sequence of the K+-dependent acetyl phos-phatase activity of the Na+ pump. Biochim. Biophys. Acta (Amst.) 241, 650–660 (1971)Google Scholar
  81. Dunham, E.T., Glynn, I.M.: Adenosine triphosphatase activity and the active movements of alkali metal ions. J. Physiol. (Lond.) 156, 274–293 (1961)Google Scholar
  82. Dutta, S., Goswami, S., Datta, D.K., Lindower, J.O., Marks, B.H.: The uptake and binding of six radiolabeled cardiac glycosides by guinea-pig hearts and by isolated sarcoplasmic reticulum. J. Pharmacol. Exp. Ther. 164, 10–21 (1968)PubMedGoogle Scholar
  83. Ebner, F., Reiter, M.: The dependence on contraction frequency of the positive inotropic effect of dihydro-ouabain. Naunyn-Schmiedebergs Arch. Pharmacol. 300, 1–9 (1977)Google Scholar
  84. Edelman, I.S.: Thyroidal regulation of renal energy metabolism and (Na+ + K +)-activated adenosine triphosphatase activity. Med. Clin. N. Amer. 59, 605–614 (1975)PubMedGoogle Scholar
  85. Entman, M.L., Allen, J.C., Schwartz, A.: Calcium-ouabain interaction in a “microsomal” membrane fraction containing Na, K+-ATPase activity and calcium binding activity. J. Mol. Cell. Cardiol. 4, 435–441 (1972)PubMedGoogle Scholar
  86. Erdmann, E., Hasse, W.: Quantitative aspects of ouabain binding to human erythrocyte and cardiac membranes. J. Physiol. (Lond.) 251, 671–682 (1975)Google Scholar
  87. Erdmann, E., Schoner, W.: Ouabain-receptor interactions in (Na+K+)-ATPase preparations from different tissues and species. Determination of kinetic constants and dissociation constants. Biochim. Biophys. Acta (Amst.) 307, 386–398 (1973a)Google Scholar
  88. Erdmann, E., Schoner, W.: Ouabain-receptor interactions in (Na+ + K +)-ATPase preparations. II. Effects of cations and nucleotides on rate constants and dissociation constants. Biochim. Biophys. Acta (Amst.) 330, 302–315 (1973b)Google Scholar
  89. Erdmann, E., Schoner, W.: Ouabain-receptor interactions in (Na+ +K+)-ATPase preparations. III. On the stability of the ouabain receptor against physical treatment, hydrolases, and SH reagents. Biochim. Biophys. Acta (Amst.) 330, 316–324 (1973c)Google Scholar
  90. Erdmann, E., Schoner, W.: Ouabain-receptor intüractions in (Na ++K+)-ATPase preparations. IV. The molecular structure of different cardioactive steroids and other substances and their affinity to the glycoside receptor. Naunyn-Schmiedebergs Arch. Pharmacol. 283, 335–356 (1974a)Google Scholar
  91. Erdmann, E., Schoner, W.: Eigenschaften des Rezeptors für Herzglykoside. Klin. Wochenschr. 52, 705–718 (1974b)Google Scholar
  92. Erdmann, E., Bolte, H.-D., Luderitz, B.: The (Na+ + K +)-ATPase activity of guinea pig heart muscle in potassium deficiency. Arch. Biochem. Biophys. 145, 121–125 (1971)Google Scholar
  93. Erdmann, E., Bolte, H.-D., Schoner, W.: Cardiac glycoside receptor in potassium depletion. Recent Adv. in studies on cardiac structure and metabolism. Basic functions of cations in myocardial activity. Fleckenstein, A., Dhalla, N.S. (eds.), Vol. 5, pp. 351–358. Baltimore: University Park Press 1975Google Scholar
  94. Erdmann, E., Patzelt, R., Schoner, W.: The cardiac glycoside receptor: Its properties and its correlation to nucleotide binding sites, phosphointermediate, and (Na + + K +)- ATPase activity. Recent Adv. in studies on cardiac structure and metabolism. The Sarcolemma. Roy, P-E., Dhalla, N.S. (eds.), Vol. 9, pp. 329–335. Baltimore: University Park Press 1976aGoogle Scholar
  95. Erdmann, E., Philipp, G., Tanner, G.: Ouabain-receptor interactions in (Na + + K +)-ATPase preparations. A contribution to the problem of nonlinear Scatchard plots. Biochim. Biophys. Acta (Amst.) 455, 287–296 (1976b)Google Scholar
  96. Erlij, D., Elizalde, A.: Rapidly reversible inhibition of frog muscle sodium pump caused by cardiotonic steroids with modified lactone rings. Biochim. Biophys. Acta (Amst.) 345, 49–54 (1974)Google Scholar
  97. Flasch, H., Heinz, N.: Correlation between inhibition of (Na+ + K +)-membrane-ATPase and positive inotropic activity of cardenolides in isolated papillary muscles of guinea pig. Naunyn-Schmiedebergs Arch. Pharmacol. 304, 37–44 (1978)Google Scholar
  98. Forbush, B., Kaplan, J.H., Hoffman, J.F.: Characterization of a new photoaffinity derivative of ouabain: Labeling of the large polypeptide and of a proteolipid component of the Na, K-ATPase. Biochemistry 17, 3667–3676 (1978)PubMedGoogle Scholar
  99. Fricke, U.: Lack of interaction of spironolactone with ouabain in guinea pig isolated heart muscle praparations. Eur. J. Pharmacol. 49, 363–371 (1978)PubMedGoogle Scholar
  100. Fricke, U., Klaus, W.: Die Reversibilität der Wirkung von Digitoxin, Strophanthidin und Strophanthidin-3-bromazetat am Papillarmuskel und einer mikrosomalen Na+-K+-aktivierbaren ATPase des Meerschweinchens. Experientia 25, 685–686 (1969)PubMedGoogle Scholar
  101. Fricke, U., Klaus, W.: Comparative studies of the influence of various K+ concentrations on the action of k-strophanthidin, digitoxin, and strophanthidin-3-bromoacetate on papillary muscle and on membrane-ATPase of guinea pig hearts. Eur. J. Pharmacol. 15, 1–7 (1971a)Google Scholar
  102. Fricke, U., Klaus, W.: Über die Wirkung von Strophanthidin-3-bromacetat am Papillarmuskel des Meerschweinchens. Naunyn-Schmiedebergs Arch. Pharmacol. 268, 192–199 (1971b)Google Scholar
  103. Fricke, U., Klaus, W.: Die Haftung verschiedener Cardenolide am Papillarmuskel und einer mikrosomalen ATPase des Meerschweinchenherzens. Naunyn-Schmiedebergs Arch. Pharmacol. 268, 200–209 (1971c)Google Scholar
  104. Fricke, U., Klaus, W.: Evidence for two different Na+-dependent (3H)-ouabain binding sites of a Na+-K+-ATPase of guinea-pig hearts. Brit. J. Pharmacol. 61, 423–428 (1977)Google Scholar
  105. Fricke, U., Klaus, W.: Sodium-dependent cardiac glycoside binding: Experimental evidence and hypothesis. Brit. J. Pharmacol. 62, 255–257 (1978)Google Scholar
  106. Fricke, U., Hollborn, U., Klaus, W.: Inotropic action, myocardial uptake, and subcellular distribution of ouabain, digoxin, and digitoxin in isolated rat hearts. Naunyn-Schmiedebergs Arch. Pharmacol. 288, 195–214 (1975)Google Scholar
  107. Fujino, S., Kawagishi, S., Eguchi, N., Tanaka, M.: Binding site of ouabain in cardiac muscle cell and its positive inotropic effect in cat. Jpn. J. Pharmacol. 21, 423–425 (1971)Google Scholar
  108. Gardner, J.D., Kiino, D.R.: Ouabain binding and cation transport in human erythrocytes. J. Clin. Invest. 52, 1845–1851 (1973)PubMedGoogle Scholar
  109. Gervais, A., Lane, L.K., Anner, B.M., Lindenmayer, G.E., Schwartz, A.: A possible molecular mechanism of the action of digitalis. Ouabain action on calcium binding to sites associated with a purified sodium-potassium-activated adenosine triphosphatase from kidney. Circ. Res. 40, 8–14 (1977)Google Scholar
  110. Glitsch, H.G.: Hemmung der elektrogenen Na-Pumpe am Meerschweinchenvorhof durch Digitoxigenin. Pflügers Arch. 335, 243–251 (1972)PubMedGoogle Scholar
  111. Glitsch, H.G.: An effect of the electrogenic sodium pump on the membrane potential in beating guinea-pig atria. Pflügers Arch. 344, 169–180 (1973)PubMedGoogle Scholar
  112. Glynn, I.M.: The action of cardiac glycosides on ion movements. Pharmacol. Rev. 16, 381–407 (1964)Google Scholar
  113. Godfraind, T.: The therapeutic mode of action of cardiac glycosides. Arch. Int. Pharmacodyn. Ther. 206, 384–388 (1973)PubMedGoogle Scholar
  114. Godfraind, T., Ghysel-Burton, J.: Binding sites related to ouabain-induced stimulation or inhibition of the sodium pump. Nature (Lond.) 265, 165–166 (1977)Google Scholar
  115. Goodman, S.L., Wheeler, K.P.: Ouabain binding to phospholipid-dependent adenosine triphosphatase. Biochem. J. 169, 313–320 (1977)Google Scholar
  116. Goldman, R.H., Coltart, D.J., Friedman, J.P., Nola, G.T., Berke, D.K., Schweizer, E., Harrison, D.C.: The inotropic effects of digoxin in hyperkalemia. Relation to (Na, K+)ATPase inhibition in the intact animal. Circulation 48, 830–838 (1973)PubMedGoogle Scholar
  117. Goldman, R.H., Coltart, D.J., Schweizer, E., Snidow, G., Harrison, D.C.: Dose response in vivo to digoxin in nonno-and hyperkalaemia: Associated biochemical changes. Cardiovasc. Res. 9, 515–523 (1975)Google Scholar
  118. Grobecker, V.H., Piechowski, U., Greeff, K.: Die Wirkung des k-Strophanthins und Digitonins auf den lonentransport und die Membran-ATPase der Erythrocyten von Menschen, Meerschweinchen und Ratten. Med. Exp. 9, 273–282 (1963)Google Scholar
  119. Gubitz, R.H., Akera, T., Brody, T.M.: Control of brain slice respiration by (Na+ + K +)- activated adenosine triphosphatase and the effects of enzyme inhibitors. Biochim. Biophys. Acta (Amst.) 459, 263–277 (1977)Google Scholar
  120. Hajdu, S., Leonard, E.: The cellular basis of cardiac glycoside action. Pharmacol. Rev. 11, 173–209 (1959)Google Scholar
  121. Hall, R.J., Gelbart, A., Silverman, M., Goldman, R.H.: Studies on digitalis-induced arrhythmias in glucose-and insulin-induced hypokalemia. J. Pharmacol. Exp. Ther. 201, 711–722 (1977)PubMedGoogle Scholar
  122. Hansen, O.: The relationship between g-strophanthin-binding capacity and ATPase activity in plasma-membrane fragments from ox brain. Biochim. Biophys. Acta (Amst.) 233, 122–132 (1971)Google Scholar
  123. Hansen, O.: Non-uniform populations of g-strophanthin binding sites of (Na ++K+)-activated ATPase: Apparent conversion to uniformity by K Biochim. Biophys. Acta (Amst.) 433, 383–392 (1976)Google Scholar
  124. Hansen, O.: The effect of sodium on inorganic phosphate-and paranitrophenyl phosphate-facilitated ouabain binding to (Na ++K+)-activated ATPase. Biochim Biophys. Acta (Amst.) 511, 10–22 (1978)Google Scholar
  125. Hansen, O., Jensen, J., Norby, J.G.: Mutual exclusion of ATP, ADP, and g-strophanthin binding to NaK-ATPase. Nature New Biol. 234, 122–124 (1971)PubMedGoogle Scholar
  126. Harris, W.E., Swanson, P.D., Stahl, W.L.: Ouabain binding sites and the (Na+, K+)ATPase of brain microsomal membranes. Biochim. Biophys. Acta (Amst.) 298, 680–689 (1973)Google Scholar
  127. Haustein, K.-O.: Studies on cardioactive steroids. I. Structure-activity relationships on the isolated atrium. Pharmacology 11, 117–126 (1974)PubMedGoogle Scholar
  128. Haustein, K.-O., Hauptmann, J.: Studies on cardioactive steroids. Pharmacology 11, 129138 (1974)Google Scholar
  129. Hegyvary, C.: Covalent labeling of the digitalis-binding component of plasma membranes. Mol. Pharmacol. 11, 588–594 (1975)Google Scholar
  130. Hegyvary, C.: Ouabain binding and phosphorylation of (Na ++K+)-ATPase treated with N-ethylmaleimide or oligomycin. Biochim. Biophys. Acta (Amst.) 422, 365–379 (1976)Google Scholar
  131. Hegyvary, C.: Alterations of cardiac NaK-ATPase by the thyroid state in the rat. Res. Commun. Chem. Path. Pharmacol. 17, 689–702 (1977)Google Scholar
  132. Hegyvary, C., Post, R.L.: Binding of adenosine triphosphate to sodium and potassium ion-stimulated adenosine triphosphatase. J. Biol. Chem. 246, 5234–5240 (1971)PubMedGoogle Scholar
  133. Heinen, E., Noack, E.: Effects of k-strophanthin and digitoxigenin on contractile force, calcium content and exchange in guinea-pig isolated atria. Naunyn-Schmiedebergs Arch. Pharmacol. 275, 359–371 (1972)Google Scholar
  134. Hess, H.H., Pope, A.: Effect of metal cations on adenosine triphosphatase activity of rat brain. Fed. Proc. 16, 196 (1957)Google Scholar
  135. Hilden, S., Rhee, H.M., Hokin, L.E.: Sodium transport by phospholipid vesicles containing purified sodium and potassium ion-activated adenosine triphosphatase. J. Biol. Chem. 249, 7432–7440 (1974)PubMedGoogle Scholar
  136. Hoffman, J.F.: The red cell membrane and the transport of sodium and potassium. Am. J. Med. 41, 666–680 (1966)PubMedGoogle Scholar
  137. Hoffman, J.F.: The interaction between tritiated ouabain and the Na-K pump in red blood cells. J. Gen. Physiol. 54, 343S–350S (1969)Google Scholar
  138. Hokin, L.E., Dahl, J.L., Deupree, J.D., Dixon, J.F., Hackney, J.F., Perdue, J.F.: Studies on the characterization of the sodium-potassium transport adenosine triphosphatase. X. Purification of the enzyme from the rectal gland of Squalus acanthias. J. Biol. Chem. 248, 2593–2605 (1973)PubMedGoogle Scholar
  139. Hougen, T.J., Smith, T.W Inhibition of myocardial monovalent cation active transport by subtoxic doses of ouabain in the dog. Circ. Res. 42, 856–863 (1978)Google Scholar
  140. Huang, W., Askari, A.: Transport ATPase of erythrocyte membrane: Sensitivities of Na, K+-ATPase and K+-phosphatase activities to ouabain. Arch. Biochem. Biophys. 175, 185–189 (1976)Google Scholar
  141. Inagaki, C., Lindenmayer, G.E., Schwartz, A.: Effects of sodium and potassium on binding of ouabain to the transport adenosine triphosphatase. J. Biol. Chem. 249, 5135–5140 (1974)PubMedGoogle Scholar
  142. Jones, L.R., Besch, H.R. Jr., Watanabe, A.M.: Significance of a cardiac microsomal Na plus K+-stimulated ATPase apparently insensitive to ouabain. Fed. Proc. 35, 833 (1976)Google Scholar
  143. Jorgensen, P.L.: Purification of Nat, K+-ATPase: Active site determination and criteria of purity. Ann. N.Y. Acad. Sci. 242: 36–52 (1974)PubMedGoogle Scholar
  144. Jorgensen, P.L.: Purification and characterization of (Nat, K+)-ATPase. V. Conformational changes in the enzyme transitions between the Na-form and the K-form studied with tryptic digestion as a tool. Biochim. Biophys. Acta (Amst.) 401, 399–415 (1975)Google Scholar
  145. Jorgensen, P.L., Skou, J.C.: Purification and characterization of (Na ++K+)-ATPase. I. The influence of detergents on the activity of (Na+ +K+)-ATPase in preparations from the outer medulla of rabbit kidney. Biochim. Biophys. Acta (Amst.) 233, 366–380 (1971)Google Scholar
  146. Jorgensen, P.L., Hansen, O., Glynn, I.M., Cavieres, J.D.: Antibodies to pig kidney (Na+ +K+)-ATPase inhibit the Na+ pump in human red cells provided they have access to the inner surface of the cell membrane. Biochim. Biophys. Acta (Amst.) 291, 795–800 (1973)Google Scholar
  147. Kim, N.D., Bailey, L.E., Dresel, P.E.: Correlation of the subcellular distribution of digoxin with the positive inotropic effect. J. Pharmacol. Exp. Ther. 181, 377–385 (1972)PubMedGoogle Scholar
  148. Köhler, E., Greeff, K.: Der Einfluß des Blut-pH auf die Toxicität herzwirksamer Glycoside. Res. Exp. Med. 159, 65–74 (1972)Google Scholar
  149. Ku, D., Akera, T., Pew, C.L., Brody, T.M.: Cardiac glycosides: Correlation among Na+, K+-ATPase, sodium pump and contractility in the guinea pig heart. Naunyn-Schmiedebergs Arch. Pharmacol. 285, 185–200 (1974)Google Scholar
  150. Ku, D.D., Akera, T., Tobin, T., Brody, T.M.: Comparative species studies on the effect of monovalent cations and ouabain on cardiac Na, K+-ATPase and contractile force. J. Pharmacol. Exp. Ther. 197, 458–469 (1976)PubMedGoogle Scholar
  151. Ku, D.D., Akera, T., Brody, T.M., Weaver, L.C.: Chronic digoxin treatment on canine myocardial Na+, K+-ATPase. Naunyn-Schmiedebergs Arch. Pharmacol. 301, 39–47 (1977)Google Scholar
  152. Kyte, J.: Phosphorylation of a purified (Na + + K +) adenosine triphosphatase. Biochem. Biophys. Res. Commun. 43, 1259–1265 (1971)Google Scholar
  153. Kyte, J.: The titration of the cardiac glycoside binding site of the (Na+ + K +)-adenosine triphosphatase. J. Biol. Chem. 247, 7634–7641 (1972)PubMedGoogle Scholar
  154. Kyte, J.: The reactions of sodium and potassium ion-activated adenosine triphosphatase with specific antibodies. J. Biol. Chem. 249, 3652–3660 (1974)PubMedGoogle Scholar
  155. Lane, L.K., Copenhaver, J.H. Jr., Lindenmayer, G.E., Schwartz, A.: Purification and characterization of and (3H)-ouabain binding to the transport adenosine triphosphatase from outer medulla of canine kidney. J. Biol. Chem. 248, 7197–7200 (1973)PubMedGoogle Scholar
  156. Lane, L.K., Anner, B.M., Wallick, E.T., Ray, M.V., Schwartz, A.: Effect of phospholipase A treatment on the partial reactions of and ouabain binding to a purified sodium and potassium activated adenosine triphosphatase. Biochem. Pharmacol. 27, 225–231 (1977)Google Scholar
  157. Langer, G.A.: Ion fluxes in cardiac excitation and contraction and their relation to myocardial contractility. Physiol. Rev. 48, 708–757 (1968)Google Scholar
  158. Langer, G.A.: The intrinsic control of myocardial contraction–ionic factors. New Engl. J. Med. 285, 1065–1071 (1971)Google Scholar
  159. Langer, G.A.: Effects of digitalis on myocardial ionic exchange. Circulation 46, 180–187 (1972a)Google Scholar
  160. Langer, G.A.: Myocardial K+ loss and contraction frequency. J. Mol. Cell. Cardiol. 4, 85–86 (1972b)Google Scholar
  161. Langer, G.A.: Relationship between myocardial contractility and the effects of digitalis on ionic exchange. Fed. Proc. 36, 2231–2234 (1977)Google Scholar
  162. Langer, G.A., Serena, S.D.: Effects of strophanthidin upon contraction and ionic exchange in rabbit ventricular myocardium: Relative to control of active state. J. Mol. Cell. Cardiol. 1, 65–90 (1970)PubMedGoogle Scholar
  163. Lee, C.O., Fozzard, H.A.: Activities of potassium and sodium ions in rabbit neart muscle. J. Gen. Physiol. 65, 695–708 (1975)PubMedGoogle Scholar
  164. Lee, K.S., Klaus, W.: The subcellular basis for the mechanism of inotropic action of cardiac glycosides. Pharmacol. Rev. 23, 193–261 (1971)Google Scholar
  165. Lee, K.S., Yu, D.H.: A study of the sodium-and potassium-activated adenosinetriphosphatase activity of heart microsomal fraction. Biochem. Pharmacol. 12, 1253–1264 (1963)Google Scholar
  166. Lee, K.S., Shin, M.R., Kang, D.H., Chen, K.K.: Studies on the mechanism of cardiac glycoside action. Biochem. Pharmacol. 19, 1055–1069 (1970)Google Scholar
  167. Lelievre, L., Charlemagne, D., Paraf, A.: Plasma membrane studies on drug-sensitive and -resistant cell lines. II. Ouabain sensitivity of (Na + + K +)stimulated Mg’ -ATPase. Biochim. Biophys. Acta (Amst.) 455, 277–286 (1976)Google Scholar
  168. Lin, M.H., Akera, T.: Increased (Na+, K+)-ATPase concentrations in various tissues of rats caused by thyroid hormone treatment. J. Biol. Chem. 253, 723–726 (1978)PubMedGoogle Scholar
  169. Lin, M.H., Romsos, D.R., Akera, T., Leveille, G.A.: Na+, K+-ATPase enzyme units in skeletal muscle from lean and obese mice. Biochem. Biophys. Res. Commun. 80, 398–404 (1978)Google Scholar
  170. Lindenmayer, G.E., Schwartz, A.: Conformational changes induced in Na+, K+-ATPase by ouabain through a K+-sensitive reaction: Kinetic and spectroscopic studies. Arch. Biochem. Biophys. 140, 371–378 (1970)Google Scholar
  171. Lindenmayer, G.E., Schwartz, A.: Nature of the transport adenosine triphosphatase digitalis complex. IV. Evidence that sodium-potassium competition modulates the rate of ouabain interaction with (Na + + K +) adenosine triphosphatase during enzyme catalysis. J. Biol. Chem. 248, 1291–1300 (1973)PubMedGoogle Scholar
  172. Lindenmayer, G.E., Laughter, A.H., Schwartz, A.: Incorporation of inorganic phosphate-32 into a Na+ + K+-ATPase preparation: Stimulation by ouabain. Arch. Biochem. Biophys. 127, 187–192 (1968)Google Scholar
  173. Lishko, V.K., Malysheva, M.K., Grevisirskaya, T.I.: The interaction of the (Na +, K+)-ATPase of erythrocyte ghosts with ouabain. Biochim. Biophys. Acta (Amst.) 288, 103–106 (1972)Google Scholar
  174. Lo, C.S., Edelman, I.S.: Effect of triiodothyronine on the synthesis and degradation of renal cortical (Na+ + K +)-adenosine triphosphatase. J. Biol. Chem. 251, 7834–7840 (1976)PubMedGoogle Scholar
  175. Lo, C.S., August, T.R., Liberman, U.A., Edelman, I.S.: Dependence of renal (Na+ +K+)-adenosine triphosphatase activity on thyroid status. J. Biol. Chem. 251, 7826–7833 (1976)PubMedGoogle Scholar
  176. Löhr, E., Makoski, H.B., Gobbeler, T., Strötges, M.W.: Beitrag zu der Membranpermeabilität von Cardiaca (g-Strophanthin, Digoxin, Oxyfedrin) auf Grund von Mikroautoradiographien am Meerschweinchenherzen. Arzneim. Forsch. (Drug Res.) 21, 921–927 (1971)Google Scholar
  177. Lüllmann, H., Peters, T.: Action of cardiac glycosides on the excitation-contraction coupling in heart muscle. Prog. Pharmacol. 2, 5–57 (1979)Google Scholar
  178. Lüllmann, H., Peters, T.: Studies on the site of action of cardiac glycosides. In: Digitalis. Storstein, O. (ed.), p. 125. Oslo: Gyldendal Norsk Forlag 1974Google Scholar
  179. Lüllmann, H., Peters, T.: On the sarcolemmal site of action of cardiac glycosides. Recent Adv. in studies on cardiac structure and metabolism. The sarcolemma. Roy, P.-E., Dhalla, N.S. (eds.), Vol. 9, pp. 311–328. Baltimore: University Park Press 1976Google Scholar
  180. Lüllmann, H., Peters, T., Preuner, J., Rüther, T.: Influence of ouabain and dihydroouabain on the circular dichroism of cardiac plasmalemmal microsomes. Naunyn-Schmiedebergs Arch. Pharmacol. 290, 1–19 (1975)Google Scholar
  181. Malur, J., Repke, K.R.H.: Modelluntersuchungen über die Beteiligung einer WasserstoffBrücken-Bindung an der Komplexbildung zwischen Cardenolidverbindungen and Na + K+-aktivierter, Mg’ -abhängiger Adenosintriphosphat-Phosphohydrolase. Acta Biol. Med. Ger. 24, K67—K72 (1970)Google Scholar
  182. Matsui, H., Schwartz, A.: Kinetic analysis of ouabain-K + and Na + interaction on a Na+, K+-dependent adenosinetriphosphatase from cardiac tissue. Biochem. Biophys. Res. Commun. 25, 147–152 (1966)Google Scholar
  183. Matsui, H., Schwartz, A.: Mechanism of cardiac glycoside inhibition of the (Na +-K +)-dependent ATPase from cardiac tissue. Biochim. Biophys. Acta (Amst.) 151, 655–663 (1968)Google Scholar
  184. Matsui, H., Hayashi, Y., Homareda, H., Kimimura, M.: Ouabain-sensitive 42K binding to Na +, K+-ATPase purified from canine kidney outer medulla. Biochem. Biophys. Res. Commun. 75, 373–380 (1977)Google Scholar
  185. Mayer, M., Avi-Dor, Y.: Fluorescence of 8-anilino-l-naphthalene-sulfonate bound to ox-brain Nat and K +-stimulated adenosine triphosphatase. Isr. J. Med. Sci. 6, 726–731 (1970)PubMedGoogle Scholar
  186. McCans, J.L., Lane, L.K., Lindenmayer, G.E., Butler, V.P. Jr., Schwartz, A.: Effects of an antibody to a highly purified Na+, K+-ATPase from canine renal medulla: Separation of the “holoenzyme antibody” into catalytic and cardiac glycoside receptor-specific components. Proc. Natl. Acad. Sci. U.S.A. 71, 2449–2452 (1974)PubMedGoogle Scholar
  187. Michael, L., Wallick, E.T., Schwartz, A.: Modification of (Na +, K+)-ATPase function by purified antibodies to the holoenzyme — effects on enzyme activity and 3H ouabain binding. J. Biol. Chem. 252, 8476–8480 (1977)PubMedGoogle Scholar
  188. Michael, L., Pitts, B.J.R., Schwartz, A.: Is pump stimulation associated with positive inotropy of the heart? Science 200, 1287–1289 (1978)PubMedGoogle Scholar
  189. Murthy, R.V., Kidwai, A.M., Daniel, E.E.: Dissociation of contractile effect and binding and inhibition of Na +-K +-adenosine triphosphatase by cardiac glycosides in rabbit myometrium. J. Pharmacol. Exp. Ther. 188, 575–581 (1974)PubMedGoogle Scholar
  190. Nagai, K., Lindenmayer, G.E., Schwartz, A.: Direct evidence for the conformational nature of the Na, K -ATPase system: Fluorescence and circular dichroism studies. Arch. Biochem. Biophys. 139, 252–254 (1970)Google Scholar
  191. Nagatomo, T., Jarmakani, J.M., Philipson, K.D., Nakazawa, M.: Effect of anoxia on membrane-bound ATPase and K+-p-nitrophenyl phosphatase activities in rabbit heart. J. Mol. Cell. Cardiol. 10, 981–989 (1978)PubMedGoogle Scholar
  192. Nâidoo, B.K., Witty, T.R., Remers, W.A., Besch, H.R. Jr.: Cardiotonic steroids: I Impor- tance of 14ß-hydroxy group in digitoxigenin. J. Pharm. Sci. 63, 1391–1394 (1974)PubMedGoogle Scholar
  193. Nayler, W.G., Stone, J., Carson, V., Chipperfield, D.: Effect of ischemia on cardiac contractility and calcium exchangeability. J. Mol. Cell. Cardiol. 2, 125–143 (1971)PubMedGoogle Scholar
  194. Okarma, T.B., Tramell, P., Kalman, S.M.: Inhibition of sodium-and potassium-dependent adenosine triphosphatase by digoxin covalently bound to sepharose. Mol. Pharmacol. 8, 476–480 (1972)Google Scholar
  195. Okita, G.T.: Dissociation of Na, K+-ATPase inhibition from digitalis inotropy. Fed. Proc. 36, 2225–2230 (1977)Google Scholar
  196. Okita, G.T., Richardson, F., Roth-Schechter, B.F.: Dissociation of the positive inotropic action of digitalis from inhibition of sodium-and potassium-activated adenosine triphosphatase. J. Pharmacol. Exp. Ther. 185, 1–11 (1973)PubMedGoogle Scholar
  197. Park, M.K., Vincenzi, F.F.: Rate of onset of cardiotonic steroid-induced inotropism: Influence of temperature and beat interval. J. Pharmacol. Exp. Ther. 195, 140–150 (1975)PubMedGoogle Scholar
  198. Perrone, J.R., Blostein, R.: Asymmetric interaction of inside-out and right-side-out erythrocyte membrane vesicles with ouabain. Biochim. Biophys. Acta (Amst.) 291, 680–689 (1973)Google Scholar
  199. Pert, C., Snyder, S.: Opiate receptor binding of agonists and antagonists affected differentially by sodium. Mol. Pharmacol. 10, 868–879 (1974)Google Scholar
  200. Peters, T., Raben, R.H., Wassermann, O.: Evidence for a dissociation between positive isotropic effect and inhibition of the Na +-K + -ATPase by ouabain, cassaine, and their alkylating derivatives. Eur. J. Pharmacol. 26, 166–174 (1974)PubMedGoogle Scholar
  201. Pitts, B.J.R., Wallick, E.T., Van Winkle, W.B., Allen, J.C., Schwartz, A.: On the lack of isotropy of cardiac glycosides on skeletal muscle: A comparison of Na+, K +-ATPases from skeletal and cardiac muscle. Arch. Biochem. Biophys. 184, 431–440 (1977)Google Scholar
  202. Poole-Wilson, P.A., Langer, G.A.: Glycoside inotropy in the absence of an increase in potassium efflux in the rabbit heart. Circ. Res. 37, 390–395 (1975)Google Scholar
  203. Post, R.L., Merritt, C.R., Kinsolving, C.R., Albright, C.D.: Membrane adenosine triphosphatase as a participant in the active transport of sodium and potassium in the human erythrocyte. J. Biol. Chem. 235, 1796–1802 (1960)PubMedGoogle Scholar
  204. Post, R.L., Kume, S., Tobin, T., Orcutt, B., Sen, A.K.: Flexibility of an active center in sodium-plus-potassium adenosine triphosphatase. J. Gen. Physiol. 54, 306S–326S (1969)Google Scholar
  205. Prindle, K.H. Jr., Skelton, C.L., Epstein, S.E., Marcus, F.I.: Influence of extracellular potassium concentration on myocardial uptake and inotropic effect of tritiated digoxin. Circ. Res. 28, 337–345 (1971)Google Scholar
  206. Repke, K.: Metabolism of cardiac glycosides. In: Proc. 1 st International Pharmacol. Meeting, vol. 3, pp. 47–73. Oxford: Pergamon Press 1963Google Scholar
  207. Repke, K.: Über den biochemischen Wirkungsmodus von Digitalis. Klin. Wochenschr. 42, 157–165 (1964)Google Scholar
  208. Repke, K.: Effect of digitalis on membrane adenosine triphosphatase of cardiac muscle. In: Drugs and enzymes. Proc. 2 nd International Pharmacol. Meeting, Prague. Brodie, B.B., Gillette, J. (eds.), vol. 4, pp. 65–87. Oxford: Pergamon, Prague: Chechoslovak Medical Press 1965Google Scholar
  209. Repke, K., Portius, H.J.: Über die Identität der Ionenpumpen-ATPase in der Zellmembran des Herzmuskels mit einem Digitalis-Rezeptorenzym. Experientia 19, 452–458 (1963)PubMedGoogle Scholar
  210. Repke, K.R.H., Schön, R.: Flip-flop model of (NaK)-ATPase function. Acta Biol. Med. Germ. 31, K19—K39 (1973)Google Scholar
  211. Repke, K., Est, M., Portius, H.J.: Über die Ursache der Speciesunterschiede in der Digitalisempfindlichkeit. Biochem. Pharmacol. 14, 1785–1802 (1965)Google Scholar
  212. Reuter, H.: Exchange of calcium ions in the mammalian myocardium: Mechanisms and physiological significance. Circ. Res. 34, 599–605 (1974)Google Scholar
  213. Rhee, H.M., Dutta, S., Marks, B.H.: Cardiac NaK ATPase activity during positive inotro-pic and toxic action of ouabain. Eur. J. Pharmacol. 37, 141–153 (1976)PubMedGoogle Scholar
  214. Ross, C.R., Pessah, N.I.: Reversible inhibition of (Nat +K+)-ATPase with a cardiac gly-coside. Eur. J. Pharmacol. 33, 223–226 (1975)PubMedGoogle Scholar
  215. Roth-Schechter, B.F., Okita, G.T., Thomas, R.E., Richardson, F.F.: On the positive inotropic action of alkylating bromoacetates of strophanthidin and strophanthidol-(19-H3). J. Pharmacol. Exp. Ther. 171, 13–19 (1970)PubMedGoogle Scholar
  216. Ruoho, A., Kyte, J.: Photoaffinity labeling of the ouabain-binding site on (Nat +K+)adenosinetriphosphatase. Proc. Natl. Acad. Sci. U.S.A. 71, 2352–2356 (1974)PubMedGoogle Scholar
  217. Ruoho, A.E., Hokin, L.E., Hemingway, R.J., Kupchan, S.M.: Hellebrigenin 3-haloacetates: Potent site-directed alkylators of transport adenosinetriphosphatase. Science 159, 1354–1355 (1968)PubMedGoogle Scholar
  218. Sachs, J.R.: Interaction of external K, Na, and cardioactive steroids with the Na-K pump of the human red blood cell. J. Gen. Physiol. 63, 123–143 (1974)PubMedGoogle Scholar
  219. Schatzmann, H.J.: Herzglycoside als Hemmstoffe für den aktiven Kalium-und Natrium- transport durch die Erythrocytenmembran. Helv. Physiol. Acta 11, 346–354 (1953)Google Scholar
  220. Scholz, H.: Effect of a “therapeutic” concentration of digitoxigenine on myocardial potassium and sodium content in Ca-poor media. Naunyn-Schmiedebergs Arch. Pharmacol. 273, 434–437 (1972)Google Scholar
  221. Schön, R., Schönfeld, W., Repke, K.R.H.: Zur Charakterisierung des Ouabain-bindenden Konformationszustandes der (Nat +K+)-aktivierten ATPase. Acta Biol. Med. Germ. 24, K61 - K65 (1970)Google Scholar
  222. Schön, R., Schönfeld, W., Menke, K.-H., Repke, K.R.H.: Mechanism and role of Na+/ Ca’ competition in (NaK)-ATPase. Acta Biol. Med. Germ. 29, 643–659 (1972)Google Scholar
  223. Schönfeld, W., Schön, R., Menke, K.-H., Repke, K.R.H.: Identification of conformational states of transport ATPase by kinetic analysis of ouabain binding. Acta Biol. Med. Germ. 28, 935–956 (1972)Google Scholar
  224. Schuurmans Stekhoven, F.M.A.H., DePont, J.J.H.H.M., Bonting, S.L.: Studies on (Na++K+)-activated ATPase. XXXVII. Stabilization by cations of the enzyme-ouabain complex formed with Mg’ and inorganic phosphate. Biochim Biophys. Acta (Amst.) 419, 137–149 (1976)Google Scholar
  225. Schwartz, A.: Is the cell membrane Na+, K +-ATPase enzyme system the pharmacological receptor for digitalis? Circ. Res. 39, 2–7 (1976)Google Scholar
  226. Schwartz, A., Matsui, H., Laughter, A.H.: Tritiated digoxin binding to (Na + + K +)-acti- vated adenosine triphosphatase: Possible allosteric site. Science 160, 323–325 (1968)PubMedGoogle Scholar
  227. Schwartz, A., Allen, J.C., Harigaya, S.: Possible involvement of cardiac Na +, K + -adenosine triphosphatase in the mechanism of action of cardiac glycosides. J. Pharmacol. Exp. Ther. 168, 31–41 (1969)PubMedGoogle Scholar
  228. Schwartz, A., Wood, J.M., Allen, J.C., Bornet, E.P., Entman, M.L., Goldstein, M.A., Sordahl, L.A., Suzuki, M.: Biochemical and morphologic correlates of cardiac ischemia. I. Membrane system. Am. J. Cardiol. 32, 46–61 (1973)Google Scholar
  229. Schwartz, A., Allen, J.C., Van Winkle, W.B., Munson, R.: Further studies on the correlation between the inotropic action of ouabain and its interaction with the Na+, K+-adenosine triphosphatase: Isolated perfused rabbit and cat hearts. J. Pharmacol. Exp. Ther. 191, 119–127 (1974)PubMedGoogle Scholar
  230. Schwartz, A., Lindenmayer, G.E., Allen, J.C.: The sodium-potassium adenosine triphosphatase: Pharmacological, physiological, and biochemical aspects. Pharmacol. Rev. 27, 3–134 (1975)Google Scholar
  231. Sen, A.K., Tobin, T., Post, R.L.: A cycle for ouabain inhibition of sodium-and potassium-dependent adenosine triphosphatase. J. Biol. Chem. 244, 6596–6604 (1969)PubMedGoogle Scholar
  232. Sharma, V.K., Banerjee, S.P.: Specific [3H]ouabain binding to rat heart and skeletal muscle: Effects of thyroidectomy. Mol. Pharmacol. 14, 122–129 (1978)Google Scholar
  233. Siegel, G.J., Josephson, J.: Ouabain reaction with microsomal (sodium-plus-potassium)-activated adenosine-triphosphatase: Characteristics of substrate and ion dependencies. Eur. J. Biochem. 25, 323–335 (1972)PubMedGoogle Scholar
  234. Siegel, G.J., Koval, G.J., Albers, R.W.: Sodium-potassium-activated adenosine triphosphatase. VI. Characterization of the phosphoprotein formed from orthophosphate in the presence of ouabain. J. Biol. Chem. 244, 3264–3269 (1969)PubMedGoogle Scholar
  235. Singh, C.M., Flear, C.T.G., Nandra, A., Ross, D.N.: Electrolyte changes in the human myocardium after anoxic arrest. Cardiology 56, 128–135 (1971)PubMedGoogle Scholar
  236. Skou, J.C.: The influence of some cations on an adenosine triphosphatase from peripheral nerves. Biochim. Biophys. Acta (Amst.) 23, 394–401 (1957)Google Scholar
  237. Skou, J.C.: Further investigations on a Mg++Na+-activated adenosinetriphosphatase, possibly related to the active, linked transport of Na+ and K+ across the nerve membrane. Biochim. Biophys. Acta (Amst.) 42, 6–23 (1960)Google Scholar
  238. Skou, J.C.: Enzymatic basis for active transport of Na and K across cell membrane. Physiol. Rev. 45, 596–617 (1965)Google Scholar
  239. Skou, J.C.: Study on the influence of the concentration of Mg’, Pi, K+, Na+, and Tris on (Mg2++Pi)-supported G-strophanthin binding to (Na + + K +)-activated ATPase from ox brain. Biochim Biophys. Acta (Amst.) 311, 51–66 (1973)Google Scholar
  240. Skou, J.C., Hilberg, C.: The effect of cations, G-strophanthin and oligomycin on the labeling from (32P) ATP of the (Na+ + K+)-activated enzyme system and the effect of cations and G-strophanthin on the labeling from (32P) ITP and 32Pi. Biochim. Biophys. Acta (Amst.) 185, 198–219 (1969)Google Scholar
  241. Skou, J.C., Butler, K.W., Hansen, O.: The effect of magnesium, ATP, Pi, and sodium on the inhibition of the (Na + + K +)-activated enzyme system by g-strophanthin. Biochim. Biophys. Acta (Amst.) 241, 443–461 (1971)Google Scholar
  242. Smith, T.W., Haber, E.: Digitalis. New Engl. J. Med. 289, 1125–1129 (1973)Google Scholar
  243. Smith, T.W., Wagner, H. Jr.: Effects of (Na + + K +)-ATPase-specific antibodies on enzy-matic activity and monovalent cation transport. J. Membrane Biol. 25, 341–360 (1975)Google Scholar
  244. Smith, T.W., Wagner, H. Jr., Markis, J.E., Young, M.: Studies on the localization of the cardiac glycoside receptor. J. Clin. Invest. 51, 1777–1789 (1972)PubMedGoogle Scholar
  245. Smith, T.W., Wagner, H. Jr., Young, M.: Cardiac glycoside interaction with solubilized myocardial sodium-and potassium-dependent adenosine triphosphatase. Mol. Pharmacol. 10, 626–633 (1974)Google Scholar
  246. Stickney, J L Inhibition of 3H-1-norepinephrine uptake by ouabain is species dependent. Res. Commun. Chem. Pathol. Pharmacol. 14, 227–236 (1976)Google Scholar
  247. Swanson, P.D.: Temperature dependence of sodium ion activation of the cerebral microsomal adenosine triphosphatase. J. Neurochem. 13, 229–236 (1966)PubMedGoogle Scholar
  248. Sybers, H.D., Helmer, P.R., Murphy, Q.R.: Effect of hypoxia on myocardial potassium balance. Am. J. Physiol. 220, 2047–2050 (1971)PubMedGoogle Scholar
  249. Taniguchi, K., Iida, S.: The binding of ouabain to Na + -K +-dependent ATPase treated with phospholipase. Biochim. Biophys. Acta (Amst.) 233, 831–833 (1971)Google Scholar
  250. Taniguchi, K., Iida, S.: Two apparently different ouabain binding sites of (Na + + K +)-ATPase. Biochim. Biophys. Acta (Amst.) 288, 98–102 (1972)Google Scholar
  251. Taniguchi, K., Iida, S.: The role of phospholipids in the binding of ouabain to sodium-and potassium-dependent adenosine triphosphatase. Mol. Pharmacol. 9, 350–359 (1973)Google Scholar
  252. Thomas, R.C.: Electrogenic sodium pump in nerve and muscle cells. Physiol. Rev. 52, 563–594 (1972)Google Scholar
  253. Thomas, R., Boutagy, J., Gelbart, A.: Cardenolide analogs. V. Cardiotonic activity of semi- synthetic analogs of digitoxigenin. J. Pharmacol. Exp. Ther. 191, 219–231 (1974)PubMedGoogle Scholar
  254. Tobin, T., Brody, T.M.: Rates of dissociation of enzyme-ouabain complexes and K0.5 values in (Na + + K +) adenosine triphosphatase from different species. Biochem. Pharmacol. 21, 1553–1560 (1972)Google Scholar
  255. Tobin, T., Sen, A.K.: Stability and ligand sensitivity of (3H) ouabain binding to (Na ++ K+)-ATPase. Biochim. Biophys. Acta (Amst.) 198, 120–131 (1970)Google Scholar
  256. Tobin, T., Baskin, S.I., Akera, T., Brody, T.M.: Nucleotide specificity of the Na+-stimulated phosphorylation and (3H) ouabain-binding reactions of (Na + + K +)-dependent adenosine triphosphatase. Mol. Pharmacol. 8, 256–263 (1972a)Google Scholar
  257. Tobin, T., Henderson, R., Sen, A.K.: Species and tissue differences in the rate of dissociation of ouabain from (Na + + K +)-ATPase. Biochim. Biophys. Acta (Amst.) 274, 551–555 (1972b)Google Scholar
  258. Tobin, T., Akera, T., Baskin, S.I., Brody, T.M.: Calcium ion and sodium-and potassium-dependent adenosine triphosphatase: Its mechanism of inhibition and identification of the E1-P intermediate. Mol. Pharmacol. 9, 336–349 (1973a)Google Scholar
  259. Tobin, T., Akera, T., Hogg, R.E., Brody, T.M.: Ouabain binding to sodium-and potassium-dependent adenosine triphosphatase- Inhibition by the ß-y-methylene analogue of adenosine triphosphate. Mol. Pharmacol. 9, 278–281 (1973b)Google Scholar
  260. Tobin, T., Akera, T., Ku, D.: Reversibility of the interaction of strophanthidin bromoacetate with the cardiotonic steroid binding site of sodium-and potassium-dependent adenosine triphosphatase. Mol. Pharmacol. 9, 676–685 (1973c)Google Scholar
  261. Tobin, T., Akera, T., Brody, T.M.: Studies on the two phosphoenzyme conformations of Na++K+-ATPase. Ann. N.Y. Acad. Sci. 242, 120–132 (1974a)Google Scholar
  262. Tobin, T., Akera, T., Lee, C.Y., Brody, T.M.: Ouabain binding to (Na+ +K+)-ATPase: Effects of nucleotide analogues and ethacrynic acid. Biochim. Biophys. Acta (Amst.) 345, 102–117 (1974b)Google Scholar
  263. Tuttle, R.S., Witt, P.N., Farah, A.: Therapeutic and toxic effects of ouabain on K+ fluxes in rabbit atria. J. Pharmacol. Exp. Ther. 137, 24–30 (1962)PubMedGoogle Scholar
  264. Vick, R.L., Kahn, J.B.,Jr.: The effects of ouabain and veratridine on potassium movement in the isolated guinea pig heart. J. Pharmacol. Exp. Ther. 121, 389–401 (1957)Google Scholar
  265. Wallick, E.T., Schwartz, A.: Thermodynamics of the rate of binding of ouabain to the sodium, potassium adenosine triphosphatase. J. Biol. Chem. 249, 5141–5147 (1974)PubMedGoogle Scholar
  266. Wallick, E.T., Dowd, F., Allen, J.C., Schwartz, A.: The nature of the transport adenosine triphosphatase-digitalis complex. VII. Characteristics of ouabagenin-Na+, K+-adenosine triphosphatase interaction. J. Pharmacol. Exp. Ther. 189, 434–444 (1974)PubMedGoogle Scholar
  267. Wallick, E.T., Lindenmayer, G.E., Lane, L.K., Allen, J.C., Pitts, B.J.R., Schwartz, A.: Recent advances in cardiac glycoside–Na+, K+-ATPase interaction. Fed. Proc. 36, 2214–2218 (1977)Google Scholar
  268. Weaver, L.C., Akera, T., Brody, T.M.: Digitalis toxicity: Lack of marked effect on brain Na +, K+-adenosine triphosphatase in the cat. J. Pharmacol. Exp. Ther. 200, 638–646 (1977)PubMedGoogle Scholar
  269. Whittam, R., Wheeler, K.P., Blake, A.: Oligomycin and active transport reactions in cell membranes. Nature (Lond.) 203, 720–724 (1964)Google Scholar
  270. Whittam, R., Hallam, C., Wattam, D.G.: Observations on ouabain binding and membrane phosphorylation by the sodium pump. Proc. Roy. Soc. London B 193, 217–234 (1976)Google Scholar
  271. Wilbrandt, W.: Zum Wirkungsmechanismus der Herzglykoside. Schweiz. Med. Wochenschr. 85, 315–320 (1955)Google Scholar
  272. Willerson, J.T., Scales, F., Mukherjee, A., Platt, M., Templeton, G.H., Fink, G.S., Buja, L.M.: Abnormal myocardial fluid retention as an early manifestation of ischemic injury. Am. J. Pathol. 87, 159–181 (1977)PubMedGoogle Scholar
  273. Wilson, W.E., Sivitz, W.I., Hanna, L.T.: Inhibition of calf brain membranal sodium-and potassium-dependent adenosine triphosphatase by cardioactive sterols. A binding site model. Mol. Pharmacol. 6, 449–459 (1970)Google Scholar
  274. Yamamoto, S., Akera, T., Brody, T.M.: Sodium influx rate and ouabain-sensitive rubidium uptake in isolated guinea pig atria. Biochim. Biophys. Acta (Amst.) 555, 270–284 (1979)Google Scholar
  275. Yoda, A.: Structure-activity relationships of cardiotonic steroids for the inhibition of sodium-and potassium-dependent adenosine triphosphatase. I. Dissociation rate constants of various enzyme-cardiac glycoside complexes formed in the presence of magnesium and phosphate. Mol. Pharmacol. 9, 51–60 (1973)Google Scholar
  276. Yoda, A.: Association and dissociation rate constants of the complexes between various car-diac monoglycosides and Na, K-ATPase. Ann. N.Y. Acad. Sci. 242, 598–616 (1974)PubMedGoogle Scholar
  277. Yoda, A.: Binding of digoxigenin to sodium-and potassium-dependent adenosine triphos-phatase. Mol. Pharmacol. 12, 399–408 (1976)Google Scholar
  278. Yoda, A., Hokin, L.E.: On the reversibility of binding of cardiotonic steroids to a partially purified (Na + K)-activated adenosinetriphosphatase from beef brain. Biochem. Biophys. Res. Commun. 40, 880–886 (1970)Google Scholar
  279. Yoda, A., Hokin, L.E.: Studies on the characterization of the sodium-potassium transport adenosine triphosphatase. VIII. Effects of ligands on fluorescence due to interaction of the enzyme with a fluorescent derivative of Hellebrigenin. Mol. Pharmacol. 8, 30–40 (1972)Google Scholar
  280. Yoda, A., Yoda, S.: Structure-activity relationships of cardiotonic steroids for the inhibition of sodium-and potassium-dependent adenosine triphosphatase. III. Dissociation rate constants of various enzyme-cardiac glycoside complexes formed in the presence of sodium, magnesium, and adenosine triphosphate. Mol. Pharmacol. 10, 494–500 (1974a)Google Scholar
  281. Yoda, A., Yoda, S.: Influence of certain ligands on the dissociation rate constants of cardiac glycoside complexes with sodium-and potassium-dependent adenosine triphosphatase. Mol. Pharmacol. 10, 810–819 (1974b)Google Scholar
  282. Yoda, A., Yoda, S.: Structure-activity relationships of cardiotonic steroids for the inhibition of sodium-and potassium-dependent adenosine triphosphatase. V. Dissociation rate constants of digitoxin acetates. Mol. Pharmacol. 11, 653–662 (1975)Google Scholar
  283. Yoda, A., Yoda, S.: Association and dissociation rate constants of the complexes between various cardiac aglycones and sodium-and potassium-dependent adenosine triphosphatase formed in the presence of magnesium and phosphate. Mol. Pharmacol. 13, 352–361 (1977)Google Scholar
  284. Yoda, A., Yoda, S.: Influence of pH on the interaction of cardiotonic steroids with sodium-and potassium-dependent adenosine triphosphatase. Mol. Pharmacol. 14, 624–632 (1978)Google Scholar
  285. Yoda, A., Yoda, S., Sarrif, A.M.: Structure-activity relationships of cardiotonic steroids for the inhibition of sodium-and potassium-dependent adenosine triphosphatase. II. Association rate constants of various enzyme-cardiac glycoside complexes. Mol. Pharmacol. 9, 766–773 (1973)Google Scholar
  286. Yoda, S., Sarrif, A.M., Yoda, A.: Structure-activity relationships of cardiotonic steroids for the inhibition of sodium-and potassium-dependent adenosine triphosphatase. IV. Dissociation rate constants for complexes of the enzyme with cardiac oligodigitoxides. Mol. Pharmacol. 11, 647–652 (1975)Google Scholar
  287. Zavecz, J.H., Dutta, S.: The relationship between Na, K+-ATPase inhibition and cardiac glycoside-induced arrhythmia in dogs. Naunyn-Schmiedebergs Arch. Pharmacol. 297, 91–98 (1977)Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1981

Authors and Affiliations

  • T. Akera

There are no affiliations available

Personalised recommendations