Abstract
The inhibition of the Na+, K+-pump by cardiac glycosides is very well documented. Since the earlier work of Schatzmann (1953) and of Glynn (1964) the analysis of the mechanism of this inhibition which paralleled the study of the properties of Na+, K+-ATPase (initially described by Skou, 1957) has allowed us to describe the biochemical mechanism of the Na+, K+-pump. Furthermore, the presence of a Na+, K+-pump in most of the cells and the multiple functions controlled by its activity have been demonstrated by using ouabain as a tool. The sensitivity of a physiologic process to a high dose of ouabain is generally considered as a convincing argument for its relation to the Na+, K+-pump. Several cellular processes are coupled to the activity of the Na+, K+-pump; some appear to be very different one from the other, e.g., the membrane potential or the uptake of amino acids.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Aronson, J.K., Grahame-Smith, D.G., Hallis, K.F., Hibble, A., Wigley, F.: Monitoring digoxin therapy: I plasma concentrations and an in vitro assay of tissue response. Br. J. Clin. Pharmacol. 4, 213–222 (1977)
Astrup, J.: Changes in sodium and potassium in human red cells in vivo related to treatment with digoxin, to hypokalemia, and to cell density. Ann. N.Y. Acad. Sci. 242, 683–702 (1974)
Baker, P.F., Willis, J.S.: Inhibition of the sodium pump in squid axons by cardiac glycosides: The dependence on extracellular ions and metabolism. J. Physiol. (Lond.) 224, 463–475 (1972)
Belpaire, F.M., Bogaert, M.G.: Methods for assay of cardiac glycosides. In: Plasma digitalis concentration and digitalis therapy. Godfraind, T. (ed.). Bruxelles: Arscia 1977
Blood, B.E., Noble, D.: Glycoside induced inotropism of the heart — more than one mechanism: J. Physiol. (Lond.) 266, 76P - 78P (1977)
Boyer, P.K., Pointdexter, C.A.: The influence of digitalis on the electrolyte and water balance of heart muscle. Am. Heart J. 20, 586–191 (1940)
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)
Deitmer, J.W., Ellis, D.: The intracellular sodium activity of cardiac Purkinje fibres during inhibition and reactivation of the Na-K pump. J. Physiol. (Lond.) 284, 241–259 (1978)
De Pover, A., Godfraind, T.: Interaction of ouabain with (Na+ + K+)-ATPase from human heart and from guinea-pig heart. Biochem. Pharmacol. 28, 3051–3056 (1979)
Ellis, D.: The effects of external cations and duabain on the intracellular sodium activity of sheep heart Purkinje fibres. J. Physiol. (Lond.) 273, 211–240 (1977)
Fry, C.H., Galindez, E., Poole-Wilson, P.A.: Potassium exchange and the positive inotropic effect of ouabain in rabbit and human myocardium. J. Physiol. (Lond.) 280, 72–73P (1978)
Ghysel-Burton, J., Godfraind, T.: Stimulation and inhibition by ouabain of the sodium pump in guinea-pig atria. Br. J. Pharmacol. 55, 249P (1975)
Ghysel-Burton, J., Godfraind, T.: Importance of the lactone ring for the action of therapeutic doses of ouabain in guinea-pig atria. J. Physiol. (Lond.) 266, 75–76 (1976)
Ghysel-Burton, J., Godfraind, T.: Stimulation and inhibition of the sodium pump by cardioactive steroids in relation to their binding sites and their inotropic effect on guinea-pig isolated atria. Brit. J. Pharmacol. 66, 175–184 (1979)
Glitsch, H.G., Reuter, H., Scholz, H.: The effect of the internal sodium concentration on calcium fluxes in isolated guinea-pig auricles. J. Physiol. (Lond.) 209, 25–43 (1970)
Glynn, I.M.: The action of cardiac glycosides on ion movements. Pharmacol. Rev. 16, 381–407 (1964)
Godfraind, T.: Pharmacologie des récepteurs digitaliques. Bull. Acad. Roy. Med. Belg. 12, 403–443 (1972)
Godfraind, T.: The therapeutic mode of action of cardiac glycosides. Arch. Int. Pharmacodyn. Ther. 206, 384–388 (1973)
Godfraind, T., De Pover, A.: La pharmacologie de la (Na++K+)-ATPase du muscle cardiaque humain. Bull. Acad. Roy. Belg. 131, 295–311 (1976)
Godfraind, T., Ghysel-Burton, J.: Binding sites related to ouabain-induced stimulation or inhibition of the sodium pump. Nature (Lond.) 265, 165–166 (1977)
Godfraind, T., Ghysel-Burton, J.: The action of digoxin and digoxigenin-monodigitoxoside on the sodium pump and on the contractility in isolated guinea-pig atria. Arch. Int. Pharmacodyn. Ther. 234, 340 (1978)
Godfraind, T., Ghysel-Burton, J.: The cardioactive properties of SC4453, a digoxin analogue with a C17 pyridazine ring. Eur. J. Pharmacol. 60, 337–344 (1979)
Godfraind, T., Ghysel-Burton, J.: Independence of the positive inotropic of ouabain from the inhibition of the heart Na-K pump. Proc. Natl. Acad. Sci. USA 77, 3067–3069 (1980)
Godfraind, T., Godfraind-de Becker, A.: The action of ouabain on the response of the isolated guinea-pig auricles to catecholamines in relation with its inotropic and chronotropic effects. Arch. Int. Pharmacodyn. Ther. 158, 453–465 (1965)
Godfraind, T., Lesne, M.: Estimation of digitoxin uptake by isolated cardiac and smooth muscle preparations. Arch. Int. Pharmacodyn. Ther. 166, 195–199 (1967)
Godfraind, T., Lesne, M.: The uptake of cardiac glycosides in relation to their actions in isolated cardiac muscle. Br. J. Pharmacol. 46, 488–497 (1972)
Godfraind, T., Tona Lutete, N.: Inhibition of digoxin and SC4453 of (Na++K+)-ATPase prepared from human heart, guinea-pig heart, and guinea-pig brain. Eur. J. Pharmacol. 60, 329–336 (1979)
Godfraind, T., Koch, M.C., Verbeke, N.: The action of EGTA on the catecholamines stim- ulation of rat brain Na-K-ATPase. Biochem. Pharmacol. 23, 3505–3511 (1974)
Godfraind, T., De Pover, A., Verbeke, N.: Influence of pH and sodium on the inhibition of guinea-pig heart (Na++K+)-ATPase by calcium. Biochim. Biophys. Acta 451, 202–211 (1977)
Godfraind, T., De Pover, A., Tona Lutete, N.: Identification with potassium and vanadate of two classes of specific ouabain binding sites in a (Na++K+)-ATPase preparation from the guinea-pig heart. Biochem. Pharmacol. 29, 1195–1199 (1980)
Hagen, P.S.: The effects of digilanid C in varying dosages upon the potassium and water content of rabbit heart muscle. J. Pharm. Exp. Ther. 67, 50–55 (1939)
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)
Heller, M., Beck, S.: Interactions of cardiac glycosides with cells and membranes. Properties and structural aspects of two receptor sites for ouabain in erythrocytes. Biochim. Biophys. Acta 514, 332–347 (1978)
Jundt, H., Porzig, H., Reuter, H., Stucki, J.W.: The effect of substances releasing intracellular calcium ions on sodium — dependent calcium efflux from guinea-pig auricles. J. Physiol. (Lond.) 246, 229–253 (1975)
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)
Kuschinsky, K., Lahrtz, H.G., Lüllmann, H., van Zwieten, P.A.: Accumulation and release of 3H-digoxin by guinea-pig heart muscle. Br. J. Pharmacol. 30, 317–328 (1967)
Lamb, J.F., McCall, D.: Effect of prolonged ouabain treatment and fluxes in cultured human cells. J. Physiol. (Lond.) 225, 599–617 (1972)
Landowne, D., Ritchie, J.M.: The binding of tritiated ouabain to non-myelinated nerve fibres. J. Physiol. (Lond.) 207, 529–537 (1970)
Langer, G.A.: Ion fluxes in cardiac excitation and contraction and their relation to myocardial contractility. Physiol. Rev. 48, 708–757 (1968)
Langer, G.A.: Relationship between myocardial contractility and the effects of digitalis on ionic exchange. Fed. Proc. 36, 2231–2234 (1977)
Lesne, M.: Principe et utilisation du dosage radioimmunologique des digitaliques. In: Plasma digitalis concentration and digitalis therapy. Godfraind, T. (ed.). Bruxelles: Arscia 1977
Lew, V.L., Ferreira, H.G.: Calcium transport and the properties of a calcium-activated potassium channel in red cell membranes. In: Current topics in membranes and transport, Vol. 10, pp. 218–270. New York: Academic Press 1978
Lüllmann, H., Peters, T.: On the sarcolemmal site of action of cardiac glycosides. In: Recent advances in studies on cardiac structure and metabolism, Vol. 9: The sarcolemma. Roy and Dhalla (eds.), pp. 311–328. Baltimore: University Park Press 1976
Müller, P.: Ouabain effects on cardiac contractions, action potential and cellular potassium. Circ. Res. 17, 46–56 (1965)
Noack, E., Felgenträger, J., Zettner, B.: Changes in myocardial Na and K content during the development of cardiac glycoside inotropy. J. Mol. Cell Cardiol. 11, 1189–1194 (1979)
Reiter, M.: Cardioactive steroids with special reference to calcium. In: Calcium and cellular function. Cuthbert (ed.), pp. 270–279. London: Macmillan 1970
Schatzmann, H.J.: Herzglycoside als Hemmstoffe für den aktiven Kalium-und Natriumtransport durch die Erythrocytenmembran. Heiv. Physiol. Acta 11, 346–354 (1953)
Skou, J.C.: The influence of some cations on an adenosine triphosphatase from peripheral nerves. Biochim. Biophys. Acta 23, 394–401 (1957)
Steiness, E., Valentin, N.: Myocardial digoxin uptake: dissociation between digitalis-induced inotropism and myocardial loss of potassium. Brit. J. Pharmacol. 58, 183–188 (1976)
Thomas, R., Allen, J.C., Pitts, B. Jr., Schwartz, A.: Cardenolide analogs. An explanation for the unusual properties of AY 22241. Eur. J. Pharmacol. 53, 227–237 (1979)
Thomas, R., Boutagy, J., Gelbart, A.: Synthesis and biological activity of semisynthetic digitalis analogs. J. Pharm. Sci. 11, 1645–1683 (1974a)
Thomas, R., Boutagy, J., Gelbart, A.: Cardenolide analogs. V. Cardiotonic activity of semisynthetic analogs of digitoxigenin. J. Pharmacol. Exp. Ther. 191, 219–231 (1974b)
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 (1974)
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1981 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Godfraind, T. (1981). Stimulation and Inhibition of the Na+, K+-Pump by Cardiac Glycosides. In: Greeff, K. (eds) Cardiac Glycosides. Handbook of Experimental Pharmacology, vol 56 / 1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-68163-9_16
Download citation
DOI: https://doi.org/10.1007/978-3-642-68163-9_16
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-68165-3
Online ISBN: 978-3-642-68163-9
eBook Packages: Springer Book Archive