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Correlation between inhibition of (Na+, K+)-membrane-ATPase and positive inotropic activity of cardenolides in isolated papillary muscles of guinea pig

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Summary

Concentrations of 17 cardenolides, cardenolide glucuronides and sulfates producing halfmaximal inhibition of (Na+, K+)-membrane-ATPase from different organs and animal species were determined in vitro. In addition the concentrations that increased the contractility of guinea pig isolated papillary muscles to a particular level were investigated. Comparisons between ATPase-inhibiting and positive inotropic cardiac activities showed extensive parallelism: the correlation coefficients after log/log transformation were between 0.92 and 0.97. The same close correlations are found if dissociation constants of cardenolide receptor complexes and concentrations causing 86Rb-uptake inhibition in human erythrocytes are examined.

The concentrations necessary for inhibition of (Na+, K+)-membrane-ATPase of the guinea pig heart and the concentrations required to achieve a defined positive inotropic effect in guinea pig papillary muscle showed a log/log correlation coefficient of 0.97 (P<0.001). In both tests the potencies covered more than three orders of magnitude. The results support Repke's hypothesis on the digitalis receptor.

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References

  • Akera, T., Brody, T. M.: Inotropic action of digitalis and ion transport. Life Sci. 18, 135–142 (1976)

    Google Scholar 

  • Akera, T., Baskin, S. I., Tobin, T., Brody, T. M.: Ouabain: Temporal relationship between the inotropic effect and the in vitro binding to, and dissociation from, (Na+, K+)-activated ATPase. Naunyn-Schmiedeberg's Arch. Pharmacol. 277, 151–162 (1973)

    Google Scholar 

  • Belz, G. G., Heinz, N.: The influence of polar and non-polar digoxin and digitoxin metabolites on the 86Rb-uptake of human erythrocytes and the contractility of guinea pig papillary muscles. Arzneim.-Forsch./Drug-Res. 27, 653–655 (1977)

    Google Scholar 

  • Brown, B. T., Wright, S. E.: Hydrogenation of digitalis genins and anhydrogenins. J. Pharm. Pharmacol. 13, 262–267 (1961)

    Google Scholar 

  • Doherty, J. E.: Digitalis glycosides, pharmacokinetics and their clinical implications. Ann. Int. Med. 79, 229–238 (1973)

    Google Scholar 

  • Dutta, S., Zavecz, J. H., Marks, B. H., Rhee, H. M., Brar, S., Richards, S. R., Bhat, H. B.: Dog heart sodium plus potassium activated ATPase activity during and after arrhythmic response to AY-22.241. Ann. N.Y. Acad. Sci. 242, 671–682 (1974)

    Google Scholar 

  • ten Eick, R. E., Bassett, A. L., Okita, G. T.: Dissociation of electrophysiological and inotropic actions of strophanthidin-3-bromo-acetate: Possible role of adenosine triphosphatase in the maintenance of the myocardial transmembrane Na+ and K+ gradients. J. Pharmacol. Exp. Ther. 185, 12–23 (1973)

    Google Scholar 

  • Erdmann, E., Schoner, W.: Eigenschaften des Rezeptors für Herzglykoside. Klin. Wochenschr. 52, 705–718 (1974)

    Google Scholar 

  • Flasch, H., Heinz, N., Petersen, R.: Affinität von polaren Digoxin-und Digitoxin-Antikörpern. Arzneim.-Forsch./Drug Res. 27, 649–653 (1977)

    Google Scholar 

  • Fricke, U.: Neuere Erkenntnisse über den Wirkungsmechanismus der Herzglykoside. Fortschr. Med. 94, 1837–1845 (1976)

    Google Scholar 

  • Haustein, K.-O.: Studies on cardioactive steroids. I. Structure-activity relationships on the isolated atrium. Pharmacology 11, 117–126 (1974)

    Google Scholar 

  • Haustein, K.-O., Hauptmann, J.: Studies on cardioactive steroids II. Structure-activity relationships in the isolated guinea-pig heart. Pharmacology 11, 129–138 (1974)

    Google Scholar 

  • Heyns, K., Paulsen, H.: Selektive katalytische Oxydation mit Edelmetall-Katalysatoren. In: Neuere Methoden der präparativen organischen Chemie (W. Foerst, ed.), Bd. II, S. 208. Weinheim: Verlag Chemie 1960

    Google Scholar 

  • Jacobs, W. A., Gurtus, E. L.: Strophanthidin XIII: Isostrophanthidin and its derivatives. J. Biol. Chem. 74, 811–827 (1959)

    Google Scholar 

  • Ku, D., Akera, T., Pew, C. L., Brody, T. M.: Cardiac glycosides: Correlations among Na+, K+-ATPase, sodium pump and contractility in the guinea pig heart. Naunyn-Schmiedeberg's Arch. Pharmacol. 285, 185–200 (1974)

    Google Scholar 

  • Ku, D. D., Akera, T., Tobin, Th., Brody, Th. M.: Comparative species studies on the effect of monovalent cations and ouabain on cardiac Na+, K+-adenosine triphosphatase and contractile force. J. Pharmacol. Exp. Ther. 197, 458–469 (1976)

    Google Scholar 

  • Lee, K. S., Klaus, W.: The subcellular basis for the mechanism of inotropic action of cariac glycosides. Pharmacol. Rev. 23, 193–261 (1971)

    Google Scholar 

  • Lindenmayer, G. E.: Mechanism of action of digitalis glycosides at the subcellular level. Pharmacol. Ther. B. 2, 843–861 (1976)

    Google Scholar 

  • Lowry, O. H., Rosebrough, N. J., Fow, A. L., Randall, A. L.: Protein measurements with the folin phenol reagent. J. Biol. Chem. 193, 265–275 (1951)

    Google Scholar 

  • Lüllmann, H., Peters, T.: The cardioactivity of digitoxin metabolites. Eur. J. Pharmacol. 14, 204–205 (1971)

    Google Scholar 

  • Lüllmann, H., Peters, T., Seiler, U.-H.: Über die Verteilung und Biotransformation verschiedener Herzglykoside. Dtsch. Med. Wschr. 23, 1018–1021 (1971)

    Google Scholar 

  • 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)

    Google Scholar 

  • Petersen, R., Flasch, H., Heinz, N.: Darstellung und Eigenschaften einiger Glucuronide und Sulfate von Cardenoliden und Cardenolidglykosiden. Arzneim.-Forsch./Drug Res. 27, 642–649 (1977)

    Google Scholar 

  • Reichelt, P.-P.: Synthese von C-3-substituierten Digitoxigeninderivaten und Wirkung der Derivate auf die Na+, K+-aktivierte ATPase. Inaugural-Dissertation. Aus dem Institut f. Biochemie und Endokrinologie der Justus Liebig-Universität, Gießen (1976)

    Google Scholar 

  • Repke, K.: Metabolism of cardiac glycosides. In: Proceedings of the first international pharmacological meeting. Vol. 3: New aspects of cardiac glycosides (W. Wilbrandt, ed.), pp. 47–73 New York: Pergamon Press 1963

    Google Scholar 

  • Repke, K.: Über den biochemischen Wirkungsmodus von Digitalis. Klin. Wochenschr. 42, 157–165 (1964)

    Google Scholar 

  • Repke, K. R. H.: Biochemische Aspekete der Digitalistherapie. Festvortrag. Ber. Ges. Inn. Med. 7, 8–17 (1970)

    Google Scholar 

  • Repke, K. R. H.: Biochemische Grundlagen der Entwicklung neuartiger Herzmittel des Digitalistyps. Pharmazie 27, 11, 693–701 (1972)

    Google Scholar 

  • Repke, K. R. H., Portius, H. J.: Über die Identität der Ionenpumpen-ATPase in der Zellmembran des Herzmuskels mit einem Digitalis-Rezeptorenzym. Experientia 19, 452–458 (1963)

    Google Scholar 

  • Repke, K. R. H., Portius, H. J.: Molekularbiologische Wertbestimmung von Verbindungen des Digitalistyps. Planta Med. 20, 66–78 (1971)

    Google Scholar 

  • Repke, K. R. H., Herrmann, I., Kunze, R., Portius, H. J., Schön, R., Schönfeld, W.: Mechanism of digitalis action and the importance of the kinetics of the formation and decomposition of glycoside-receptor complex for understanding of overall pharmacokinetics of digitalis compounds. Symposium on Digitalis (O. Storstein, ed.), pp. 143–151. Oslo: Gyldendal Norsk Forlag 1973

    Google Scholar 

  • Rhee, H. M., Dutta, S., Marks, B. H.: Cardiac NaK ATPase activity during positive inotropic and toxic action of ouabain. Eur. J. Pharmacol. 37, 141–153 (1976)

    Google Scholar 

  • Sawlewicz, W., Weiß, E., Linde, H. H. A., Meyer, K.: 3α- und 3β-Amino-3-desoxy-digitoxigenin. Helv. Chim. Acta 55, 2452–2460 (1972)

    Google Scholar 

  • Schoner, W., Ilbery, C. von, Kramer, R., Seubert, W.: On the mechanism of Na+- and K+-stimulated hydrolysis of adenosine triphosphate. 1. Purification and properties of a Na+- and K+-activated ATPase from ox brain. Eur. J. Biochem. 1, 334–343 (1967)

    Google Scholar 

  • Schwartz, A.: Is the cell membrane Na+ K+-ATPase enzyme system the pharmacological receptor for digitalis?. Circ. Res. 39, 2–7 (1976)

    Google Scholar 

  • Schwartz, A., Nagano, K., Nahao, M., Lindenmayer, G. E., Allen, J. C.: The sodium- and potassium-activated adenosine-triphosphatase system. In: Methods in pharmacology (A. Schwartz, ed.), Vol. 1, pp. 301–388. New York: Appleton-Century-Crofts 1971

    Google Scholar 

  • Schwartz, A., Allen, J. C., Barry van Winkle, W., 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)

    Google Scholar 

  • Schwartz, A., Lindenmayer, G. E., Allen, J. C.: The sodiumpotassium adenosine triphosphatase: Pharmacological, physiological and biochemical aspects. Pharmacol. Rev. 27, 3–134 (1975)

    Google Scholar 

  • Steiness, E., Valentin, N.: Myocardial digoxin uptake: Dissociation between digitalis-induced inotropism and myocardial loss of potassium. Br. J. Pharmacol. 58, 183–188 (1976)

    Google Scholar 

  • Storstein, L.: Studies on digitalis X: Digitoxin metabolites in human myocardium and relationship between myocardial and serum concentrations of digitoxin in patients on maintenance treatment. Clin. Pharmacol. Ther. 21, 395–408 (1977a)

    Google Scholar 

  • Storstein, L.: Studies on digitalis XI: Digitoxin metabolism in patients with impaired renal function. Clin. Pharmacol. Ther. 21, 536–546 (1977b)

    Google Scholar 

  • Zavecz, J. H., Dutta, S.: The relationship between Na+, K+-ATPase inhibition and cardiac glycoside-induced arrhythmia in dogs. Naunyn-Schmiedeberg's Arch. Pharmacol. 297, 91–98 (1977)

    Google Scholar 

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  1. Pharma-Forschung Beiersdorf AG, Unnastrasse 48, D-2000, Hamburg 20, Germany

    H. Flasch & N. Heinz

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  1. H. Flasch
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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-Schmiedeberg's Arch. Pharmacol. 304, 37–44 (1978). https://doi.org/10.1007/BF00501375

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  • DOI: https://doi.org/10.1007/BF00501375

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