Summary
Relationships among positive inotropic response to cardiac glycosides, Na+,K+-ATPase inhibition and monovalent cation pump activities were studied using paced Langendorff preparations of guinea-pig heart. Na+,K+-ATPase activity was estimated from the initial velocity of (3H)-ouabain binding in ventricular homogenates, and cation pump activity from ouabain-sensitive 86Rb uptake of ventricular slices. These parameters were assayed in control, ouabain- or digitoxintreated hearts either at the time of inotropic response to the cardiac glycosides or during the course of drug washout. Development and loss of the inotropic response during ouabain or digitoxin perfusion and washout was accompanied by reduction and subsequent recovery of the initial ouabain binding velocity, respectively. If homogenates from glycoside-treated hearts were incubated at 37°C for 10 min during ouabain-binding studies, the levels of binding were not different from those of control hearts, indicating a rapid dissociation of the glycosides from cardiac Na+,K+-ATPase in this species. Despite differences in the time course of the loss of inotropic responses produced by ouabain or digitoxin, the relationship between Na+,K+-ATPase inhibition and inotropic responses were similar. Inotropic responses to digitoxin during perfusion, and subsequent los during washout, also were accompanied by a reduction and subsequent recovery of 86Rb uptake. A correlation between inhibition of cation pump activity and positive inotropy has hitherto not been demonstrated. Thus, it appears that with cardiac glycosides, a relationship exists among contractility, cardiac Na+,K+-ATPase and monovalent cation pump activities.
Similar content being viewed by others
References
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)
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)
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)
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)
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. molec. cell. Cardiol. 3, 297–300 (1971a)
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 (1971b)
Bernstein, J. C., Israel, Y.: Active transport of 86Rb in human red cells and rat brain slices. J. Pharmacol. exp. Ther. 174, 323–329 (1970)
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)
Besch, H. R., Jr., Schwartz, A.: On mechanism of action of digitalis. J. molec. cell. Cardiol. 1, 195–199 (1970)
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 (Basel) 25, 685–686 (1969)
Fricke, U., Klaus, W.: Über die Wirkung von Strophanthidin-3-bromazetat am Papillarmuskel des Meerschweinchens. Naunyn-Schmiedebergs Arch. Pharmak. 268, 192–199 (1971a)
Fricke, U., Klaus, W.: Die Haftung verschiedener Cardenolide am Papillarmuskel und einer mikrosomalen ATPase des Meerschweinchenherzens. Naunyn-Schmiedebergs Arch. Pharmak. 268, 200–209 (1971b)
Glynn, I. M.: The action of cardiac glycosides on ion movements. Pharmacol. Rev. 16, 381–407 (1964)
Hajdu, S., Leonard, E.: The cellular basis of cardiac glycoside action. Pharmacol. Rev. 11, 173–209 (1959)
Hansen, O., Jensen, J., Norby, J. G.: Mutual exclusion of ATP, ADP and g-strophanthin binding to Na+,K+-ATPase. Nature (Lond.) 234, 122–123 (1971)
Hokin, L. E., Mokotoff, M., Kupchan, S. M.: Alkylation of a brain transport adenosine-triphosphatase at the cardiotonic steroid site by strophanthidin-3-haloacetates. Proc. nat. Acad. Sci. (Wash.) 55, 797–804 (1966)
Langer, G. A.: The intrinsic control of myocardial contraction-ionic factors. New Engl. J. Med. 285, 1065–1071 (1971)
Lee, K. S., Shin, M. R., Kang, D. H., Chan, K. K.: Studies on the mechanism of cardiac glycosides action. Biochem. Pharmacol. 19, 1055–1059 (1970)
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)
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)
Nakamura, Y., Schwartz, A.: Possible control of intracellular calcium metabolism by (H+): Sarcoplasmic reticulum of skeletal muscle and cardiac muscle. Biochem. biophys. Res. Commun. 41, 830–836 (1970)
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)
Okita, G. T., Richardson, F., Roth-Schechter, B. F., Thomas, R. E.: Indirect evidence for the dissociation of Na+,K+-activated ATPase inhibition from positive inotropic action of strophanthidin-3-bromoacetate. Fed. Proc. 28, 607 (1969)
Peters, T., Raben, R.-H., Wassermann, O.: Evidence for a dissociation between positive inotropic effect and inhibition of the Na+−K+-ATPase by ouabain, cassaine and their alkylating derivatives. Europ. J. Pharmacol. 26, 166–174 (1974)
Prindle, K. H., Skelton, C. L., Epstein, S. E., Marcus, F.: Influence of extracellular potassium concentration on myocardial uptake and inotropic effect of tritiated digoxin. Circulat. Res. 28, 337–345 (1971)
Repke, K.: Effect of digitalis on membrane adenosine triphosphatase of cardiac muscle. In: Proceedings of the Second International Pharmacological Meeting, Prague, vol. 4, Drugs and Enzymes, ed. by B. B. Brodie and J. R. Gillette, pp. 65–88. New York: Pergamon Press 1965
Repke, K., Est, M., Portius, H. J.: Über die Ursache der Speciesunterschiede in der Digitalisempfindlichkeit. Biochem. Pharmacol. 14, 1785–1802 (1965)
Repke, K., Portius, H. J.: Über die Identität der Ionenpumpen-ATPase in der Zellmembran des Herzmuskels mit eienum Digitalis-Rezeptorenzym. Experientia (Basel) 19, 452–458 (1963)
Roth-Schechter, B. F., Okita, G. T., Thomas, R. E., Richardson, F.: On the positive inotropic action of alkylating bromoacetates of strophanthidin and strophanthidol-(19-H3). J. Pharmacol. exp. Ther. 171, 13–19 (1970)
Schwartz, A., Allen, J. C., Harigaya, S.: Possible involvement of cardiac Na+,K+-activated triphosphatase in the mechanism of action of cardiac glycosides. J. Pharmacol. exp. Ther. 168, 31–41 (1969)
Schwartz, A., Matsui, H., Laughter, A. H.: Tritiated digoxin binding to Na+,K+-activated adenosine triphosphatase: possible allosteric site. Science 160, 323–325 (1968)
Skou, J. C.: The influence of some cations on an adenosine triphosphatase from peripheral nerves. Biochim. biophys. Acta (Amst.) 23, 394–401 (1957)
Skou, J. C.: Enzymatic basis for active transport of Na+ and K+ across cell membranes. Physiol. Rev. 45, 596–617 (1965)
Ten Eick, R. E., Bassett, A. L., Okita, G. T.: Dissociation of electrophysiological and inotropic actions of strophanthidin-3-bromoacetate: Possible role of the myocardial transmembrane Na+ and K+ gradients. J. Pharmacol. exp. Ther. 185, 12–13 (1973)
Thomas, R. E., Roth-Schechter, B. F., Okita, G. T.: Synthesis and positive inotropic effect of strophanthidol-3-bromoacetate-(19-H3). J. med. Chem. 13, 357–359 (1970)
Tobin, T., Akera, T., Ku, D., Lu, M.: Reversibility of the interaction of strophanthidin-3-bromoacetate with the cardiotonic steroid binding site of Na+,K+-dependent ATPase. Molec. Pharmacol. 9, 676–685 (1973)
Tobin, T., Brody, T. M.: Rates of dissociation of enzyme-ouabain complex and K0.5 values in Na+,K+-ATPase from different species. Biochem. Pharmacol. 21, 1553–1560 (1972)
Winegrad, S., Shanes, A. M.: Calcium flux and contractility in guinea pig atria. J. gen. Physiol. 45, 371–394 (1962)
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. Molec. Pharmacol. 9, 51–60 (1973)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ku, D., Akera, T., Pew, C.L. et al. 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). https://doi.org/10.1007/BF00501153
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00501153