Summary
It has recently been demonstrated that both Tl+ and Li+ produce concentration-and time-dependent positive inotropic effects in guinea-pig atrial preparations although Tl+ inhibits and Li+ stimulates isolated Na+, K+-ATPase in vitro. In order to elucidate the mechanism of the positive inotropic actions of these cations, the effects of Tl+ and Li+ on sodium pump activity were studied. Active 86Rb uptake in guinea-pig ventricular slices, an estimate of sodium pump activity, was highly sensitive to the inhibitory effect of the cardiac glycosides. Preincubation of slices with Tl+ caused a dose-and time-dependent inhibition of active 86Rb uptake. Similar concentration-and time-dependent inhibition of active 86Rb uptake was observed when Na+ in a Krebs-Henseleit solution was partially replaced with Li+. Lithium, however, stimulated a partially purified Na+, K+-ATPase in vitro. During heart slice incubation, Tl+ and Li+ accumulated in a time-dependent manner. This accumulation was not readily reversible when slices were transferred into Tl+-or Li+-free solutions. It appears that the inhibition of sodium pump activity is related to the positive inotropic action of these cations.
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References
Akera, T.: Membrane adenosinetriphosphatase: A digitalis receptor? Science 198, 569–574 (1974)
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)
Bentfeld, M., Lüllmann, H., Peters, T., Proppe, D.: Interdependence of iontransport and action of ouabain in heart muscle. Br. J. Pharmacol. 61, 19–27 (1977)
Besch, H. R. Jr., Schwartz, A.: On mechanism of action of digitalis. J. Mol. Cell. Cardiol. 1, 195–199 (1970)
Bianchi, C.P., Frazer, A., Mendels, J.: Lithium alteration of sodium-potassium transport ratio in sodium loaded sciatic nerve. Fed. Proc. 36, 3794 (1977)
Bose, D., Innes, I. R.: The role of sodium pump in the inhibition of smooth muscle responsiveness to agonists during potassium restoration. Br. J. Pharmacol. 49, 466–479 (1973)
Britten, J. S., Blank, M.: Thallium activation of the (Na+-K+)-activated ATPase of rabbit kidney. Biochim. Biophys. Acta 159, 160–166 (1968)
Gehring, P. J. Hammond, P. B.: The interrelationship between thallium and potassium in animals. J. Pharmacol. Exp. Ther. 155, 187–201 (1967)
Glynn, I. M.: The action of cardiac glycosides on ion movements. Pharmacol. Rev. 16, 381–407 (1964)
Gutman, Y. M., Hochman, S., Wald, H.: The differential effect of Li+ on microsomal ATPase in cortex, medulla, and papilla of the rat kidney. Biochim. Biophys. Acta, 298, 284–290 (1973)
Inturrisi, C. E.: Thallium induced dephosphorylation of a phosphorylated intermediate of the (sodium + thallium-activated) ATPase. Biochim. Biophys. Acta 179, 630–633 (1959)
Keynes, R. D., Swan, R. C.: The permeability of frog muscle fibres to lithium ions. J. Physiol. (Lond.) 147, 626–638 (1959)
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 (1974a)
Ku, D., Akera, T., Tobin, T., Brody, T. M.: Effects of rubidium on cardiac tissue: Inhibition of Na+, K+-ATPase and stimulation of contractile force. Res. Comm. Chem. Path. Pharmacol. 9, 431–440 (1974b)
Ku, D., Akera, T., Tobin, T., Brody, T. M.: Effects of monovalent cations on cardiac Na+, K+-ATPase activity and on contractile force. Naunyn-Schmiedeberg's Arch. Pharmacol. 290, 113–131 (1975)
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+-adenosine triphosphatase and contractile force. J. Pharmacol. Exp. Ther. 197, 458–469 (1976)
Ku, D. D., Akera, T., Frank, M., Brody, T. M., Iwasa, J.: The effects of grayanotoxin I and α-dihydrograyanotoxin II on guinea pig myocardium. J. Pharmacol. Exp. Ther. 200, 363–372 (1977)
Langer, G. A.: The intrinsic control of myocardial contraction —ionic factors. New Engl. J. Med. 285, 1065–1071 (1971)
Levy, J. V.: Isolated atrial preparations. In: Methods in Pharmacology (A. Schwartz, ed.), Vol. 1, pp. 77–104. New York: Appleton-Cetury-Crofts 1971
Lowry, O. H., Rosebrough, N. J. Farr, A. L., Randall, R. J.: Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193, 265–275 (1951)
Maslova, M. N., Natichin, Y. V., Skulskii, I. A.: Inhibition of active sodium transport and activation of Na+, K+-ATPase by ions Tl+ in frog skin. Biochimiya 36, 867–869 (1971)
Post, R. L.: The salt pump of animal cell membranes. In: Regulatory Functions of Biological Membranes, pp. 163–176.Amsterdam: Elsevier 1968
Post, R. L., Hegyvary, G., Kume, S.: Activation by adenosine triphosphate in the phosphorylation kinetics of sodium and potassium ion transport adenosine triphosphatase. J. Biol. Chem. 247, 6530–6540 (1972)
Repke, K., Est, U., Portius, H. J.: Über die Ursache der Speciesunterschiede in der Digitalisempfindlichkeit. Biochem. Pharmacol. 14, 1785–1802 (1965)
Schwartz, A.: Is the cell membrane Na+, K+-ATPase enzyme system the pharmacological receptor for digitalis? Circ. Res. 39, 2–7 (1976)
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)
Skou, J. C.: Enzymatic basis for active transport of Na+ and K+ across cell membrane. Physiol. Rev. 45, 596–617 (1965)
Skulskii, I. A., Manninen, V., Järnefelt, J.: Interaction of thallous ions with the cation transport mechanism in erythrocytes. Biochim. Biophys. Acta 298, 702–709 (1973)
Skulskii, I. A., Manninen, V., Järnefelt, J.: Thallium inhibition of ouabain-sensitive sodium transport and of the (Na++K+)-ATPase in human erythrocytes. Biochim. Biophys. Acta 394, 569–576 (1975)
Temma, K., Akera, T., Brody, T. M., Manian, A. A.: Hydroxylated chlorpromazine metabolites: Positive inotropic action and the release of catecholamines. Mol. Pharmacol. 13, 1076–1085 (1977)
Temma, K., Akera, T., Ku, D. D., Brody, T. M.: Sodium pump inhibition by sulfhydryl inhibitors and myocardial contractility. Naunyn-Schmiedeberg's Arch. Pharmacol. 302, 63–71 (1978)
Thomas, R. C.: Electrogenic sodium pump in nerve and muscle cells. Physiol. Rev. 52, 563–594 (1972)
Tobin, T., Akera, T., Han, S. C., Brody, T. M.: Lithium and rubidium interactions with sodium-and potassium-dependent adenosine triphosphatase: A molecular basis for the pharmacological actions of these ions. Mol. Pharmacol. 10, 501–508 (1974)
Willis, J. S., Fang, L. S. T.: Li+ stimulation of ouabain-sensitive respiration and (Na+, K+)-ATPase of kidney cortex of ground squirrels. Biochim. Biophys. Acta 219, 486–489 (1970)
Winegrad, S., Shanes, A. M.: Calcium flux and contractility in guinea pig atria. J. Gen. Physiol. 45, 371–394 (1962)
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Ku, D.D., Akera, T., Olgaard, M.K. et al. Effects of lithium and thallous ions on sodium pump activity in the guinea-pig heart and their relationship to the positive inotropic action. Naunyn-Schmiedeberg's Arch. Pharmacol. 304, 167–173 (1978). https://doi.org/10.1007/BF00495553
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DOI: https://doi.org/10.1007/BF00495553