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. 1984 Oct;74(4):1481–1488. doi: 10.1172/JCI111561

Effects of thyroid hormone on sodium pump sites, sodium content, and contractile responses to cardiac glycosides in cultured chick ventricular cells.

D Kim, T W Smith
PMCID: PMC425318  PMID: 6090505

Abstract

Sensitivity of cardiac muscle to digitalis glycosides depends on the thyroid state. The mechanism of this interaction was investigated at the cellular level using spontaneously beating monolayers of cultured chick embryo ventricular cells. Cells were grown for 48 h in serum-free medium containing concentrations of triiodothyronine (T3) from zero to 10(-7) M, and the total number of sodium pump sites, sodium content, and contractile amplitude in the presence and absence of various concentrations of ouabain were determined. T3 caused a concentration-dependent increase in the number of specific ouabain binding sites; the maximal increase to 160% of control was observed in response to 10(-8) M T3. T3 lowered steady-state cellular sodium content in a concentration-dependent manner, also. Ouabain (1 microM) exposure elevated cellular sodium content in all cells, but the increase was greatest in cells grown in T3-free medium and least in cells grown in 10(-8) M T3. The positive inotropic and toxic effects of ouabain in cells grown in 10(-8) M T3 were diminished at any given ouabain concentration, and thus, the dose-response curve was shifted to the right. These results indicate that T3 causes induction of additional sodium pump sites that are functional. The increased tolerance of hyperthyroid cells and reduced tolerance of hypothyroid cells to cardiac glycosides can be explained by these changes in the number of sodium pump sites and cellular sodium content, and consequently, calcium influx via sodium-calcium exchange.

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Selected References

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  1. Aiton J. F., Lamb J. F., Ogden P. Down-regulation of the sodium pump following chronic exposure of HeLa cells and chick embryo heart cells to ouabain. Br J Pharmacol. 1981 Jun;73(2):333–340. doi: 10.1111/j.1476-5381.1981.tb10426.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Akera T., Brody T. M. The role of Na+,K+-ATPase in the inotropic action of digitalis. Pharmacol Rev. 1977 Sep;29(3):187–220. [PubMed] [Google Scholar]
  3. Barry W. H., Biedert S., Miura D. S., Smith T. W. Changes in cellular Na+, K+, and Ca2+ contents, monovalent cation transport rate, and contractile state during washout of cardiac glycosides from cultured chick heart cells. Circ Res. 1981 Jul;49(1):141–149. doi: 10.1161/01.res.49.1.141. [DOI] [PubMed] [Google Scholar]
  4. Barry W. H., Smith T. W. Mechanisms of transmembrane calcium movement in cultured chick embryo ventricular cells. J Physiol. 1982 Apr;325:243–260. doi: 10.1113/jphysiol.1982.sp014148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Biedert S., Barry W. H., Smith T. W. Inotropic effects and changes in sodium and calcium contents associated with inhibition of monovalent cation active transport by ouabain in cultured myocardial cells. J Gen Physiol. 1979 Oct;74(4):479–494. doi: 10.1085/jgp.74.4.479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Biron R., Burger A., Chinet A., Clausen T., Dubois-Ferrière R. Thyroid hormones and the energetics of active sodium-potassium transport in mammalian skeletal muscles. J Physiol. 1979 Dec;297(0):47–60. doi: 10.1113/jphysiol.1979.sp013026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Buccino R. A., Spann J. F., Jr, Pool P. E., Sonnenblick E. H., Braunwald E. Influence of the thyroid state on the intrinsic contractile properties and energy stores of the myocardium. J Clin Invest. 1967 Oct;46(10):1669–1682. doi: 10.1172/JCI105658. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Croxson M. S., Ibbertson H. K. Serum digoxin in patients with thyroid disease. Br Med J. 1975 Sep 6;3(5983):566–568. doi: 10.1136/bmj.3.5983.566. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Curfman G. D., Crowley T. J., Smith T. W. Thyroid-induced alterations in myocardial sodium-potassium-activated adenosine triphosphatase, monovalent cation active transport, and cardiac glycoside binding. J Clin Invest. 1977 Mar;59(3):586–590. doi: 10.1172/JCI108675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. DOHERTY J. E., PERKINS W. H. Studies with tritiated digoxin in human subjects after intravenous administration. Am Heart J. 1962 Apr;63:528–536. doi: 10.1016/0002-8703(62)90310-1. [DOI] [PubMed] [Google Scholar]
  11. Ebner F., Reiter M. The dependence on contraction frequency of the positive inotropic effect of dihydro-ouabain. Naunyn Schmiedebergs Arch Pharmacol. 1977 Oct;300(1):1–9. doi: 10.1007/BF00505073. [DOI] [PubMed] [Google Scholar]
  12. Edelman I. S. Thyroid thermogenesis. N Engl J Med. 1974 Jun 6;290(23):1303–1308. doi: 10.1056/NEJM197406062902308. [DOI] [PubMed] [Google Scholar]
  13. Eickenbusch W., Lahrtz H., Seppelt U., van Zwieten P. A. Serum concentration and urinary excretion of 3 H-ouabain and 3 H-digitoxin in patients suffering from hyperthyroidism or hypothyroidism. Klin Wochenschr. 1970 Mar 1;48(5):270–275. doi: 10.1007/BF01486435. [DOI] [PubMed] [Google Scholar]
  14. FRYE R. L., BRAUNWALD E. Studies on digitalis. III. The influence of triiodothyronine on digitalis requirements. Circulation. 1961 Mar;23:376–382. doi: 10.1161/01.cir.23.3.376. [DOI] [PubMed] [Google Scholar]
  15. 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. 1977 Jan;40(1):8–14. doi: 10.1161/01.res.40.1.8. [DOI] [PubMed] [Google Scholar]
  16. Hegyvary C. Alterations of cardiac NaK-ATPase by the thyroid state in the rat. Res Commun Chem Pathol Pharmacol. 1977 Aug;17(4):689–702. [PubMed] [Google Scholar]
  17. Horackova M., Vassort G. Sodium-calcium exchange in regulation of cardiac contractility. Evidence for an electrogenic, voltage-dependent mechanism. J Gen Physiol. 1979 Apr;73(4):403–424. doi: 10.1085/jgp.73.4.403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ismail-Beigi F., Bissell D. M., Edelman I. S. Thyroid thermogenesis in adult rat hepatocytes in primary monolayer culture: direct action of thyroid hormone in vitro. J Gen Physiol. 1979 Mar;73(3):369–383. doi: 10.1085/jgp.73.3.369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Ismail-Beigi F., Edelman I. S. Effects of thyroid status on electrolyte distribution in rat tissues. Am J Physiol. 1973 Nov;225(5):1172–1177. doi: 10.1152/ajplegacy.1973.225.5.1172. [DOI] [PubMed] [Google Scholar]
  20. Ismail-Beigi F., Edelman I. S. The mechanism of the calorigenic action of thyroid hormone. Stimulation of Na plus + K plus-activated adenosinetriphosphatase activity. J Gen Physiol. 1971 Jun;57(6):710–722. doi: 10.1085/jgp.57.6.710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. KOCH-WESER J., BLINKS J. R. Analysis of the relation of the positive inotropic action of cardiac glycosides to the frequency of contraction of heart muscle. J Pharmacol Exp Ther. 1962 Jun;136:305–317. [PubMed] [Google Scholar]
  22. Kazazoglou T., Renaud J. F., Rossi B., Lazdunski M. Two classes of ouabain receptors in chick ventricular cardiac cells and their relation to (Na+,K+)-ATPase inhibition, intracellular Na+ accumulation, Ca2+ influx, and cardiotonic effect. J Biol Chem. 1983 Oct 25;258(20):12163–12170. [PubMed] [Google Scholar]
  23. Koch-Weser J. Myocardial contraction frequency and onset of cardiac glycoside action. Circ Res. 1971 Jan;28(1):34–48. doi: 10.1161/01.res.28.1.34. [DOI] [PubMed] [Google Scholar]
  24. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  25. Langer G. A. Relationship between myocardial contractility and the effects of digitalis on ionic exchange. Fed Proc. 1977 Aug;36(9):2231–2234. [PubMed] [Google Scholar]
  26. Lin M. H., Akera T. Increased (Na+,K+)-ATPase concentrations in various tissues of rats caused by thyroid hormone treatment. J Biol Chem. 1978 Feb 10;253(3):723–726. [PubMed] [Google Scholar]
  27. Lo C. S., Edelman I. S. Effect of triiodothyronine on the synthesis and degradation of renal cortical (Na+ + k+)-adenosine triphosphatase. J Biol Chem. 1976 Dec 25;251(24):7834–7840. [PubMed] [Google Scholar]
  28. Lo C. S., Lo T. N. Effect of triiodothyronine on the synthesis and degradation of the small subunit of renal cortical (Na+ + K+)-adenosine triphosphatase. J Biol Chem. 1980 Mar 10;255(5):2131–2136. [PubMed] [Google Scholar]
  29. Lo S. C., August T. R., Liberman U. A., Edelman I. S. Dependence of renal (Na+ + k+)-adenosine triphosphatase activity on thyroid status. J Biol Chem. 1976 Dec 25;251(24):7826–7833. [PubMed] [Google Scholar]
  30. Lüllmann H., Weber R., van Zwieten P. A. The correlation between the decline of the positive inotropic effect and the loss of cardiac glycosides from isolated atria during wash-out. Eur J Pharmacol. 1969;6(3):235–240. doi: 10.1016/0014-2999(69)90180-0. [DOI] [PubMed] [Google Scholar]
  31. McCall D. Cation exchange and glycoside binding in cultured rat heart cells. Am J Physiol. 1979 Jan;236(1):C87–C95. doi: 10.1152/ajpcell.1979.236.1.C87. [DOI] [PubMed] [Google Scholar]
  32. 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. Eur J Pharmacol. 1974 May;26(2):166–174. doi: 10.1016/0014-2999(74)90223-4. [DOI] [PubMed] [Google Scholar]
  33. Philipson K. D., Edelman I. S. Thyroid hormone control of Na+-K+-ATPase and K+-dependent phosphatase in rat heart. Am J Physiol. 1977 May;232(5):C196–C201. doi: 10.1152/ajpcell.1977.232.5.C196. [DOI] [PubMed] [Google Scholar]
  34. Reuter H., Seitz N. The dependence of calcium efflux from cardiac muscle on temperature and external ion composition. J Physiol. 1968 Mar;195(2):451–470. doi: 10.1113/jphysiol.1968.sp008467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Shenfield G. M., Thompson J., Horn D. B. Plasma and urinary digoxin in thyroid dysfunction. Eur J Clin Pharmacol. 1977 Dec 28;12(6):437–443. doi: 10.1007/BF00561063. [DOI] [PubMed] [Google Scholar]
  36. Temma K., Akera T. Enhancement of cardiac actions of ouabain and its binding to Na+, K+-adenosine triphosphatase by increased sodium influx in isolated guinea-pig heart. J Pharmacol Exp Ther. 1982 Nov;223(2):490–496. [PubMed] [Google Scholar]

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