Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1993 Apr;108(4):1043–1050. doi: 10.1111/j.1476-5381.1993.tb13503.x

Digoxin activates sarcoplasmic reticulum Ca(2+)-release channels: a possible role in cardiac inotropy.

S J McGarry 1, A J Williams 1
PMCID: PMC1908139  PMID: 8387382

Abstract

1. The effect of digoxin on rapid 45Ca2+ efflux from cardiac and skeletal sarcoplasmic reticulum (SR) vesicles was investigated. Additionally the interaction of digoxin with single cardiac and skeletal muscle SR Ca(2+)-release channels incorporated into planar phospholipid bilayers and held under voltage clamp was determined. 2. Digoxin (1 nM) increased the initial rate and amount of Ca(2+)-induced release of 45Ca2+ from cardiac SR vesicles, passively loaded with 45CaCl2, at an extravesicular [Ca2+] of 0.1 microM. The efflux in the presence and absence of digoxin was inhibited at pM extravesicular Ca2+ and blocked by 5 mM Mg2+. 3. To elucidate the mechanism of action of digoxin, single-channel recording was used. Digoxin (1-20 nM) increased single-channel open probability (Po) when added to the cytosolic but not the luminal face of the cardiac channel in the presence of sub-maximally activating Ca2+ (0.1 microM-10 microM) with an EC50 of 0.91 nM at 10 microM Ca2+. The mechanisms underlying the action of digoxin appear to be concentration-dependent. The activation observed at 1 nM digoxin appears to be consistent with the sensitization of the channel to the effects of Ca2+. At higher concentrations the drug appears to interact synergistically with Ca2+ to produce values of Po considerably greater than those seen with Ca2+ as the sole activating ligand. 4. Digoxin had no effect on single-channel conductance or the Ca2+/Tris permeability ratio. In channels activated by digoxin the Po was decreased by Mg2+.(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
1043

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allen D. G., Eisner D. A., Orchard C. H. Factors influencing free intracellular calcium concentration in quiescent ferret ventricular muscle. J Physiol. 1984 May;350:615–630. doi: 10.1113/jphysiol.1984.sp015221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Allen D. G., Eisner D. A., Pirolo J. S., Smith G. L. The relationship between intracellular calcium and contraction in calcium-overloaded ferret papillary muscles. J Physiol. 1985 Jul;364:169–182. doi: 10.1113/jphysiol.1985.sp015737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ashley R. H., Williams A. J. Divalent cation activation and inhibition of single calcium release channels from sheep cardiac sarcoplasmic reticulum. J Gen Physiol. 1990 May;95(5):981–1005. doi: 10.1085/jgp.95.5.981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bers D. M., Bridge J. H. Effect of acetylstrophanthidin on twitches, microscopic tension fluctuations and cooling contractures in rabbit ventricle. J Physiol. 1988 Oct;404:53–69. doi: 10.1113/jphysiol.1988.sp017278. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Blatz A. L., Magleby K. L. Quantitative description of three modes of activity of fast chloride channels from rat skeletal muscle. J Physiol. 1986 Sep;378:141–174. doi: 10.1113/jphysiol.1986.sp016212. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Boyett M. R., Hart G., Levi A. J. Dissociation between force and intracellular sodium activity with strophanthidin in isolated sheep Purkinje fibres. J Physiol. 1986 Dec;381:311–331. doi: 10.1113/jphysiol.1986.sp016329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cohen I., Daut J., Noble D. An analysis of the actions of low concentrations of ouabain on membrane currents in Purkinje fibres. J Physiol. 1976 Aug;260(1):75–103. doi: 10.1113/jphysiol.1976.sp011505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dupont Y. A rapid-filtration technique for membrane fragments or immobilized enzymes: measurements of substrate binding or ion fluxes with a few-millisecond time resolution. Anal Biochem. 1984 Nov 1;142(2):504–510. doi: 10.1016/0003-2697(84)90496-2. [DOI] [PubMed] [Google Scholar]
  9. Dutta S., Goswami S., Datta D. K., Lindower J. O., Marks B. H. The uptake and binding of six radiolabeled cardiac glycosides by guinea-pig hearts and by isolated sarcoplasmic reticulum. J Pharmacol Exp Ther. 1968 Nov;164(1):10–21. [PubMed] [Google Scholar]
  10. Eisner D. A., Lederer W. J. The role of the sodium pump in the effects of potassium-depleted solutions on mammalian cardiac muscle. J Physiol. 1979 Sep;294:279–301. doi: 10.1113/jphysiol.1979.sp012930. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Eisner D. A. The Wellcome prize lecture. Intracellular sodium in cardiac muscle: effects on contraction. Exp Physiol. 1990 Jul;75(4):437–457. doi: 10.1113/expphysiol.1990.sp003422. [DOI] [PubMed] [Google Scholar]
  12. FATT P., GINSBORG B. L. The ionic requirements for the production of action potentials in crustacean muscle fibres. J Physiol. 1958 Aug 6;142(3):516–543. doi: 10.1113/jphysiol.1958.sp006034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fricke U., Klaus W. Sodium-dependent cardiac glycoside binding: experimental evidence and hypothesis. Br J Pharmacol. 1978 Feb;62(2):255–257. doi: 10.1111/j.1476-5381.1978.tb08453.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ghysel-Burton J., Godfraind T. Low-potassium or ouabain inotropy in cardiac muscle [proceedings]. J Physiol. 1979 Oct;295:52P–53P. [PubMed] [Google Scholar]
  15. Godfraind T., Ghysel-Burton J. Binding sites related to ouabain-induced stimulation or inhibition of the sodium pump. Nature. 1977 Jan 13;265(5590):165–166. doi: 10.1038/265165a0. [DOI] [PubMed] [Google Scholar]
  16. Hart G., Noble D., Shimoni Y. The effects of low concentrations of cardiotonic steroids on membrane currents and tension in sheep Purkinje fibres. J Physiol. 1983 Jan;334:103–131. doi: 10.1113/jphysiol.1983.sp014483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. LaBella F. S., Bihler I., Kim R. S. Progesterone derivative binds to cardiac ouabain receptor and shows dissociation between sodium pump inhibition and increased contractile force. Nature. 1979 Apr 5;278(5704):571–573. doi: 10.1038/278571a0. [DOI] [PubMed] [Google Scholar]
  18. Marban E., Tsien R. W. Enhancement of calcium current during digitalis inotropy in mammalian heart: positive feed-back regulation by intracellular calcium? J Physiol. 1982 Aug;329:589–614. doi: 10.1113/jphysiol.1982.sp014321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Meissner G., Henderson J. S. Rapid calcium release from cardiac sarcoplasmic reticulum vesicles is dependent on Ca2+ and is modulated by Mg2+, adenine nucleotide, and calmodulin. J Biol Chem. 1987 Mar 5;262(7):3065–3073. [PubMed] [Google Scholar]
  20. Miller C. Open-state substructure of single chloride channels from Torpedo electroplax. Philos Trans R Soc Lond B Biol Sci. 1982 Dec 1;299(1097):401–411. doi: 10.1098/rstb.1982.0140. [DOI] [PubMed] [Google Scholar]
  21. Morgan J. P. The effects of digitalis on intracellular calcium transients in mammalian working myocardium as detected with aequorin. J Mol Cell Cardiol. 1985 Nov;17(11):1065–1075. doi: 10.1016/s0022-2828(85)80122-x. [DOI] [PubMed] [Google Scholar]
  22. Moutin M. J., Dupont Y. Rapid filtration studies of Ca2+-induced Ca2+ release from skeletal sarcoplasmic reticulum. Role of monovalent ions. J Biol Chem. 1988 Mar 25;263(9):4228–4235. [PubMed] [Google Scholar]
  23. Musgrave G. E., Born C. K., Davidson C. P., Hamrick M. E. Interaction of spironolactone and digoxin in dogs. J Pharmacol Exp Ther. 1977 Sep;202(3):696–701. [PubMed] [Google Scholar]
  24. Noble D. Mechanism of action of therapeutic levels of cardiac glycosides. Cardiovasc Res. 1980 Sep;14(9):495–514. doi: 10.1093/cvr/14.9.495. [DOI] [PubMed] [Google Scholar]
  25. Sitsapesan R., Williams A. J. Mechanisms of caffeine activation of single calcium-release channels of sheep cardiac sarcoplasmic reticulum. J Physiol. 1990 Apr;423:425–439. doi: 10.1113/jphysiol.1990.sp018031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Smith J. S., Coronado R., Meissner G. Sarcoplasmic reticulum contains adenine nucleotide-activated calcium channels. Nature. 1985 Aug 1;316(6027):446–449. doi: 10.1038/316446a0. [DOI] [PubMed] [Google Scholar]
  27. Tomlins B., Harding S. E., Kirby M. S., Poole-Wilson P. A., Williams A. J. Contamination of a cardiac sarcolemmal preparation with endothelial plasma membrane. Biochim Biophys Acta. 1986 Mar 27;856(1):137–143. doi: 10.1016/0005-2736(86)90020-9. [DOI] [PubMed] [Google Scholar]
  28. Weingart R., Kass R. S., Tsien R. W. Is digitalis inotropy associated with enhanced slow inward calcium current? Nature. 1978 Jun 1;273(5661):389–392. doi: 10.1038/273389a0. [DOI] [PubMed] [Google Scholar]
  29. Wier W. G., Hess P. Excitation-contraction coupling in cardiac Purkinje fibers. Effects of cardiotonic steroids on the intracellular [Ca2+] transient, membrane potential, and contraction. J Gen Physiol. 1984 Mar;83(3):395–415. doi: 10.1085/jgp.83.3.395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Williams A. J., Holmberg S. R. Sulmazole (AR-L 115BS) activates the sheep cardiac muscle sarcoplasmic reticulum calcium-release channel in the presence and absence of calcium. J Membr Biol. 1990 May;115(2):167–178. doi: 10.1007/BF01869455. [DOI] [PubMed] [Google Scholar]
  31. Williams A. J. Ion conduction and discrimination in the sarcoplasmic reticulum ryanodine receptor/calcium-release channel. J Muscle Res Cell Motil. 1992 Feb;13(1):7–26. doi: 10.1007/BF01738423. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES