Skip to main content
The Journal of General Physiology logoLink to The Journal of General Physiology
. 1986 Feb 1;87(2):223–242. doi: 10.1085/jgp.87.2.223

Relationship between force and intracellular [Ca2+] in tetanized mammalian heart muscle

DT Yue, E Marban, WG Wier
PMCID: PMC2217602  PMID: 2419483

Abstract

To determine features of the steady state [Ca2+]-tension relationship in intact heart, we measured steady force and intracellular [Ca2+] ([Ca2+]i) in tetanized ferret papillary muscles. [Ca2+]i was estimated from the luminescence emitted by muscles that had been microinjected with aequorin, a Ca2+-sensitive, bioluminescent protein. We found that by raising extracellular [Ca2+] and/or by exposing muscles to the Ca2+ channel agonist Bay K 8644, tension development could be varied from rest to an apparently saturating level, at which increases in [Ca2+]i produced no further rise in force. 95% of maximal Ca2+-activated force was reached at a [Ca2+]i of 0.85 +/- 0.06 microM (mean +/- SEM; n = 7), which suggests that the sensitivity of the myofilaments to [Ca2+]i is far greater than anticipated from studies of skinned heart preparations (or from previous studies using Ca2+-sensitive microelectrodes in intact heart). Our finding that maximal force was reached by approximately 1 microM also allowed us to calculate that the steady state [Ca2+]i-tension relationship, as it might be observed in intact muscle, should be steep (Hill coefficient of greater than 4), which is consistent with the Hill coefficient estimated from the entire [Ca2+]i-tension relationship derived from families of variably activated tetani (6.08 +/- 0.68; n = 7). Finally, with regard to whether steady state measurements can be applied directly toward understanding physiological contractions, we found that the relation between steady force and [Ca2+]i obtained during tetani was steeper than that between peak force and peak [Ca2+]i observed during physiological twitches.

Full Text

The Full Text of this article is available as a PDF (1.1 MB).

Selected References

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

  1. Allen D. G., Blinks J. R. Calcium transients in aequorin-injected frog cardiac muscle. Nature. 1978 Jun 15;273(5663):509–513. doi: 10.1038/273509a0. [DOI] [PubMed] [Google Scholar]
  2. Allen D. G., Blinks J. R., Prendergast F. G. Aequorin luminescence: relation of light emission to calcium concentration--a calcium-independent component. Science. 1977 Mar 11;195(4282):996–998. doi: 10.1126/science.841325. [DOI] [PubMed] [Google Scholar]
  3. Allen D. G., Kurihara S. Calcium transients in mammalian ventricular muscle. Eur Heart J. 1980;Suppl A:5–15. doi: 10.1093/eurheartj/1.suppl_1.5. [DOI] [PubMed] [Google Scholar]
  4. Allen D. G., Orchard C. H. Intracellular calcium concentration during hypoxia and metabolic inhibition in mammalian ventricular muscle. J Physiol. 1983 Jun;339:107–122. doi: 10.1113/jphysiol.1983.sp014706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Blinks J. R., Wier W. G., Hess P., Prendergast F. G. Measurement of Ca2+ concentrations in living cells. Prog Biophys Mol Biol. 1982;40(1-2):1–114. doi: 10.1016/0079-6107(82)90011-6. [DOI] [PubMed] [Google Scholar]
  6. Brandt P. W., Cox R. N., Kawai M., Robinson T. Effect of cross-bridge kinetics on apparent Ca2+ sensitivity. J Gen Physiol. 1982 Jun;79(6):997–1016. doi: 10.1085/jgp.79.6.997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cannell M. B., Allen D. G. Model of calcium movements during activation in the sarcomere of frog skeletal muscle. Biophys J. 1984 May;45(5):913–925. doi: 10.1016/S0006-3495(84)84238-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chapman R. A. Control of cardiac contractility at the cellular level. Am J Physiol. 1983 Oct;245(4):H535–H552. doi: 10.1152/ajpheart.1983.245.4.H535. [DOI] [PubMed] [Google Scholar]
  9. Eisner D. A., Orchard C. H., Allen D. G. Control of intracellular ionized calcium concentration by sarcolemmal and intracellular mechanisms. J Mol Cell Cardiol. 1984 Feb;16(2):137–146. doi: 10.1016/s0022-2828(84)80702-6. [DOI] [PubMed] [Google Scholar]
  10. Fabiato A. Calcium release in skinned cardiac cells: variations with species, tissues, and development. Fed Proc. 1982 May;41(7):2238–2244. [PubMed] [Google Scholar]
  11. Fabiato A., Fabiato F. Contractions induced by a calcium-triggered release of calcium from the sarcoplasmic reticulum of single skinned cardiac cells. J Physiol. 1975 Aug;249(3):469–495. doi: 10.1113/jphysiol.1975.sp011026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fabiato A., Fabiato F. Effects of pH on the myofilaments and the sarcoplasmic reticulum of skinned cells from cardiace and skeletal muscles. J Physiol. 1978 Mar;276:233–255. doi: 10.1113/jphysiol.1978.sp012231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fabiato A., Fabiato F. Myofilament-generated tension oscillations during partial calcium activation and activation dependence of the sarcomere length-tension relation of skinned cardiac cells. J Gen Physiol. 1978 Nov;72(5):667–699. doi: 10.1085/jgp.72.5.667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Fabiato A. Myoplasmic free calcium concentration reached during the twitch of an intact isolated cardiac cell and during calcium-induced release of calcium from the sarcoplasmic reticulum of a skinned cardiac cell from the adult rat or rabbit ventricle. J Gen Physiol. 1981 Nov;78(5):457–497. doi: 10.1085/jgp.78.5.457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fabiato A. Rapid ionic modifications during the aequorin-detected calcium transient in a skinned canine cardiac Purkinje cell. J Gen Physiol. 1985 Feb;85(2):189–246. doi: 10.1085/jgp.85.2.189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Forman R., Ford L. E., Sonnenblick E. H. Effect of muscle length on the force-velocity relationship of tetanized cardiac muscle. Circ Res. 1972 Aug;31(2):195–206. doi: 10.1161/01.res.31.2.195. [DOI] [PubMed] [Google Scholar]
  17. Hess P., Wier W. G. Excitation-contraction coupling in cardiac Purkinje fibers. Effects of caffeine on the intracellular [Ca2+] transient, membrane currents, and contraction. J Gen Physiol. 1984 Mar;83(3):417–433. doi: 10.1085/jgp.83.3.417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hilgemann D. W., Delay M. J., Langer G. A. Activation-dependent cumulative depletions of extracellular free calcium in guinea pig atrium measured with antipyrylazo III and tetramethylmurexide. Circ Res. 1983 Dec;53(6):779–793. doi: 10.1161/01.res.53.6.779. [DOI] [PubMed] [Google Scholar]
  19. Hill T. L. Two elementary models for the regulation of skeletal muscle contraction by calcium. Biophys J. 1983 Dec;44(3):383–396. doi: 10.1016/S0006-3495(83)84312-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kort A. A., Lakatta E. G., Marban E., Stern M. D., Wier W. G. Fluctuations in intracellular calcium concentration and their effect on tonic tension in canine cardiac Purkinje fibres. J Physiol. 1985 Oct;367:291–308. doi: 10.1113/jphysiol.1985.sp015825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Krueger J. W., Pollack G. H. Myocardial sarcomere dynamics during isometric contraction. J Physiol. 1975 Oct;251(3):627–643. doi: 10.1113/jphysiol.1975.sp011112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Marban E., Rink T. J., Tsien R. W., Tsien R. Y. Free calcium in heart muscle at rest and during contraction measured with Ca2+ -sensitive microelectrodes. Nature. 1980 Aug 28;286(5776):845–850. doi: 10.1038/286845a0. [DOI] [PubMed] [Google Scholar]
  23. Marban E., Wier W. G. Ryanodine as a tool to determine the contributions of calcium entry and calcium release to the calcium transient and contraction of cardiac Purkinje fibers. Circ Res. 1985 Jan;56(1):133–138. doi: 10.1161/01.res.56.1.133. [DOI] [PubMed] [Google Scholar]
  24. Moisescu D. G. Kinetics of reaction in calcium-activated skinned muscle fibres. Nature. 1976 Aug 12;262(5569):610–613. doi: 10.1038/262610a0. [DOI] [PubMed] [Google Scholar]
  25. PAGE E. Cat heart muscle in vitro. III. The extracellular space. J Gen Physiol. 1962 Nov;46:201–213. doi: 10.1085/jgp.46.2.201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Robertson S. P., Johnson J. D., Holroyde M. J., Kranias E. G., Potter J. D., Solaro R. J. The effect of troponin I phosphorylation on the Ca2+-binding properties of the Ca2+-regulatory site of bovine cardiac troponin. J Biol Chem. 1982 Jan 10;257(1):260–263. [PubMed] [Google Scholar]
  27. Schramm M., Thomas G., Towart R., Franckowiak G. Novel dihydropyridines with positive inotropic action through activation of Ca2+ channels. Nature. 1983 Jun 9;303(5917):535–537. doi: 10.1038/303535a0. [DOI] [PubMed] [Google Scholar]
  28. Shiner J. S., Solaro R. J. Activation of thin-filament-regulated muscle by calcium ion: considerations based on nearest-neighbor lattice statistics. Proc Natl Acad Sci U S A. 1982 Aug;79(15):4637–4641. doi: 10.1073/pnas.79.15.4637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Shiner J. S., Solaro R. J. The hill coefficient for the Ca2+-activation of striated muscle contraction. Biophys J. 1984 Oct;46(4):541–543. doi: 10.1016/S0006-3495(84)84051-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Stern M. D., Kort A. A., Bhatnagar G. M., Lakatta E. G. Scattered-light intensity fluctuations in diastolic rat cardiac muscle caused by spontaneous Ca++-dependent cellular mechanical oscillations. J Gen Physiol. 1983 Jul;82(1):119–153. doi: 10.1085/jgp.82.1.119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Strobeck J. E., Krueger J., Sonnenblick E. H. Load and time considerations in the force-length relation of cardiac muscle. Fed Proc. 1980 Feb;39(2):175–182. [PubMed] [Google Scholar]
  32. Sutko J. L., Kenyon J. L. Ryanodine modification of cardiac muscle responses to potassium-free solutions. Evidence for inhibition of sarcoplasmic reticulum calcium release. J Gen Physiol. 1983 Sep;82(3):385–404. doi: 10.1085/jgp.82.3.385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wendt I. R., Stephenson D. G. Effects of caffeine on Ca-activated force production in skinned cardiac and skeletal muscle fibres of the rat. Pflugers Arch. 1983 Aug;398(3):210–216. doi: 10.1007/BF00657153. [DOI] [PubMed] [Google Scholar]
  34. Wier W. G. Calcium transients during excitation-contraction coupling in mammalian heart: aequorin signals of canine Purkinje fibers. Science. 1980 Mar 7;207(4435):1085–1087. doi: 10.1126/science.7355274. [DOI] [PubMed] [Google Scholar]
  35. 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]
  36. Wier W. G., Kort A. A., Stern M. D., Lakatta E. G., Marban E. Cellular calcium fluctuations in mammalian heart: direct evidence from noise analysis of aequorin signals in Purkinje fibers. Proc Natl Acad Sci U S A. 1983 Dec;80(23):7367–7371. doi: 10.1073/pnas.80.23.7367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Winegrad S. Regulation of cardiac contractile proteins. Correlations between physiology and biochemistry. Circ Res. 1984 Nov;55(5):565–574. doi: 10.1161/01.res.55.5.565. [DOI] [PubMed] [Google Scholar]
  38. Winegrad S. Studies of cardiac muscle with a high permeability to calcium produced by treatment with ethylenediaminetetraacetic acid. J Gen Physiol. 1971 Jul;58(1):71–93. doi: 10.1085/jgp.58.1.71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Yue D. T., Wier W. G. Estimation of intracellular [Ca2+] by nonlinear indicators. A quantitative analysis. Biophys J. 1985 Sep;48(3):533–537. doi: 10.1016/S0006-3495(85)83810-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of General Physiology are provided here courtesy of The Rockefeller University Press

RESOURCES