Skip to main content
PMC home page
The Journal of Physiology logoLink to The Journal of Physiology
. 1990 Nov;430:519–536. doi: 10.1113/jphysiol.1990.sp018305

A mechanism for the effects of caffeine on Ca2+ release during diastole and systole in isolated rat ventricular myocytes.

S C O'Neill 1, D A Eisner 1
PMCID: PMC1181751  PMID: 2086772

Abstract

1. The fluorescent indicator Indo-1 was used to measure both [Ca2+]i and [caffeine]i in single ventricular myocytes. 2. Caffeine (at concentrations of 1 mM or above) produced a transient increase of resting [Ca2+]i attributed to the release of Ca2+ ions from the sarcoplasmic reticulum (SR). Simultaneous measurement of [caffeine]i showed that the Ca2+ release only began when [caffeine]i had risen to about 1 mM. Subsequently the rate of release was a steep function of [caffeine]i. It is suggested that this results from a positive feedback as the Ca2+ released activates further release. 3. If external Ca2+ was removed the release of Ca2+ produced by caffeine was delayed such that [caffeine]i rose to a greater concentration before release was initiated. This suggests that an increase of [Ca2+]i increases the efficacy of caffeine to release Ca2+ ions from the SR. 4. Lower concentrations of caffeine (50-500 microM) had no effect on diastolic [Ca2+]i. In contrast they increased systolic [Ca2+]i and contraction. This increase was most obvious if the systolic contraction had previously been decreased either by reducing [Ca2+]o from 1 to 0.25 mM or (in voltage-clamped cells) by decreasing the magnitude of the depolarizing pulse. 5. If the exposure to caffeine was prolonged, this increase of systolic [Ca2+]i and contraction was completely transient. On removal of caffeine, systolic [Ca2+]i and contraction decreased to below control before recovering. 6. During these transient changes of systolic [Ca2+]i and contraction there was no change of the sarcolemmal Ca2+ current. 7. It is suggested that the increase of systolic [Ca2+]i is due to caffeine increasing the fraction of the SR Ca2+ content released during the twitch. 8. The above results concerning both diastolic and systolic [Ca2+]i can be explained by a model in which caffeine increases the affinity with which Ca2+ ions activate Ca2(+)-induced Ca2+ release. At high enough [caffeine], the threshold [Ca2+]i for regenerative Ca2(+)-induced Ca2+ release will be reduced to below the resting [Ca2+]i thus producing a diastolic increase of [Ca2+]i. At lower [caffeine] the threshold is higher than resting [Ca2+]i and caffeine only serves to enhance the release produced during systole.

Full text

PDF
522

Selected References

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

  1. Beuckelmann D. J., Wier W. G. Mechanism of release of calcium from sarcoplasmic reticulum of guinea-pig cardiac cells. J Physiol. 1988 Nov;405:233–255. doi: 10.1113/jphysiol.1988.sp017331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Blinks J. R., Olson C. B., Jewell B. R., Bravený P. Influence of caffeine and other methylxanthines on mechanical properties of isolated mammalian heart muscle. Evidence for a dual mechanism of action. Circ Res. 1972 Apr;30(4):367–392. doi: 10.1161/01.res.30.4.367. [DOI] [PubMed] [Google Scholar]
  3. Dobmeyer D. J., Stine R. A., Leier C. V., Greenberg R., Schaal S. F. The arrhythmogenic effects of caffeine in human beings. N Engl J Med. 1983 Apr 7;308(14):814–816. doi: 10.1056/NEJM198304073081405. [DOI] [PubMed] [Google Scholar]
  4. Eisner D. A., Nichols C. G., O'Neill S. C., Smith G. L., Valdeolmillos M. The effects of metabolic inhibition on intracellular calcium and pH in isolated rat ventricular cells. J Physiol. 1989 Apr;411:393–418. doi: 10.1113/jphysiol.1989.sp017580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Eisner D. A., Valdeolmillos M. The mechanism of the increase of tonic tension produced by caffeine in sheep cardiac Purkinje fibres. J Physiol. 1985 Jul;364:313–326. doi: 10.1113/jphysiol.1985.sp015747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fabiato A. Time and calcium dependence of activation and inactivation of calcium-induced release of calcium from the sarcoplasmic reticulum of a skinned canine cardiac Purkinje cell. J Gen Physiol. 1985 Feb;85(2):247–289. doi: 10.1085/jgp.85.2.247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. 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]
  8. Kimoto Y., Saito M., Goto M. Effects of caffeine on the membrane potentials, membrane currents and contractility of the bullfrog atrium. Jpn J Physiol. 1974 Oct;24(5):531–542. doi: 10.2170/jjphysiol.24.531. [DOI] [PubMed] [Google Scholar]
  9. Kirino Y., Osakabe M., Shimizu H. Ca2+-induced Ca2+ release from fragmented sarcoplasmic reticulum: Ca2+-dependent passive Ca2+ efflux. J Biochem. 1983 Oct;94(4):1111–1118. doi: 10.1093/oxfordjournals.jbchem.a134454. [DOI] [PubMed] [Google Scholar]
  10. Lederer W. J., Tsien R. W. Transient inward current underlying arrhythmogenic effects of cardiotonic steroids in Purkinje fibres. J Physiol. 1976 Dec;263(2):73–100. doi: 10.1113/jphysiol.1976.sp011622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Lüttgau H. C., Oetliker H. The action of caffeine on the activation of the contractile mechanism in straited muscle fibres. J Physiol. 1968 Jan;194(1):51–74. doi: 10.1113/jphysiol.1968.sp008394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Nagasaki K., Kasai M. Fast release of calcium from sarcoplasmic reticulum vesicles monitored by chlortetracycline fluorescence. J Biochem. 1983 Oct;94(4):1101–1109. doi: 10.1093/oxfordjournals.jbchem.a134453. [DOI] [PubMed] [Google Scholar]
  13. Niedergerke R., Page S. Analysis of caffeine action in single trabeculae of the frog heart. Proc R Soc Lond B Biol Sci. 1981 Nov 13;213(1192):303–324. doi: 10.1098/rspb.1981.0068. [DOI] [PubMed] [Google Scholar]
  14. Näbauer M., Callewaert G., Cleemann L., Morad M. Regulation of calcium release is gated by calcium current, not gating charge, in cardiac myocytes. Science. 1989 May 19;244(4906):800–803. doi: 10.1126/science.2543067. [DOI] [PubMed] [Google Scholar]
  15. O'Neill S. C., Donoso P., Eisner D. A. The role of [Ca2+]i and [Ca2+] sensitization in the caffeine contracture of rat myocytes: measurement of [Ca2+]i and [caffeine]i. J Physiol. 1990 Jun;425:55–70. doi: 10.1113/jphysiol.1990.sp018092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Robertson D., Frölich J. C., Carr R. K., Watson J. T., Hollifield J. W., Shand D. G., Oates J. A. Effects of caffeine on plasma renin activity, catecholamines and blood pressure. N Engl J Med. 1978 Jan 26;298(4):181–186. doi: 10.1056/NEJM197801262980403. [DOI] [PubMed] [Google Scholar]
  17. Rousseau E., Ladine J., Liu Q. Y., Meissner G. Activation of the Ca2+ release channel of skeletal muscle sarcoplasmic reticulum by caffeine and related compounds. Arch Biochem Biophys. 1988 Nov 15;267(1):75–86. doi: 10.1016/0003-9861(88)90010-0. [DOI] [PubMed] [Google Scholar]
  18. Rousseau E., Meissner G. Single cardiac sarcoplasmic reticulum Ca2+-release channel: activation by caffeine. Am J Physiol. 1989 Feb;256(2 Pt 2):H328–H333. doi: 10.1152/ajpheart.1989.256.2.H328. [DOI] [PubMed] [Google Scholar]
  19. Sandow A. Excitation-contraction coupling in skeletal muscle. Pharmacol Rev. 1965 Sep;17(3):265–320. [PubMed] [Google Scholar]
  20. Satoh H., Vassalle M. Role of calcium in caffeine-norepinephrine interactions in cardiac Purkinje fibers. Am J Physiol. 1989 Jul;257(1 Pt 2):H226–H237. doi: 10.1152/ajpheart.1989.257.1.H226. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Smith G. L., Valdeolmillos M., Eisner D. A., Allen D. G. Effects of rapid application of caffeine on intracellular calcium concentration in ferret papillary muscles. J Gen Physiol. 1988 Sep;92(3):351–368. doi: 10.1085/jgp.92.3.351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Valdeolmillos M., O'Neill S. C., Smith G. L., Eisner D. A. Calcium-induced calcium release activates contraction in intact cardiac cells. Pflugers Arch. 1989 Apr;413(6):676–678. doi: 10.1007/BF00581820. [DOI] [PubMed] [Google Scholar]
  24. 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]

Articles from The Journal of Physiology are provided here courtesy of The Physiological Society

RESOURCES