Skip to main content
PMC home page
The Journal of Physiology logoLink to The Journal of Physiology
. 1997 Jun 15;501(Pt 3):509–516. doi: 10.1111/j.1469-7793.1997.509bm.x

Effect of the immunosupressant FK506 on excitation-contraction coupling and outward K+ currents in rat ventricular myocytes.

W H duBell 1, P A Wright 1, W J Lederer 1, T B Rogers 1
PMCID: PMC1159452  PMID: 9218211

Abstract

1. We examined the effects of the immunosupressant drug FK506 on excitation-contraction coupling in isolated rat ventricular myocytes. [Ca2+]i transients were recorded using the intracellular Ca2+ indicators fluo-3 and indo-1 while action potentials (APs) or membrane currents were recorded using patch-type microelectrodes in the whole cell mode. 2. FK506 (25 microM) rapidly and reversibly increased the magnitude of the [Ca2+]i transient in intact cells without changing resting [Ca2+]i or the kinetics of the [Ca2+]i transient, a finding consistent with previous reports that investigated the actions of FK506 on the sarcoplasmic reticulum Ca2+ release channel. 3. The 36% increase in the [Ca2+]i transient produced by FK506 was accompanied by a 293% increase in AP duration (by 293%). Importantly, the addition of FK506 had no effect on the [Ca2+]i transient when the depolarizing duration was controlled in voltage clamp experiments. The increased AP duration could be explained by a marked inward shift in the net membrane current that was observed in these experiments. 4. The net inward current change was not directly responsible for a change in Ca2+ influx, since no change in L-type Ca2+ current (ICa) was observed. Instead, FK506 inhibited both the transient outward K+ current (Ito) and the delayed rectifier K+ current (IK). 5. We conclude that FK506 increases the [Ca2+]i transient during normal contractions by an indirect action: it prolongs the action potential. This action does not appear to depend on the established action of FK506 on the ryanodine receptor. Instead, the inhibition of outward K+ currents prolongs the AP which secondarily increases Ca2+ influx and/or decreases Ca2+ efflux.

Full text

PDF
509

Selected References

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

  1. Abraham R. T., Wiederrecht G. J. Immunopharmacology of rapamycin. Annu Rev Immunol. 1996;14:483–510. doi: 10.1146/annurev.immunol.14.1.483. [DOI] [PubMed] [Google Scholar]
  2. Apkon M., Nerbonne J. M. Alpha 1-adrenergic agonists selectively suppress voltage-dependent K+ current in rat ventricular myocytes. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8756–8760. doi: 10.1073/pnas.85.22.8756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Apkon M., Nerbonne J. M. Characterization of two distinct depolarization-activated K+ currents in isolated adult rat ventricular myocytes. J Gen Physiol. 1991 May;97(5):973–1011. doi: 10.1085/jgp.97.5.973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Armitage J. M., Kormos R. L., Fung J., Starzl T. E. The clinical trial of FK 506 as primary and rescue immunosuppression in adult cardiac transplantation. Transplant Proc. 1991 Dec;23(6):3054–3057. [PMC free article] [PubMed] [Google Scholar]
  5. Bram R. J., Hung D. T., Martin P. K., Schreiber S. L., Crabtree G. R. Identification of the immunophilins capable of mediating inhibition of signal transduction by cyclosporin A and FK506: roles of calcineurin binding and cellular location. Mol Cell Biol. 1993 Aug;13(8):4760–4769. doi: 10.1128/mcb.13.8.4760. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brillantes A. B., Ondrias K., Scott A., Kobrinsky E., Ondriasová E., Moschella M. C., Jayaraman T., Landers M., Ehrlich B. E., Marks A. R. Stabilization of calcium release channel (ryanodine receptor) function by FK506-binding protein. Cell. 1994 May 20;77(4):513–523. doi: 10.1016/0092-8674(94)90214-3. [DOI] [PubMed] [Google Scholar]
  7. Clipstone N. A., Crabtree G. R. Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature. 1992 Jun 25;357(6380):695–697. doi: 10.1038/357695a0. [DOI] [PubMed] [Google Scholar]
  8. Fedida D., Bouchard R. A. Mechanisms for the positive inotropic effect of alpha 1-adrenoceptor stimulation in rat cardiac myocytes. Circ Res. 1992 Sep;71(3):673–688. doi: 10.1161/01.res.71.3.673. [DOI] [PubMed] [Google Scholar]
  9. Fedida D., Braun A. P., Giles W. R. Alpha 1-adrenoceptors in myocardium: functional aspects and transmembrane signaling mechanisms. Physiol Rev. 1993 Apr;73(2):469–487. doi: 10.1152/physrev.1993.73.2.469. [DOI] [PubMed] [Google Scholar]
  10. Galat A. Peptidylproline cis-trans-isomerases: immunophilins. Eur J Biochem. 1993 Sep 15;216(3):689–707. doi: 10.1111/j.1432-1033.1993.tb18189.x. [DOI] [PubMed] [Google Scholar]
  11. Lam E., Martin M. M., Timerman A. P., Sabers C., Fleischer S., Lukas T., Abraham R. T., O'Keefe S. J., O'Neill E. A., Wiederrecht G. J. A novel FK506 binding protein can mediate the immunosuppressive effects of FK506 and is associated with the cardiac ryanodine receptor. J Biol Chem. 1995 Nov 3;270(44):26511–26522. doi: 10.1074/jbc.270.44.26511. [DOI] [PubMed] [Google Scholar]
  12. McCall E., Li L., Satoh H., Shannon T. R., Blatter L. A., Bers D. M. Effects of FK-506 on contraction and Ca2+ transients in rat cardiac myocytes. Circ Res. 1996 Dec;79(6):1110–1121. doi: 10.1161/01.res.79.6.1110. [DOI] [PubMed] [Google Scholar]
  13. Sigal N. H., Dumont F. J. Cyclosporin A, FK-506, and rapamycin: pharmacologic probes of lymphocyte signal transduction. Annu Rev Immunol. 1992;10:519–560. doi: 10.1146/annurev.iy.10.040192.002511. [DOI] [PubMed] [Google Scholar]
  14. Xiao R. P., Valdivia H. H., Bogdanov K., Valdivia C., Lakatta E. G., Cheng H. The immunophilin FK506-binding protein modulates Ca2+ release channel closure in rat heart. J Physiol. 1997 Apr 15;500(Pt 2):343–354. doi: 10.1113/jphysiol.1997.sp022025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. duBell W. H., Lederer W. J., Rogers T. B. Dynamic modulation of excitation-contraction coupling by protein phosphatases in rat ventricular myocytes. J Physiol. 1996 Jun 15;493(Pt 3):793–800. doi: 10.1113/jphysiol.1996.sp021423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. duBell W. H., Lewartowski B., Spurgeon H. A., Silverman H. S., Lakatta E. G. Repletion of sarcoplasmic reticulum Ca after ryanodine in rat ventricular myocytes. Am J Physiol. 1993 Aug;265(2 Pt 2):H604–H615. doi: 10.1152/ajpheart.1993.265.2.H604. [DOI] [PubMed] [Google Scholar]

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

RESOURCES