Effects of FK-506 on contraction and Ca2+ transients in rat cardiac myocytes

Eileen McCall, Li Li, Hiroshi Satoh, Thomas R. Shannon, Lothar A. Blatter, Donald M Bers

Research output: Contribution to journalArticle

94 Scopus citations

Abstract

FK-506 binding protein (FKBP) has been reported to be closely associated with the ryanodine receptor in skeletal and cardiac muscle and to modulate sarcoplasmic reticulum (SR) Ca2+ release channel gating in isolated channels. FK-506 can inhibit the activity of FKBP, thereby reversing its effects on SR Ca2+ release. We investigated the function of FKBP during normal contractions and Ca2+ transients in intact rat ventricular myocytes loaded with fluorescent Ca2+ indicators. FK-506 significantly increased steady state twitch Ca2+ transients and contraction amplitudes even under conditions in which the SR Ca2+ lead and Ca2+ current were unaltered, suggesting that FK-506 increases the fraction of SR Ca2+ released during excitation-contraction (E-C) coupling. Action potentials were somewhat prolonged, consistent with the larger Ca2+ transients causing greater inward Na+-Ca2+ exchange current. FK-506 did not affect SR Ca2+ uptake but modestly decreased Ca2+ extrusion via Na+Ca2+ exchange in intact cells (although no effect on Na+-Ca2+ exchange was seen in sarcolemmal vesicles). In most cells, FK-506 caused an increase in SR Ca2+ content during steady state stimulation, as assessed by caffeine induced contractures. This was probably due to the inhibition of Ca2+ efflux via Na+-Ca2+ exchange. FK-506 also accelerated the rest decay of SR Ca2+ content and increased the frequency of resting Ca2+ sparks about fourfold. The increase in frequency of these basic Ca2+ release events was not associated with changes in the amplitude or duration of the Ca2+ sparks. We conclude that FK-506 increases the fraction of SR Ca2+ released during normal twitches and enhances the rate of SR Ca2+ release during rest. FK- 506 also inhibits Na+-Ca2+ exchange, although this effect may be indirect. These effects are consistent with an important SR stabilizing effect of FKBP in intact rat ventricular myocytes.

Original languageEnglish (US)
Pages (from-to)1110-1121
Number of pages12
JournalCirculation Research
Volume79
Issue number6
StatePublished - 1996
Externally publishedYes

Keywords

  • cardiac muscle
  • FK-506
  • ryanodine receptor
  • sarcolemmal Ca channel
  • sarcoplasmic reticulum

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Effects of FK-506 on contraction and Ca<sup>2+</sup> transients in rat cardiac myocytes'. Together they form a unique fingerprint.

  • Cite this

    McCall, E., Li, L., Satoh, H., Shannon, T. R., Blatter, L. A., & Bers, D. M. (1996). Effects of FK-506 on contraction and Ca2+ transients in rat cardiac myocytes. Circulation Research, 79(6), 1110-1121.