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

Circulation Research
E McCallDonald M Bers

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+ load 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 prob...Continue Reading

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