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(Circulation Research. 1996;79:1110-1121.)
© 1996 American Heart Association, Inc.

Articles

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

the Department of Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, Ill.

Correspondence to Donald M. Bers, PhD, Department of Physiology, Loyola University Chicago, Stritch School of Medicine, 2160 S First Ave, Maywood, IL 60153. E-mail dbers@luc.edu.

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 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.

Key Words: FK-506 • cardiac muscle • sarcolemmal Ca²⁺ channel • sarcoplasmic reticulum • ryanodine receptor

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