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Effect of the immunosupressant FK506 on excitation—contraction coupling and outward K + currents in rat ventricular myocytes
Author(s) -
DuBell William H.,
Wright Pamela A.,
Lederer W. J.,
Rogers Terry B.
Publication year - 1997
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1111/j.1469-7793.1997.509bm.x
Subject(s) - ryanodine receptor , depolarization , biophysics , cardiac transient outward potassium current , chemistry , contraction (grammar) , endoplasmic reticulum , membrane potential , myocyte , voltage clamp , coupling (piping) , electrophysiology , medicine , repolarization , intracellular , patch clamp , excitation–contraction coupling , materials science , biology , biochemistry , metallurgy
1 We examined the effects of the immunosupressant drug FK506 on excitation–contraction coupling in isolated rat ventricular myocytes. [Ca 2+ ] i transients were recorded using the intracellular Ca 2+ 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 (μ m ) rapidly and reversibly increased the magnitude of the [Ca 2+ ] i transient in intact cells without changing resting [Ca 2+ ]i or the kinetics of the [Ca 2+ ] i transient, a finding consistent with previous reports that investigated the actions of FK506 on the sarcoplasmic reticulum Ca 2+ release channel. 3 The 36% increase in the [Ca 2+ ] 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 [Ca 2+ ] 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 Ca 2+ influx, since no change in L‐type Ca 2+ current ( I Ca ) was observed. Instead, FK506 inhibited both the transient outward K + current ( I to ) and the delayed rectifier K + current ( I K ). 5 We conclude that FK506 increases the [Ca 2+ ] 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 Ca 2+ influx and/or decreases Ca 2+ efflux.