Frequency-dependent and proarrhythmogenic effects of FK-506 in rat ventricular cells.
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Am. J. Physiol. Heart Circ. Physiol. 288 (2): H778-86 (February 2005)

FK-506, a widely used immunosuppressant, has caused a few clinical cases with QT prolongation and torsades de pointe at high blood concentration. The proarrhytmogenic potential of FK-506 was investigated in single rat ventricular cells using the whole cell clamp method to record action potentials (APs) and ionic currents. Fluorescence measurements of Ca$^2+$ transients were performed with indo-1 AM using a multiphotonic microscope. FK-506 (25 micromol/l) hyperpolarized the resting membrane potential (RMP; -3 mV) and prolonged APs (AP duration at 90\% repolarization increased by 21\%) at 0.1 Hz. Prolongation was enhanced by threefold at 3.3 Hz, and early afterdepolarizations (EADs) occurred in 59\% of cells. EADs were prevented by stronger intracellular Ca$^2+$ buffering (EGTA: 10 vs. 0.5 mmol/l in the patch pipette) or replacement of extracellular Na$^+$ by Li+, which abolishes Na$^+$/Ca$^2+$ exchange Na$^+$/Ca$^2+$ exchanger current (INaCa). In indo-1-loaded cells, FK-506 generated doublets of Ca$^2+$ transients associated with increased diastolic Ca$^2+$ in one-half of the cells. FK-506 reversibly decreased the L-type Ca$^2+$ current (ICaL) by 25\%, although high-frequency-dependent facilitation of ICaL persisted, and decreased three distinct K$^+$ currents: delayed rectifier K$^+$ current (IK; >80\%), transient outward K$^+$ current (<20\%), and inward rectifier K$^+$ current (IK1; >40\%). A shift in the reversal potential of IK1 (-5 mV) accounted for RMP hyperpolarization. Numerical simulations, reproducing all experimental effects of FK-506, and the use of nifedipine showed that frequency-dependent facilitation of ICaL plays a role in the occurrence of EADs. In conclusion, the effects of FK-506 on the cardiac AP are more complex than previously reported and include inhibitions of IK1 and ICaL. Alterations in Ca$^2+$ release and INaCa may contribute to FK-506-induced AP prolongation and EADs in addition to the permissive role of ICaL facilitation at high rates of stimulation.
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