%0 Journal Article %1 Fauc_2005_H778 %A Fauconnier, J�r�my %A Lacampagne, Alain %A Rauzier, Jean-Michel %A Fontanaud, Pierre %A Frapier, Jean-Marc %A Sejersted, Ole M %A Vassort, Guy %A Richard, Sylvain %D 2005 %J Am. J. Physiol. Heart Circ. Physiol. %K 15471978 Action Agents, Animals, Arrhythmia, Artificial, Calcium Calcium, Cardiac, Channels, Electrocardiography, Extracellular Gov't, Heart Immunosuppressive In Inbred Inwardly L-Type, Long Myocytes, Non-U.S. Pacemaker, Patch-Clamp Potassium Potentials, QT Rate, Rats, Rectifying, Research Sodium, Space, Support, Syndrome, Tacrolimus, Techniques, Vitro, WKY, %N 2 %P H778-86 %R 10.1152/ajpheart.00542.2004 %T Frequency-dependent and proarrhythmogenic effects of FK-506 in rat ventricular cells. %U http://dx.doi.org/10.1152/ajpheart.00542.2004 %V 288 %X 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.

@article{Fauc_2005_H778, abstract = {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 {C}a$^{2+}$ 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 {C}a$^{2+}$ buffering (EGTA: 10 vs. 0.5 mmol/l in the patch pipette) or replacement of extracellular {N}a$^{+}$ by Li+, which abolishes {N}a$^{+}$/{C}a$^{2+}$ exchange [{N}a$^{+}$/{C}a$^{2+}$ exchanger current (INaCa)]. In indo-1-loaded cells, FK-506 generated doublets of {C}a$^{2+}$ transients associated with increased diastolic {C}a$^{2+}$ in one-half of the cells. FK-506 reversibly decreased the L-type {C}a$^{2+}$ 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 {C}a$^{2+}$ 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.}, added-at = {2009-06-03T11:20:58.000+0200}, author = {Fauconnier, J�r�my and Lacampagne, Alain and Rauzier, Jean-Michel and Fontanaud, Pierre and Frapier, Jean-Marc and Sejersted, Ole M and Vassort, Guy and Richard, Sylvain}, biburl = {https://www.bibsonomy.org/bibtex/260cb8c7572a424017a24c8fdc2cc5b81/hake}, description = {The whole bibliography file I use.}, doi = {10.1152/ajpheart.00542.2004}, file = {Fauc_2005_H778.pdf:Fauc_2005_H778.pdf:PDF}, interhash = {089e92e167e8f7d5afe31b4a401e808b}, intrahash = {60cb8c7572a424017a24c8fdc2cc5b81}, journal = {Am. J. Physiol. Heart Circ. Physiol.}, key = 32, keywords = {15471978 Action Agents, Animals, Arrhythmia, Artificial, Calcium Calcium, Cardiac, Channels, Electrocardiography, Extracellular Gov't, Heart Immunosuppressive In Inbred Inwardly L-Type, Long Myocytes, Non-U.S. Pacemaker, Patch-Clamp Potassium Potentials, QT Rate, Rats, Rectifying, Research Sodium, Space, Support, Syndrome, Tacrolimus, Techniques, Vitro, WKY,}, month = Feb, number = 2, pages = {H778-86}, pii = {00542.2004}, timestamp = {2009-06-03T11:21:11.000+0200}, title = {Frequency-dependent and proarrhythmogenic effects of FK-506 in rat ventricular cells.}, url = {http://dx.doi.org/10.1152/ajpheart.00542.2004}, volume = 288, year = 2005 }