{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:43:28Z","timestamp":1791074608722,"version":"4.1.0"},"reference-count":39,"publisher":"American Physiological Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2005,2]]},"abstract":"<jats:p> 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<jats:sup>2+<\/jats:sup> transients were performed with indo-1 AM using a multiphotonic microscope. FK-506 (25 \u03bcmol\/l) hyperpolarized the resting membrane potential (RMP; \u22123 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<jats:sup>2+<\/jats:sup> buffering (EGTA: 10 vs. 0.5 mmol\/l in the patch pipette) or replacement of extracellular Na<jats:sup>+<\/jats:sup> by Li<jats:sup>+<\/jats:sup>, which abolishes Na<jats:sup>+<\/jats:sup>\/Ca<jats:sup>2+<\/jats:sup> exchange [Na+\/Ca2+ exchanger current ( I<jats:sub>NaCa<\/jats:sub>)]. In indo-1-loaded cells, FK-506 generated doublets of Ca<jats:sup>2+<\/jats:sup> transients associated with increased diastolic Ca<jats:sup>2+<\/jats:sup> in one-half of the cells. FK-506 reversibly decreased the L-type Ca<jats:sup>2+<\/jats:sup> current ( I<jats:sub>CaL<\/jats:sub>) by 25%, although high-frequency-dependent facilitation of I<jats:sub>CaL<\/jats:sub> persisted, and decreased three distinct K<jats:sup>+<\/jats:sup> currents: delayed rectifier K<jats:sup>+<\/jats:sup> current ( I<jats:sub>K<\/jats:sub>; &gt;80%), transient outward K<jats:sup>+<\/jats:sup> current (&lt;20%), and inward rectifier K<jats:sup>+<\/jats:sup> current ( I<jats:sub>K1<\/jats:sub>; &gt;40%). A shift in the reversal potential of I<jats:sub>K1<\/jats:sub> (\u22125 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 I<jats:sub>CaL<\/jats:sub> 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 I<jats:sub>K1<\/jats:sub> and I<jats:sub>CaL<\/jats:sub>. Alterations in Ca<jats:sup>2+<\/jats:sup> release and I<jats:sub>NaCa<\/jats:sub> may contribute to FK-506-induced AP prolongation and EADs in addition to the permissive role of I<jats:sub>CaL<\/jats:sub> facilitation at high rates of stimulation. <\/jats:p>","DOI":"10.1152\/ajpheart.00542.2004","type":"journal-article","created":{"date-parts":[[2004,10,8]],"date-time":"2004-10-08T00:24:14Z","timestamp":1097195054000},"page":"H778-H786","source":"Crossref","is-referenced-by-count":29,"title":["Frequency-dependent and proarrhythmogenic effects of FK-506 in rat ventricular cells"],"prefix":"10.1152","volume":"288","author":[{"given":"J\u00e9r\u00e9my","family":"Fauconnier","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Lacampagne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Michel","family":"Rauzier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Fontanaud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Marc","family":"Frapier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ole M.","family":"Sejersted","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy","family":"Vassort","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvain","family":"Richard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(00)00107-3"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8167.1998.tb00134.x"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1097\/00007890-199808150-00021"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2001.012708"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.1999.1023"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1998.275.6.H2041"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2000.278.3.H886"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1997.509bm.x"},{"key":"R9","doi-asserted-by":"crossref","unstructured":"Ermentrout B. 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