title: Effects of tacrolimus on action potential configuration and transmembrane ion currents in canine ventricular cells.
abstract: Tacrolimus is a commonly used immunosuppressive agent which causes cardiovascular complications, e.g., hypertension and hypertrophic cardiomyopathy. In spite of it, there is little information on the cellular cardiac effects of the immunosuppressive agent tacrolimus in larger mammals. In the present study, therefore, the concentration-dependent effects of tacrolimus on action potential morphology and the underlying ion currents were studied in canine ventricular cardiomyocytes. Standard microelectrode, conventional whole cell patch clamp, and action potential voltage clamp techniques were applied in myocytes enzymatically dispersed from canine ventricular myocardium. Tacrolimus (3-30 μM) caused a concentration-dependent reduction of maximum velocity of depolarization and repolarization, action potential amplitude, phase-1 repolarization, action potential duration, and plateau potential, while no significant change in the resting membrane potential was observed. Conventional voltage clamp experiments revealed that tacrolimus concentrations ≥3 μM blocked a variety of ion currents, including I(Ca), I(to), I(K1), I(Kr), and I(Ks). Similar results were obtained under action potential voltage clamp conditions. These effects of tacrolimus developed rapidly and were fully reversible upon washout. The blockade of inward currents with the concomitant shortening of action potential duration in canine myocytes is the opposite of those observed previously with tacrolimus in small rodents. It is concluded that although tacrolimus blocks several ion channels at higher concentrations, there is no risk of direct interaction with cardiac ion channels when applying tacrolimus in therapeutic concentrations.
authors.affiliation: Department of Physiology, Medical and Health Science Center, University of Debrecen, H-4012, Debrecen, P.O. Box 22, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Szabó
authors.forename: Norbert
authors.initials: N
authors.lastname: Szentandrássy
authors.forename: Kornél
authors.initials: K
authors.lastname: Kistamás
authors.forename: Bence
authors.initials: B
authors.lastname: Hegyi
authors.forename: Ferenc
authors.initials: F
authors.lastname: Ruzsnavszky
authors.forename: Krisztina
authors.initials: K
authors.lastname: Váczi
authors.forename: Balázs
authors.initials: B
authors.lastname: Horváth
authors.forename: János
authors.initials: J
authors.lastname: Magyar
authors.forename: Tamás
authors.initials: T
authors.lastname: Bányász
authors.forename: Balázs
authors.initials: B
authors.lastname: Pál
authors.forename: Péter P
authors.initials: PP
authors.lastname: Nánási
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects* / Q000503:physiopathology; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007473:Ion Channels / Q000378:metabolism; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D016559:Tacrolimus / Q000009:adverse effects*
chemical_list: D007166:Immunosuppressive Agents; D007473:Ion Channels; D016559:Tacrolimus