title: Effects of pioglitazone on cardiac ion currents and action potential morphology in canine ventricular myocytes.
abstract: Despite its widespread therapeutical use there is little information on the cellular cardiac effects of the antidiabetic drug pioglitazone in larger mammals. In the present study, therefore, the concentration-dependent effects of pioglitazone on ion currents and action potential configuration were studied in isolated canine ventricular myocytes using standard microelectrode, conventional whole cell patch clamp, and action potential voltage clamp techniques. Pioglitazone decreased the maximum velocity of depolarization and the amplitude of phase-1 repolarization at concentrations ≥3 μM. Action potentials were shortened by pioglitazone at concentrations ≥10 μM, which effect was accompanied with significant reduction of beat-to-beat variability of action potential duration. Several transmembrane ion currents, including the transient outward K(+) current (Ito), the L-type Ca(2+) current (ICa), the rapid and slow components of the delayed rectifier K(+) current (IKr and IKs, respectively), and the inward rectifier K(+) current (IK1) were inhibited by pioglitazone under conventional voltage clamp conditions. Ito was blocked significantly at concentrations ≥3 μM, ICa, IKr, IKs at concentrations ≥10 μM, while IK1 at concentrations ≥30 μM. Suppression of Ito, ICa, IKr, and IK1 has been confirmed also under action potential voltage clamp conditions. ATP-sensitive K(+) current, when activated by lemakalim, was effectively blocked by pioglitazone. Accordingly, action potentials were prolonged by 10 μM pioglitazone when the drug was applied in the presence of lemakalim. All these effects developed rapidly and were readily reversible upon washout. In conclusion, pioglitazone seems to be a harmless agent at usual therapeutic concentrations.
authors.affiliation: Department of Physiology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
authors.forename: Kornél
authors.initials: K
authors.lastname: Kistamás
authors.forename: Norbert
authors.initials: N
authors.lastname: Szentandrássy
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: László
authors.initials: L
authors.lastname: Bárándi
authors.forename: Balázs
authors.initials: B
authors.lastname: Horváth
authors.forename: Andrea
authors.initials: A
authors.lastname: Szebeni
authors.forename: János
authors.initials: J
authors.lastname: Magyar
authors.forename: Tamás
authors.initials: T
authors.lastname: Bányász
authors.forename: Valéria
authors.initials: V
authors.lastname: Kecskeméti
authors.forename: Péter P
authors.initials: PP
authors.lastname: Nánási
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004285:Dogs; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects* / Q000502:physiology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D000077205:Pioglitazone; D011188:Potassium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D007473:Ion Channels; D045162:Thiazolidinediones; D012964:Sodium; D011188:Potassium; D002118:Calcium; D000077205:Pioglitazone