Effects of pioglitazone on cardiac ion currents and action potential morphology in canine ventricular myocytes

Kornél Kistamás, Norbert Szentandrássy, Bence Hegyi, Ferenc Ruzsnavszky, Krisztina Váczi, László Bárándi, Balázs Horváth, Andrea Szebeni, János Magyar, Tamás Bányász, Valéria Kecskeméti, Péter P. Nánási

Research output: Contribution to journalArticle

4 Citations (Scopus)

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, I Ca, IKr, IKs at concentrations ≥10 μM, while IK1 at concentrations ≥30 μM. Suppression of I to, 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.

Original languageEnglish
Pages (from-to)10-19
Number of pages10
JournalEuropean Journal of Pharmacology
Volume710
Issue number1-3
DOIs
Publication statusPublished - Jun 15 2013

    Fingerprint

Keywords

  • Action potentials
  • Antidiabetic agents
  • Dog cardiomyocytes
  • Ion currents
  • Pioglitazone

ASJC Scopus subject areas

  • Pharmacology

Cite this