Can the electrophysiological action of rosiglitazone explain its cardiac side effects?

A. Szebeni, N. Szentandrássy, P. Pacher, J. Simkó, P. Nánási, V. Kecskeméti

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Recent large clinical trials found an association between the antidiabetic drug rosiglitazone therapy and increased risk of cardiovascular adverse events. The aim of this report is to elucidate the cardiac electrophysiological properties of rosiglitazone (R) on isolated rat and murine ventricular papillary muscle cells and canine ventricular myocytes using conventional microelectrode, whole cell voltage clamp, and action potential (AP) voltage clamp techniques. In histidine-decarboxylase knockout mice as well as in their wild types R (1-30 μM) shortened AP duration at 90% level of repolarization (APD 90) and increased the AP amplitude (APA) in a concentration-dependent manner. In rat ventricular papillary muscle cells R (1-30 uM) caused a significant reduction of APA and maximum velocity of depolarization (V max) which was accompanied by lengthening of APD 90. In single canine ventricular myocytes at concentrations ≥10 μM R decreased the amplitude of phase-1 repolarization, the plateau potential and reduced V max. R suppressed several ion currents in a concentration-dependent manner under voltage clamp conditions. The EC 50 value for this inhibition was 25.2±2.7 μM for the transient outward K + current (I to), 72.3±9.3 μM for the rapid delayed rectifier K + current (IKr), and 82.5±9.4 μM for the L-type Ca 2+ current (I Ca) with Hill coefficients close to unity. The inward rectifier K + current (I K1) was not affected by R up to concentrations of 100 uM. Suppression of I to, I Kr, and I Ca has been confirmed under action potential voltage clamp conditions as well. The observed alterations in the AP morphology and densities of ion currents may predict serious proarrhythmic risk in case of intoxication with R as a consequence of overdose or decreased elimination of the drug, particularly in patients having multiple cardiovascular risk factors, such as elderly diabetic patients.

Original languageEnglish
Pages (from-to)3720-3728
Number of pages9
JournalCurrent Medicinal Chemistry
Volume18
Issue number24
DOIs
Publication statusPublished - Aug 2011

Fingerprint

rosiglitazone
pamidronate
Clamping devices
Action Potentials
Muscle Cells
Electric potential
Papillary Muscles
Muscle
Rats
Cells
Ions
Canidae
Histidine Decarboxylase
Drug therapy
Microelectrodes
Depolarization
Hypoglycemic Agents
Patch-Clamp Techniques
Knockout Mice
Association reactions

Keywords

  • Action potential
  • Antidiabetic agents
  • Ion currents
  • Rosiglitazone

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Can the electrophysiological action of rosiglitazone explain its cardiac side effects? / Szebeni, A.; Szentandrássy, N.; Pacher, P.; Simkó, J.; Nánási, P.; Kecskeméti, V.

In: Current Medicinal Chemistry, Vol. 18, No. 24, 08.2011, p. 3720-3728.

Research output: Contribution to journalArticle

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