Effects of rosiglitazone on the configuration of action potentials and ion currents in canine ventricular cells

BACKGROUND AND PURPOSE In spite of its widespread clinical application, there is little information on the cellular cardiac effects of the antidiabetic drug rosiglitazone in larger experimental animals. In the present study therefore concentration‐dependent effects of rosiglitazone on action potenti...

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Bibliographic Details
Published in:British journal of pharmacology 2011-06, Vol.163 (3), p.499-509
Main Authors: Szentandrássy, N, Harmati, G, Bárándi, L, Simkó, J, Horváth, B, Magyar, J, Bányász, T, Lőrincz, I, Szebeni, A, Kecskeméti, V, Nánási, PP
Format: Article
Language:English
Subjects:
action potential
Action Potentials - drug effects
Animals
antidiabetic agents
Biological and medical sciences
Calcium Channels, L-Type - physiology
dog cardiomyocytes
Dogs
Female
Heart Ventricles - cytology
Hypoglycemic Agents - adverse effects
In Vitro Techniques
Ion Channels - physiology
ion currents
Male
Medical sciences
Muscle Cells - drug effects
Muscle Cells - physiology
Patch-Clamp Techniques
Pharmacology. Drug treatments
Potassium Channels - physiology
Research Papers with
Rosiglitazone
Sodium Channels - physiology
Thiazolidinediones - adverse effects
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Summary:BACKGROUND AND PURPOSE In spite of its widespread clinical application, there is little information on the cellular cardiac effects of the antidiabetic drug rosiglitazone in larger experimental animals. In the present study therefore concentration‐dependent effects of rosiglitazone on action potential morphology and the underlying ion currents were studied in dog hearts. EXPERIMENTAL APPROACH Standard microelectrode techniques, conventional whole cell patch clamp and action potential voltage clamp techniques were applied in enzymatically dispersed ventricular cells from dog hearts. KEY RESULTS At concentrations ≥10 µM rosiglitazone decreased the amplitude of phase‐1 repolarization, reduced the maximum velocity of depolarization and caused depression of the plateau potential. These effects developed rapidly and were readily reversible upon washout. Rosiglitazone suppressed several transmembrane ion currents, concentration‐dependently, under conventional voltage clamp conditions and altered their kinetic properties. The EC50 value for this inhibition was 25.2 ± 2.7 µM for the transient outward K+ current (Ito), 72.3 ± 9.3 µM for the rapid delayed rectifier K+ current (IKr) and 82.5 ± 9.4 µM for the L‐type Ca2+ current (ICa) with Hill coefficients close to unity. The inward rectifier K+ current (IK1) was not affected by rosiglitazone up to concentrations of 100 µM. Suppression of Ito, IKr, and ICa was confirmed also under action potential voltage clamp conditions. CONCLUSIONS AND IMPLICATIONS Alterations in the densities and kinetic properties of ion currents may carry serious pro‐arrhythmic risk in case of overdose with rosiglitazone, especially in patients having multiple cardiovascular risk factors, like elderly diabetic patients. LINKED ARTICLE This article is commented on by Hancox, pp. 496–498 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476‐5381.2011.01281.x
ISSN:0007-1188
1476-5381
DOI:10.1111/j.1476-5381.2011.01215.x