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Can the Electrophysiological Action of Rosiglitazone Explain its Cardiac Side Effects?

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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 (APD90) and increased the AP amplitude (APA) in a concentration-dependent manner. In rat ventricular papillary muscle cells R (1-30 μM) caused a significant reduction of APA and maximum velocity of depolarization (Vmax) which was accompanied by lengthening of APD90.

In single canine ventricular myocytes at concentrations ≥10 μM R decreased the amplitude of phase-1 repolarization, the plateau potential and reduced Vmax. R suppressed several ion currents in a concentration-dependent manner under voltage clamp conditions. 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 R up to concentrations of 100 μM. Suppression of Ito, IKr, and ICa 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.

Keywords: Antidiabetic agents; Suppression of Ito, Ikr and Ica; action potential; cardiovascular adverse; ion currents; microelectrode; repolarization; rosiglitazone; ventricular myocytes; ventricular papillary muscle

Document Type: Research Article


Publication date: August 1, 2011

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.

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