Dataset Information

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

ABSTRACT:

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 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 (I(Kr)) 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 rosiglitazone up to concentrations of 100 µM. Suppression of I(to), I(Kr), and I(Ca) 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.

SUBMITTER: Szentandrassy N

PROVIDER: S-EPMC3101613 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Publications

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

Szentandrássy N N Harmati G G Bárándi L L Simkó J J Horváth B B Magyar J J Bányász T T Lorincz I I Szebeni A A Kecskeméti V V Nánási P P PP

British journal of pharmacology 20110601 3

<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>Standard microelectrode techniques, conventional whole cell patch clamp and action potent ...[more]

PMID: 21232044

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Project description:Uterine contractions during labor are discretely regulated by rhythmic action potentials (AP) of varying duration and form that serve to determine calcium-dependent force production. We have employed a computational biology approach to develop a fuller understanding of the complexity of excitation-contraction (E-C) coupling of uterine smooth muscle cells (USMC). Our overall aim is to establish a mathematical platform of sufficient biophysical detail to quantitatively describe known uterine E-C coupling parameters and thereby inform future empirical investigations of physiological and pathophysiological mechanisms governing normal and dysfunctional labors. From published and unpublished data we construct mathematical models for fourteen ionic currents of USMCs: Ca2+ currents (L- and T-type), Na+ current, an hyperpolarization-activated current, three voltage-gated K+ currents, two Ca2+-activated K+ current, Ca2+-activated Cl current, non-specific cation current, Na+-Ca2+ exchanger, Na+-K+ pump and background current. The magnitudes and kinetics of each current system in a spindle shaped single cell with a specified surface area:volume ratio is described by differential equations, in terms of maximal conductances, electrochemical gradient, voltage-dependent activation/inactivation gating variables and temporal changes in intracellular Ca2+ computed from known Ca2+ fluxes. These quantifications are validated by the reconstruction of the individual experimental ionic currents obtained under voltage-clamp. Phasic contraction is modeled in relation to the time constant of changing [Ca2+]i. This integrated model is validated by its reconstruction of the different USMC AP configurations (spikes, plateau and bursts of spikes), the change from bursting to plateau type AP produced by estradiol and of simultaneous experimental recordings of spontaneous AP, [Ca2+]i and phasic force. In summary, our advanced mathematical model provides a powerful tool to investigate the physiological ionic mechanisms underlying the genesis of uterine electrical E-C coupling of labor and parturition. This will furnish the evolution of descriptive and predictive quantitative models of myometrial electrogenesis at the whole cell and tissue levels.

Dataset Information

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

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

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

Similar Datasets

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