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Role of the T-type calcium channel CaV3.2 in the chronotropic action of corticosteroids in isolated rat ventricular myocytes

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Published in Endocrinology. 2009, vol. 150, no. 8, p. 3726-3734
Abstract The mineralocorticoid receptor is involved in the development of several cardiac dysfunctions, including lethal ventricular arrhythmias associated with heart failure or hyperaldosteronism, but the molecular mechanisms responsible for these effects remain to be clarified. Reexpression of low voltage-activated T-type calcium channels in ventricular myocytes together with other fetal genes during cardiac pathologies could confer automaticity to these cells and would represent a pro-arrhythmogenic condition if occurring in vivo. In the present study, we demonstrated that in isolated neonatal rat ventricular myocytes, corticosteroids selectively induced the expression of a particular isoform of T channel, Ca(V)3.2/alpha1H. This response was accompanied by an increase of the Ca(V)3.2 T-type current, identified with the patch clamp technique by its sensitivity to nickel, and a concomitant acceleration of the myocyte spontaneous contractions. Silencing Ca(V)3.2 expression markedly reduced the chronotropic response to steroids. Moreover, modulation of the frequency of cell contractions by different redox agents was independent of channel expression but involved a direct regulation of channel activity. Although oxidants increased both Ca(V)3.2 current amplitude and beating frequency, they decreased L-type channel activity. Reducing agents had the opposite effect on these parameters. In conclusion, the acceleration of ventricular myocyte spontaneous contractions induced by corticosteroids in vitro appears dependent on the expression of the Ca(V)3.2 T channel isoform and modulated by the redox potential of the cells. These results provide a molecular model that could explain the high incidence of arrhythmias observed in patients upon combination of inappropriate activation of the mineralocorticoid receptor and oxidative stress.
Keywords Adrenal Cortex Hormones/*pharmacologyAldosterone/pharmacologyAnimalsAnimals, NewbornCalcium Channels, T-Type/*genetics/*physiologyCells, CulturedElectrophysiologyGene Expression/drug effectsHeart Ventricles/*cytologyMyocytes, Cardiac/*drug effects/*metabolismRNA Interference/physiologyRatsRats, WistarReverse Transcriptase Polymerase Chain Reaction
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PMID: 19443576
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Other version: http://endo.endojournals.org/content/150/8/3726.full.pdf
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MATURANA, Andrés et al. Role of the T-type calcium channel CaV3.2 in the chronotropic action of corticosteroids in isolated rat ventricular myocytes. In: Endocrinology, 2009, vol. 150, n° 8, p. 3726-3734. https://archive-ouverte.unige.ch/unige:19943

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Deposited on : 2012-04-23

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