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

Article Article scientifique Article Role of the T-type calcium channel CaV3.2 in the chronotropic action of corticosteroids in isolated rat ventricular myocytes eng 2009 author Maturana Andrés 58360 author Lenglet Sébastien 589285 author Python Magaly 663290 author Kuroda Shun'ichi 134434 author Rossier Michel 22435 3726-3734 10.1210/en.2008-1727 19443576 0013-7227 http://endo.endojournals.org/content/150/8/3726.full.pdf 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. Adrenal Cortex Hormones/*pharmacology Aldosterone/pharmacology Animals Animals, Newborn Calcium Channels, T-Type/*genetics/*physiology Cells, Cultured Electrophysiology Gene Expression/drug effects Heart Ventricles/*cytology Myocytes, Cardiac/*drug effects/*metabolism RNA Interference/physiology Rats Rats, Wistar Reverse Transcriptase Polymerase Chain Reaction Dewey 616 56 Département de médecine 221 false Endocrinology 150 8 bb3c2f6e-77a9-4da1-aeda-dd68bcd46ff3 Article Restricted file1.pdf 862538 application/pdf restrictedAccess Faculté de médecine / Section de médecine clinique / Département de médecine

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Role of the T-type calcium channel CaV3.2 in the chronotropic action of corticosteroids in isolated rat ventricular myocytes	Endocrinology			2009	680	0

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Kuroda, Shun'ichi