This Article Full Text Full Text (PDF) Supplemental Data Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Google Scholar Articles by Maturana, A. Articles by Rossier, M. F. PubMed PubMed Citation Articles by Maturana, A. Articles by Rossier, M. F. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Steroids

Role of the T-Type Calcium Channel Ca_V3.2 in the Chronotropic Action of Corticosteroids in Isolated Rat Ventricular Myocytes

Global-Edge Institute (A.M.), Tokyo Institute of Technology, Yokohama 226-8502, Japan; Department of Structural Molecular Biology (S.K.), The Institute of Scientific and Industrial Research, Osaka University, Osaka 567-0047, Japan; and Service of Endocrinology and Diabetology (S.L., M.P., M.F.R.), Department of Internal Medicine, and Service of Laboratory Medicine (M.F.R.), Department of Genetics and Laboratory Medicine, University Hospital of Geneva, CH-1211 Geneva, Switzerland

Address all correspondence and requests for reprints to: Dr. Michel F. Rossier, Service of Endocrinology and Diabetology, University Hospital, 24 rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland. E-mail: michel.rossier{at}hcuge.ch.

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_V3.2/1H. This response was accompanied by an increase of the Ca_V3.2 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_V3.2 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_V3.2 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_V3.2 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.