Article
Divergent testosterone impact on cardiac calcium handling: acute vs. chronic effects
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Published: | February 8, 2007 |
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Male gender, especially androgens generally have been associated with an increased cardiovascular risk, recent studies indicate potential beneficial acute effects of testosterone. However, detailed evaluation of chronic and acute actions of testosterone on the function of cardiac ICa,L and intracellular Ca2+ handling is limited. To clarify this situation we performed electrophysiological examinations of single cardiomyocytes. Whole-cell and single-channel analysis of ICa,L, recordings of Ca2+ sparks, measurements of contractility. Pre-treatment with testosterone 100 nM for 24-30 hours increased whole-cell ICa,L from 3.8±0.8 pA/pF (n=10) to 10.1±0.31 pA/pF (n=9) at +10 mV (p<0.001). Increase of ICa,L density was caused by both, increased membrane protein levels of the alpha 1c subunit of L-type calcium channel and a pronounced increment of the single-channel activity (availability 81.8±3.15% vs. 37.1±7.01%; open probability 12.8±3.09% vs. 1.0±0.62%, p<0.01). Moreover, testosterone pre-treatment significantly increased the frequency of Ca2+ sparks and improved myocytes contractility without altering SR Ca2+ load. All chronic effects could be inhibited by flutamide. In contrast acute testosterone administration significantly reduced ICa,L density. Indeed, on the single-channel level acute testosterone application completely reversed the chronic testosterone-mediated effects (open probability 15.1±4.54% vs. 2.3±0.88%; availability 81.0±3.24% vs. 42.3±10.0%; p<0.01 vs. testosterone pretreated cells, p=ns vs. controls), and antagonized the chronic testosterone effects on Ca2+ spark frequency, which was unaffected by flutamide. Testosterone chronically affects the basal level of intracellular Ca2+ handling, which in addition rapidly may be modulated by acute changes of hormone levels. These in vitro results may have clinical relevance, particularly in patients with testosterone levels outside the normal range and under hormone replacement therapy.