title: Impact of testosterone on cardiac L-type calcium channels and Ca2+ sparks: acute actions antagonize chronic effects.
abstract: While 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 I(Ca,L) and intracellular Ca2+ handling is limited. To clarify this situation we performed whole-cell and single-channel analysis of I(Ca,L), recordings of Ca2+ sparks, measurements of contractility and quantitative real-time RT-PCR in rat cardiomyocytes following testosterone pretreatment and acute testosterone application. Pretreatment with testosterone 100 nM for 24-30 h increased whole-cell I(Ca,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 I(Ca,L) density was caused by both, increased expression 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% versus 37.1+/-7.01%; open probability 12.8+/-3.09% versus 1.0+/-0.62%, p<0.01). Moreover, testosterone pretreatment 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 I(Ca,L) density. Indeed, on the single-channel level acute testosterone application completely reversed the chronic testosterone-mediated effects, and antagonized the chronic testosterone effects on Ca2+ spark frequency, which was unaffected by flutamide. Thus, testosterone pretreatment activates I(Ca,L) via nuclear receptor-mediated pathways, while testosterone acutely blocks I(Ca,L) in a direct manner. Thus, testosterone chronically affects the basal level of intracellular Ca2+ handling, which in addition rapidly may be modulated by acute changes of hormone levels.
authors.affiliation: Department of Internal Medicine III, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.
authors.forename: Fikret
authors.initials: F
authors.lastname: Er
authors.forename: Guido
authors.initials: G
authors.lastname: Michels
authors.forename: Mathias C
authors.initials: MC
authors.lastname: Brandt
authors.forename: Ismail
authors.initials: I
authors.lastname: Khan
authors.forename: Hannelore
authors.initials: H
authors.lastname: Haase
authors.forename: Michael
authors.initials: M
authors.lastname: Eicks
authors.forename: Michael
authors.initials: M
authors.lastname: Lindner
authors.forename: Uta C
authors.initials: UC
authors.lastname: Hoppe
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D002478:Cells, Cultured; D005260:Female; D015640:Ion Channel Gating / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000494:pharmacology*
chemical_list: D020746:Calcium Channels, L-Type; D013739:Testosterone; D002118:Calcium