title: Testosterone is a potent inhibitor of L-type Ca(2+) channels.
abstract: Testosterone administration is beneficial in alleviating myocardial ischaemia in men with significant coronary artery disease (CAD), a condition which is associated with hypotestosteronaemia. Infusion of physiological concentrations of testosterone into coronary arteries at angiography results in rapid vasodilatation in patients with CAD. Whilst the cardiovascular benefits of testosterone have long been documented, the underlying mechanism(s) have not yet been revealed. Here, we have investigated whether testosterone might act like widely prescribed antihypertensive dihydropyridines, as an endogenous Ca(2+) channel antagonist. To do this, we used the whole-cell patch-clamp technique to record Ca(2+) currents from the A7r5 smooth muscle cell line and HEK 293 cells stably expressing either L- or T-type Ca(2+) channels. We demonstrate that testosterone directly inhibited both native and human recombinant vascular L-type Ca(2+) channels in a manner that was voltage-independent and, crucially, displayed an IC(50) value of 38 nM, a value within the physiological range. At higher (supraphysiological) concentrations both native and human recombinant T-type channels were also inhibited by testosterone. Our data indicate that testosterone acts like widely prescribed antihypertensive dihydropyridines to reduce Ca(2+) influx into vascular smooth muscle and so promote vasodilation. This effect is likely to account for its beneficial cardiovascular actions.
authors.affiliation: Institute for Cardiovascular Research, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Scragg
authors.forename: Richard D
authors.initials: RD
authors.lastname: Jones
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Channer
authors.forename: T Hugh
authors.initials: TH
authors.lastname: Jones
authors.forename: Chris
authors.initials: C
authors.lastname: Peers
mesh_terms: D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006801:Humans; D009543:Nifedipine / Q000494:pharmacology; D011994:Recombinant Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology*; D014162:Transfection
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D011994:Recombinant Proteins; D013739:Testosterone; D009543:Nifedipine