Endocrine Abstracts

Testosterone reduces myocardial ischaemia in men with coronary artery disease (CAD) and improves symptoms and exercise capacity in men with congestive heart failure (CHF), effects proposed to be due to testosterone-induced vasodilatation. Isolated vessel studies suggest this occurs via a calcium antagonistic action upon voltage-gated Ca²⁺ channels but this has yet to be investigated directly.

We therefore employed patch clamp methodology to study the effect of testosterone (10^-9-10^-6M) upon whole-cell Ca²⁺ channel currents (using 2x10^-3M Ba²⁺ as the charge carrier), initially in A7r5 vascular smooth muscle cells and then in HEK293 cells stably expressing either the main pore-forming alpha_1C subunit of a human L-type Ca²⁺ channel (Ca_V1.2), or alpha_1H T-type Ca²⁺ channels (Ca_V3.2).

Testosterone (10^-9-10^-6M) caused a rapid, irreversible concentration-dependent inhibition of Ca²⁺ currents in A7r5 vascular smooth with an IC₅₀ of 7.21plus/minus0.06x10^-8M. A similar inhibitory effect was observed in HEK 293 cells expressing the alpha_1C L-type Ca²⁺ channel subunit, producing an IC₅₀ of 6.10plus/minus0.06x10^-8M. Current-voltage relationships indicated that testosterone caused a similar inhibition at all activating potentials, suggesting that the inhibition was voltage-independent. Testosterone (10^-9-10^-6M) also inhibited Ca²⁺ currents in HEK293 cells expressing alpha_1H T-type Ca²⁺ channels, but this effect was partially reversible with a lower IC₅₀ of 2.31plus/minus0.007x10^-7M.

Testosterone inhibits Ca²⁺ currents in A7r5 cells and in HEK293 cells stably expressing the main pore-forming alpha_1C subunit of L-type Ca²⁺ channels with a similar efficacy and potency, demonstrating that testosterone acts as an inhibitor of L-type voltage-gated Ca²⁺ channels in vascular smooth muscle, via interaction with the alpha_1C subunit. Significantly this inhibition occurred at concentrations approaching those found physiologically. Testosterone also inhibits T-type voltage-gated Ca²⁺ channels, which are also expressed in vascular smooth muscle, but with a lower potency. This calcium antagonistic action may contribute to the clinical benefits associated with testosterone therapy in men with CAD and CHF.