Testosterone is a potent inhibitor of L-type Ca2+ channels

doi:10.1016/j.bbrc.2004.04.054

Biochemical and Biophysical Research Communications

Volume 318, Issue 2, 28 May 2004, Pages 503-506

https://doi.org/10.1016/j.bbrc.2004.04.054 Get rights and content

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 Ca²⁺ channel antagonist. To do this, we used the whole-cell patch-clamp technique to record Ca²⁺ currents from the A7r5 smooth muscle cell line and HEK 293 cells stably expressing either L- or T-type Ca²⁺ channels. We demonstrate that testosterone directly inhibited both native and human recombinant vascular L-type Ca²⁺ channels in a manner that was voltage-independent and, crucially, displayed an IC₅₀ 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 Ca²⁺ influx into vascular smooth muscle and so promote vasodilation. This effect is likely to account for its beneficial cardiovascular actions.

Section snippets

Materials and methods

Ca²⁺ channel currents were recorded from HEK 293 cells stably transfected with the α_1C subunit of the human cardiovascular L-type Ca²⁺ channel (Ca_v1.2) or the peripherally distributed T-type Ca²⁺ channel, α_1H (Ca_v3.2). Cells were cultured as previously described [19], [20]. To study native L- and T-type Ca²⁺ channels, we recorded from the rat aortic smooth muscle cell line, A7r5.

Coverslip fragments with attached cells were transferred to a continually perfused recording chamber (perfusion rate

Results

Fig. 1A demonstrates partial inhibition by a very low concentration (1 nM) of testosterone of Ca²⁺ channel currents recorded in HEK 293 cells stably transfected with the α_1C subunit of a cloned human cardiovascular L-type Ca²⁺ channel (Ca_v1.2). This inhibition was only slowly reversible, as is the case for similarly lipophilic dihydropyridines, and was not associated with any discernible changes in kinetics. Analysis of current–voltage relationships showed a similar degree of current inhibition

Discussion

The major finding of this study is that testosterone is a selective and potent inhibitor of L-type Ca²⁺ channels, effective within the physiological range. This observation can account for its long-known beneficial vasodilatory effects [4], [5], [12]. Channel inhibition was rapid even when recording currents at room temperature, and during intracellular dialysis with patch pipettes, making it unlikely to be mediated through a genomic effect. Much more likely is direct channel blockade which, if

Acknowledgements

This work was supported by the British Heart Foundation.

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Testosterone is a potent inhibitor of L-type Ca2+ channels

Abstract

Section snippets

Materials and methods

Results

Discussion

Acknowledgements

Steroids

Gen. Pharmacol.

The sex differential in mortality from all causes and ischemic heart disease

Am. J. Epidemiol.

Sex, age, cardiovascular risk factors, and coronary heart disease: a prospective follow-up study of 14,786 middle-aged men and women in Finland

Circulation

Endogenous sex hormones and cardiovascular disease in men

J. Clin. Endocrinol. Metab.

Androgens and cardiovascular disease

Endocr. Rev.

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QJM

Endogenous hormones and carotid atherosclerosis in elderly men

Am. J. Epidemiol.

Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study

J. Clin. Endocrinol. Metab.

High prevalence of low testosterone levels in men with coronary heart disease and an association with hypertension and obesity—the South Yorkshire study

Endocr. Abstr.

Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease

Circulation

Acute haemodynamic effects of testosterone in men with chronic heart failure

Eur. Heart J.

Testosterone is a potent inhibitor of L-type Ca²⁺ channels