Testosterone-induced coronary vasodilatation occurs via a non-genomic mechanism: evidence of a direct calcium antagonism action

Abstract

Testosterone decreases myocardial ischaemia in men with coronary artery disease via a coronary vasodilatory action. However, long-term therapy may increase the risk of prostatic carcinoma via activation of the nuclear AR (androgen receptor). In the present study, we have investigated the mechanism of testosterone-induced vasodilatation using isolated rat coronary arteries and thoracic aortae from control and AR-deficient testicular-feminized mice. Vasodilatation induced by testosterone, T-3-OCMO [testosterone 3-(O-carboxymethyl)oxime] or T-3-OCMO conjugated to BSA was initially measured in preconstricted vessels that had undergone endothelial denudation or incubation with flutamide (10 microM). Cellular fluorescence was also measured in primary aortic SMCs (smooth muscle cells) following exposure to the above fluorescent-labelled agents. Subsequently, vessels were incubated with testosterone (100 microM) or vehicle prior to constriction with KCl (1-100 mM). Testosterone-induced vasodilatation was unaffected by endothelial denudation, flutamide treatment, AR deficiency or conjugation to BSA. Cells exposed to T-3-OCMO-BSA (10 microM) had a higher fluorescence than control cells (32.8+/-4.5 compared with 14.5+/-1.8 arbitrary units respectively; P<0.01). Incubation with testosterone (100 microM) reversibly attenuated coronary vasoconstriction to KCl (1-100 mM; 0.08+/-0.09 compared with 0.79+/-0.08 mN/mm respectively; P<0.0001). Testosterone-induced vasodilatation is independent of the vascular endothelium and nuclear AR, and is initiated at the SMC membrane, which contains testosterone binding sites. A direct calcium antagonistic action is implicated.

Elevated LH predicts ischaemic heart disease events in older men: the Health in Men Study

“…Animal and human studies also suggest direct vasoactive properties. Dose-dependent vasodilatory effects are observed in the presence of androgen receptor (AR) antagonists and in testicular feminised mice (40,41). Alternatively, some of the favourable effects attributed to testosterone may be at least partly due to oestradiol, which is also thought to have beneficial actions.…”

Hormonal effects on blood vessels

“…Similar results have been reported in different experimental conditions by other groups. [106][107][108] The involvement of potassium channels in testosterone-induced vasodilatation has also been studied by many researchers. [109][110][111] Cairrao et al 112 reported that an AR antagonist, flutamide, and an adenosine triphosphate-sensitive potassium-channel inhibitor, glibenclamide, had no influence on the testosterone relaxant effect, whereas a voltage-sensitive potassium-channel inhibitor, 4-aminopyridine, decreased this effect of testosterone.…”

Left ventricular filling pressure in male patients with type 2 diabetes and normal versus low total testosterone levels

“…Additionally, it has been shown to act as a peripheral vasodilator by affecting intracellular calcium regulation and has the potential to increase cardiac output [24]. Some studies have demonstrated that androgen action is mediated by direct calcium antagonism in the vascular smooth muscle [25]. Testosterone is a powerful antagonist of L-type voltage-operated Ca 2+ channels (LVOCCs).…”