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 μM). 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 μM) 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 μM) 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 μM) 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.
Testosterone-induced coronary vasodilatation occurs via a non-genomic mechanism: evidence of a direct calcium antagonism action
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Richard D. JONES, Kate M. ENGLISH, T. Hugh JONES, Kevin S. CHANNER; Testosterone-induced coronary vasodilatation occurs via a non-genomic mechanism: evidence of a direct calcium antagonism action. Clin Sci (Lond) 1 August 2004; 107 (2): 149–158. doi: https://doi.org/10.1042/CS20030386
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