Testosterone-induced coronary vasodilatation occurs via a non-genomic mechanism: evidence of a direct calcium antagonism action.
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.
Hormone and Vascular Biology Group, Academic Unit of Endocrinology, Division of Genomic Medicine, The University of Sheffield, Sheffield S10 2RX, UK. R.D.Jones@sheffield.ac.uk
Richard D
RD
Jones
Kate M
KM
English
T Hugh
TH
Jones
Kevin S
KS
Channer
D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002118:Calcium / Q000037:antagonists & inhibitors*; D003331:Coronary Vessels / Q000187:drug effects; D004730:Endothelium, Vascular / Q000502:physiology; D005485:Flutamide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010091:Oximes / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D013739:Testosterone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
D000726:Androgen Antagonists; D000728:Androgens; D010091:Oximes; D011944:Receptors, Androgen; C121237:testosterone 3-(O-carboxymethyl)oxime; D012710:Serum Albumin, Bovine; D013739:Testosterone; D011189:Potassium Chloride; D005485:Flutamide; D002118:Calcium