Testosterone has been implicated as a risk factor for
cardiovascular diseases and
thromboxane A2 (TXA2) may be an important pathophysiologic mediator for them.
Testosterone has been shown to increase TXA2 receptor density in several cell types.
Testosterone is reduced at the 5 alpha position to its active metabolite,
dihydrotestosterone, by
5 alpha-reductase. We determined the effects of
epristeride, a
5 alpha-reductase inhibitor, on the density of TXA2 receptors in rat aortic smooth muscle cells and human
erythroleukemia cells, a megakaryocyte-like cell, in vitro, and in rat platelets and aortic membranes in vivo. In rat aortic smooth muscle cells,
epristeride significantly (P < .01, n = 5) blocked the effect of
testosterone to increase TXA2 receptor density (Bmax: 44 +/- 3, 76 +/- 7, 48 +/- 4 and 46 +/- 4 fmol/mg
protein, for control cells, cells treated with
testosterone (200 nM), cells treated with
testosterone and
epristeride (10 nM) and cells treated with
epristeride, respectively.
Epristeride did not block the effect of
testosterone in human
erythroleukemia cells. Treatment of male rats with
epristeride for 2 weeks significantly (P < .01) decreased TXA2 receptor density in aortic membranes (41 +/- 3 for vehicle, n = 10; 27 +/- 3 fmol/mg
protein for
epristeride, n = 11) but did not significantly change TXA2 receptor density in platelets. Maximum contractile responses of rat aortas to
U46619, a TXA2 mimetic, were significantly (P < .001) lower in
epristeride-treated rats than in vehicle-treated rats (4.2 +/- 0.1 for vehicle, n = 16, 3.0 +/- 0.2 g tension for
epristeride, n = 15). In conclusion, regulation of expression of TXA2 receptors by
testosterone in cells of vascular origin, but not in platelets, appears to be via DHT.