INHIBITION OF TESTOSTERONE 5-ALPHA-REDUCTASE - EVIDENCE FOR TISSUE-SPECIFIC REGULATION OF THROMBOXANE A(2) RECEPTORS

Testosterone has been implicated as a risk factor for cardiovascular d iseases and thromboxane A(2) (TXA(2)) may be an important pathophysiol ogic mediator for them. Testosterone has been shown to increase TXA(2) receptor density in several cell types. Testosterone is reduced at th e 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 TXA(2) receptors in rat aortic smooth muscle cells and human erythroleukemia cells, a megakaryocyte-l ike 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 TXA(2) recepto r density (B-max: 44 +/- 3, 76 +/- 7, 48 +/- 4 and 46 +/- 4 fmol/mg pr otein, for control cells, cells treated with testosterone (200 nM), ce lls treated with testosterone and epristeride (10 nM) and cells treate d with epristeride, respectively. Epristeride did not block the effect of testosterone in human erythroleukemia cells. Treatment of male rat s with epristeride for 2 weeks significantly (P < .01) decreased TXA(2 ) receptor density in aortic membranes (41 +/- 3 for vehicle, n = 10; 27 +/- 3 fmol/mg protein for epristeride, n = 11) but did not signific antly change TXA(2) receptor density in platelets. Maximum contractile responses of rat aortas to U46619, a TXA(2) mimetic, were significant ly (P < .001) lower in epristeride-treated rats than in vehicle-treate d rats (4.2 +/- 0.1 for vehicle, n = 16, 3.0 +/- 0.2 g tension for epr isteride, n = 15). in conclusion, regulation of expression of TXA(2) r eceptors by testosterone in cells of vascular origin, but not in plate lets, appears to be via DHT.