Higashiura K, Blaney B, Morgan E, Mathur R S, Halushka P V
Department of Pharmacology, Medical University of South Carolina, Charleston, USA.
J Pharmacol Exp Ther. 1996 Dec;279(3):1386-91.
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.
睾酮已被认为是心血管疾病的一个风险因素，血栓素A2（TXA2）可能是其重要的病理生理介质。已有研究表明，睾酮可增加多种细胞类型中TXA2受体的密度。睾酮在5α-还原酶的作用下，在5α位还原为其活性代谢产物双氢睾酮。我们在体外测定了5α-还原酶抑制剂依立雄胺对大鼠主动脉平滑肌细胞和人红白血病细胞（一种巨核细胞样细胞）中TXA2受体密度的影响，并在体内测定了其对大鼠血小板和主动脉膜的影响。在大鼠主动脉平滑肌细胞中，依立雄胺显著（P <.01，n = 5）阻断了睾酮增加TXA2受体密度的作用（Bmax：对照细胞为44±3、用睾酮（200 nM）处理的细胞为76±7、用睾酮和依立雄胺（10 nM）处理的细胞为48±4、用依立雄胺处理的细胞为46±4 fmol/mg蛋白）。依立雄胺未阻断睾酮对人红白血病细胞的作用。用依立雄胺处理雄性大鼠2周后，主动脉膜中的TXA2受体密度显著（P <.01）降低（溶媒组为41±3，n = 10；依立雄胺组为27±3 fmol/mg蛋白，n = 11），但血小板中的TXA2受体密度未显著改变。与溶媒处理的大鼠相比，依立雄胺处理的大鼠主动脉对TXA2模拟物U46619的最大收缩反应显著（P <.001）降低（溶媒组为4.2±0.1，n = 16；依立雄胺组为3.0±0.2 g张力，n = 15）。总之，睾酮对血管源性细胞而非血小板中TXA2受体表达的调节似乎是通过双氢睾酮实现的。
