Montaño Luis M, Calixto Eduardo, Figueroa Alejandra, Flores-Soto Edgar, Carbajal Verónica, Perusquía Mercedes
Instituto de Investigaciones Biomédicas, Departamento de Biología Celular y Fisiología, and Facultad de Medicina, Departamento de Farmacología, México D.F. 04510.
Endocrinology. 2008 May;149(5):2517-26. doi: 10.1210/en.2007-1288. Epub 2008 Feb 14.
Androgen vasorelaxing action is a subject of recent interest. We investigated the involvement of l-type voltage-operated Ca(2+) channels (L-VOCCs), K(+) channels, intracellular Ca(2+) concentration ([Ca(2+)]i), and cAMP in the vasorelaxing effect of testosterone and 5beta-dihydrotestosterone (5beta-DHT) on rat thoracic aorta. Isolated aortic rings were used to study the vasorelaxing potency of testosterone and 5beta-DHT on KCl- and noradrenaline-induced contractions. Patch-clamp was used to analyze androgen effects on Ca(2+) inward and K(+) outward currents. The fluorescence technique was used to evaluate [Ca(2+)]i in single myocytes; moreover, simultaneous measurements of [Ca(2+)]i and vascular contraction were evaluated. 5beta-DHT was more potent than testosterone to relax KCl-induced contraction, but they were equipotent to relax noradrenaline contraction. l-type Ca(2+) currents were blocked by nifedipine, both androgens, and an estrogen in a concentration-dependent manner, and the order of potency was: testosterone > nifedipine > 5beta-DHT > 17beta-estradiol. We observed that testosterone has different mechanism of action by the concentration range used: at nm concentrations it was a powerful L-VOCCs antagonist, whereas at mum concentrations it was observed that: 1) its Ca(2+) antagonist property is reverted by increasing the l-type inward Ca(2+) currents (Ca(2+) agonist property); and 2) the [Ca(2+)]i and cAMP production was increased. The total K(+) currents were unaffected by testosterone or 5beta-DHT. The data show that 5beta-DHT-induced vasorelaxation is due to its selective blockade on L-VOCCs (from nm to microm concentrations), but testosterone-induced vasorelaxation involves concentration-dependent additional mechanisms: acting as an L-VOCCs antagonist at low concentrations, and increasing [Ca(2+)]i and cAMP production at high concentrations.
雄激素的血管舒张作用是近期研究的热点。我们研究了L型电压门控钙通道（L-VOCCs）、钾通道、细胞内钙浓度（[Ca²⁺]i）和环磷酸腺苷（cAMP）在睾酮和5β-二氢睾酮（5β-DHT）对大鼠胸主动脉血管舒张作用中的作用。采用离体主动脉环研究睾酮和5β-DHT对氯化钾和去甲肾上腺素诱导收缩的血管舒张效力。采用膜片钳技术分析雄激素对钙内流和钾外流电流的影响。采用荧光技术评估单个心肌细胞中的[Ca²⁺]i；此外，还评估了[Ca²⁺]i与血管收缩的同步测量。5β-DHT比睾酮更有效地舒张氯化钾诱导的收缩，但它们在舒张去甲肾上腺素诱导的收缩方面效力相当。硝苯地平、两种雄激素和一种雌激素均以浓度依赖性方式阻断L型钙电流，效力顺序为：睾酮>硝苯地平>5β-DHT>17β-雌二醇。我们观察到，睾酮在所使用的浓度范围内具有不同的作用机制：在纳摩尔浓度下，它是一种强大的L-VOCCs拮抗剂，而在微摩尔浓度下观察到：1）其钙拮抗剂特性通过增加L型内向钙电流（钙激动剂特性）而逆转；2）[Ca²⁺]i和cAMP生成增加。总钾电流不受睾酮或5β-DHT影响。数据表明，5β-DHT诱导的血管舒张是由于其对L-VOCCs的选择性阻断（从纳摩尔到微摩尔浓度），但睾酮诱导的血管舒张涉及浓度依赖性的其他机制：在低浓度下作为L-VOCCs拮抗剂起作用，在高浓度下增加[Ca²⁺]i和cAMP生成。
