Costa Tiago J, Ceravolo Graziela S, dos Santos Rosangela A, de Oliveira Maria Aparecida, Araújo Priscila X, Giaquinto Luciana R, Tostes Rita C, Akamine Eliana H, Fortes Zuleica B, Dantas Ana Paula, Carvalho Maria Helena C
Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Brazil;
Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Brazil; Department of Physiological Sciences, State University of Londrina, Londrina, Brazil;
Am J Physiol Heart Circ Physiol. 2015 Apr 1;308(7):H723-32. doi: 10.1152/ajpheart.00681.2014. Epub 2015 Jan 30.
Testosterone has been added to hormone replacement therapy to treat sexual dysfunction in postmenopausal women. Whereas estrogen has been associated with vascular protection, the vascular effects of testosterone are contradictory and the effects of its association with estrogen are largely unknown. In this study we determined the effects of testosterone associated with conjugated equine estrogen (CEE) on vascular function using a model of hypertensive postmenopausal female: ovariectomized spontaneously hypertensive rats. Female spontaneously hypertensive rats were divided into sham-operated, ovariectomized (OVX), and OVX treated for 15 days with either CEE alone (OVX+CEE) or associated with testosterone (OVX+CEE+T). Angiotensin II (ANG II)-induced contraction was markedly increased in aortic rings from OVX compared with sham-operated rats. CEE treatment restored ANG-II responses, a beneficial effect abrogated with CEE+T. CEE treatment also increased endothelium-dependent relaxation, which was impaired in OVX rats. This effect was lost by CEE+T. Treatment of aortas with losartan (ANG-II type-1 receptor antagonist) or apocynin (NADPH-oxidase inhibitor) restored the endothelium-dependent relaxation in OVX and CEE+T, establishing an interplay between ANG-II and endothelial dysfunction in OVX and CEE+T. The benefits by CEE were associated with downregulation of NADPH-oxidase subunits mRNA expression and decreased reactive oxygen species generation. The association of testosterone with CEE impairs the benefits of estrogen on OVX-associated endothelial dysfunction and reactive oxygen species generation in rat aorta by a mechanism that involves phosphorylation of the cytosolic NADPH-oxidase subunit p47(phox).
睾酮已被添加到激素替代疗法中，用于治疗绝经后女性的性功能障碍。虽然雌激素与血管保护有关，但睾酮的血管效应相互矛盾，其与雌激素联合使用的效果在很大程度上尚不清楚。在本研究中，我们使用绝经后高血压雌性大鼠模型，即去卵巢自发性高血压大鼠，来确定睾酮与结合马雌激素（CEE）联合使用对血管功能的影响。雌性自发性高血压大鼠被分为假手术组、去卵巢组（OVX），以及用单独的CEE（OVX+CEE）或与睾酮联合使用（OVX+CEE+T）处理15天的去卵巢组。与假手术组大鼠相比，OVX大鼠主动脉环中血管紧张素II（ANG II）诱导的收缩明显增加。CEE治疗可恢复ANG-II反应，而CEE+T则消除了这种有益作用。CEE治疗还增加了内皮依赖性舒张，而这种舒张在OVX大鼠中受损。CEE+T使这种作用消失。用氯沙坦（ANG-II 1型受体拮抗剂）或阿朴吗啡（NADPH氧化酶抑制剂）处理主动脉，可恢复OVX和CEE+T组的内皮依赖性舒张，表明在OVX和CEE+T组中ANG-II与内皮功能障碍之间存在相互作用。CEE的有益作用与NADPH氧化酶亚基mRNA表达的下调和活性氧生成的减少有关。睾酮与CEE联合使用会损害雌激素对OVX相关的大鼠主动脉内皮功能障碍和活性氧生成的有益作用，其机制涉及胞质NADPH氧化酶亚基p47（phox）的磷酸化。
