Araujo Priscila Xavier, Costa Tiago Januário, Echem Cinthya, Aparecida de Oliveira Maria, Santos-Eichler Rosangela Aparecida, Colli Lucas Giglio, Jiménez-Altayó Francesc, Vila Elisabet, Akamine Eliana Hiromi, Dantas Ana Paula, Ceravolo Graziela Scalianti, de Carvalho Maria Helena Catelli
Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Brazil. (P.X.A., T.J.C., C.E., M.A.O., R.A.S.E., L.G.C., E.H.A., M.H.C.C.); Department of Physiological Sciences, State University of Londrina, Londrina, Brazil. (G.S.C.), Facultat de Medicina, Departament de Farmacologia, Terapèutica i Toxicologia, Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain. (F.J.-A., E.V.); Group of Atherosclerosis and Coronary disease, Institut Clinic del Torax, Institut d'Investigaciones Biomédiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain. (A.P.D.).
Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Brazil. (P.X.A., T.J.C., C.E., M.A.O., R.A.S.E., L.G.C., E.H.A., M.H.C.C.); Department of Physiological Sciences, State University of Londrina, Londrina, Brazil. (G.S.C.), Facultat de Medicina, Departament de Farmacologia, Terapèutica i Toxicologia, Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain. (F.J.-A., E.V.); Group of Atherosclerosis and Coronary disease, Institut Clinic del Torax, Institut d'Investigaciones Biomédiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain. (A.P.D.)
J Pharmacol Exp Ther. 2017 Jul;362(1):98-107. doi: 10.1124/jpet.117.240465. Epub 2017 May 22.
Standard hormone therapy for menopausal women [conjugated equine estrogen (CEE) 0.625 mg] has been associated with increased risk of venous thrombosis. Regimens containing a lower CEE dose (0.30 mg) have been used clinically to decrease side effects of supraphysiologic doses of estrogen. In this study, we determined the effects of standard (SD) and low dose (LD) of CEE on venular function in ovariectomized (OVX) spontaneously hypertensive rats (SHR). Contractions by angiotensin-II (Ang-II 10 M) in perfused mesenteric venular bed were markedly increased in OVX (21.5 ± 1.3 mmHg) compared with Sham (14.7 ± 1.1 mm Hg, < 0.05). CEE-SD did not modify Ang-II responses in OVX, whereas CEE-LD restored Ang-II contraction to Sham levels. Endothelial nitric oxide synthase (eNOS) inhibition by L-NAME increased Ang-II contractions in Sham and CEE-LD and was without effect in venules of OVX SHR and CEE-SD. In OVX there was decreased NO generation in association with diminished eNOS phosphorylation and increased O generation in the venular wall. CEE-LD reverted the deleterious effects of ovariectomy. Although CEE-SD augmented eNOS phosphorylation in OVX, it was unable to increase NO levels, probably owing to its inability to reduce O Distinct effects by CEE-SD and CEE-LD parallel the differential modulation of Ang-II and estrogen receptors. Compared with Sham, CEE-LD increases Ang II receptor type 2, whereas CEE-SD modified ER expression in the venous bed. Interestingly, both CEE doses increased G protein-coupled estrogen receptor in OVX. Our data suggest that estrogen dose is an important factor for venous function. Although CEE-LD reversed deleterious effects of OVX, CEE-SD showed null effects despite its ability to increase eNOS activity.
绝经后女性的标准激素疗法[结合马雌激素（CEE）0.625毫克]与静脉血栓形成风险增加有关。含有较低CEE剂量（0.30毫克）的治疗方案已在临床上用于减少超生理剂量雌激素的副作用。在本研究中，我们确定了标准剂量（SD）和低剂量（LD）的CEE对去卵巢（OVX）自发性高血压大鼠（SHR）小静脉功能的影响。与假手术组（14.7±1.1毫米汞柱，P<0.05）相比，OVX组灌注肠系膜小静脉床中血管紧张素-II（Ang-II 10微摩尔）引起的收缩明显增加（21.5±1.3毫米汞柱）。CEE-SD对OVX组的Ang-II反应无影响，而CEE-LD使Ang-II收缩恢复到假手术组水平。L-NAME抑制内皮型一氧化氮合酶（eNOS）增加了假手术组和CEE-LD组的Ang-II收缩，对OVX SHR和CEE-SD组的小静脉无影响。在OVX组中，与小静脉壁中eNOS磷酸化减少和O生成增加相关的是NO生成减少。CEE-LD逆转了去卵巢的有害影响。虽然CEE-SD增加了OVX组中eNOS的磷酸化，但它无法增加NO水平，可能是由于其无法降低O。CEE-SD和CEE-LD的不同作用与Ang-II和雌激素受体的差异调节平行。与假手术组相比，CEE-LD增加了2型Ang II受体，而CEE-SD改变了静脉床中ER的表达。有趣的是，两种CEE剂量均增加了OVX组中G蛋白偶联雌激素受体。我们的数据表明，雌激素剂量是静脉功能的一个重要因素。虽然CEE-LD逆转了OVX的有害影响，但CEE-SD尽管能够增加eNOS活性，却显示出无效作用。
