Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Brazil.
Departamento de Farmacologia, Universidade Estácio de Sá, Rio de Janeiro, Brazil.
J Gerontol A Biol Sci Med Sci. 2018 Aug 10;73(9):1158-1166. doi: 10.1093/gerona/gly068.
Pulmonary hypertension (PH) is a disease of women (female-to-male ratio 4:1), and is associated with cardiac and skeletal muscle dysfunction. Herein, the activation of a new estrogen receptor (GPER) by the agonist G1 was evaluated in oophorectomized rats with monocrotaline (MCT)-induced PH. Depletion of estrogen was induced by bilateral oophorectomy (OVX) in Wistar rats. Experimental groups included SHAM or OVX rats that received a single intraperitoneal injection of MCT (60 mg/kg) for PH induction. Animals received s.c. injection of either vehicle or G1, a GPER agonist, (400 µg/kg/day) for 14 days after the onset of disease. Rats with PH exhibited exercise intolerance and cardiopulmonary alterations, including reduced pulmonary artery flow, biventricular remodeling, and left ventricular systolic and diastolic dysfunction. The magnitude of these PH-induced changes was significantly greater in OVX versus SHAM rats. G1 treatment reversed both cardiac and skeletal muscle functional aberrations caused by PH in OVX rats. G1 reversed PH-related cardiopulmonary dysfunction and exercise intolerance in female rats, a finding that may have important implications for the ongoing clinical evaluation of new drugs for the treatment of the disease in females after the loss of endogenous estrogens.
肺动脉高压（PH）是一种女性疾病（男女比例为 4:1），与心脏和骨骼肌功能障碍有关。在此，通过激动剂 G1 激活一种新的雌激素受体（GPER）在 MCT 诱导的 PH 去卵巢大鼠中进行了评估。Wistar 大鼠通过双侧卵巢切除术（OVX）诱导雌激素耗竭。实验组包括 SHAM 或 OVX 大鼠，它们接受单次腹腔注射 MCT（60mg/kg）以诱导 PH。动物在疾病发作后接受皮下注射载体或 GPER 激动剂 G1（400μg/kg/天）14 天。PH 大鼠表现出运动不耐受和心肺改变，包括肺动脉流量减少、双心室重构以及左心室收缩和舒张功能障碍。与 SHAM 大鼠相比，OVX 大鼠的这些 PH 诱导变化幅度更大。G1 治疗逆转了 OVX 大鼠 PH 引起的心脏和骨骼肌功能异常。G1 逆转了 PH 相关的心肺功能障碍和雌性大鼠的运动不耐受，这一发现可能对正在进行的临床评估在失去内源性雌激素后女性疾病治疗的新药具有重要意义。
