Division of Biomedical Sciences, Federal University of Rio de, Janeiro, Rio de Janeiro, Brazil.
Departments of Anesthesiology.
J Cardiovasc Pharmacol. 2019 Nov;74(5):443-452. doi: 10.1097/FJC.0000000000000721.
This study was aimed to clarify differences in how specific agonists of the 3 estrogen receptors (ERs) influence diastolic function and the renin-angiotensin system (RAS) after ovariectomy (OVX) in 24 female spontaneously hypertensive rat (SHR) undergoing bilateral OVX at 12 weeks of age. Eight weeks after surgery, rats were randomized (n = 6/group) to receive equipotent, daily treatments of one of the ER agonists (ERα agonist, propyl pyrazole trisphenol 94 μg/kg; ERβ agonist, diarylpropionitrile 58 μg/kg; G-protein-coupled estrogen receptor [GPER] agonist, G1 100 μg/kg), or vehicle (peanut oil). After 4 weeks of treatment, left ventricular function/structure and systemic/intracardiac pressure measurements were obtained by echocardiography and a fluid-filled catheter attached to a pressure transducer, respectively. Selective ER agonist treatment with G1 or propyl pyrazole trisphenol led to improvements in diastolic function after estrogen loss when compared with vehicle-treated OVX rats. Although mean arterial blood pressure was not overtly different among groups, chronic G1, but not the other ER ligands, enhanced the in vitro vasorelaxant responsiveness to acetylcholine in aortic rings. These favorable effects of G1 were further linked to reductions in cardiac angiotensin-converting enzyme activity, AT1R protein expression, and Ang II immunoreactivity. Activation of ERβ had no effect on cardiac function and did not alter components of the canonical cardiac RAS in comparison with vehicle-treated OVX SHR. These data imply that of the 3 ERs, GPER has a unique role in preserving diastolic function and favorably modulating the cardiac RAS independent of arterial pressure. Specifically, if GPER is pharmacologically activated, it could provide a therapeutic opportunity to limit the development and/or progression of diastolic dysfunction in hypertensive women after estrogen loss.
本研究旨在阐明 3 种雌激素受体（ER）的特定激动剂在 12 周龄时双侧卵巢切除（OVX）后对舒张功能和肾素-血管紧张素系统（RAS）的影响有何不同。手术后 8 周，将 24 只雌性自发性高血压大鼠（SHR）随机分为 6 组（每组 6 只），分别接受等效力、每日一次的 ER 激动剂（ERα激动剂，丙基吡唑三苯 94μg/kg；ERβ激动剂，二芳基丙腈 58μg/kg；G 蛋白偶联雌激素受体 [GPER]激动剂，G1 100μg/kg）或载体（花生油）治疗。治疗 4 周后，通过超声心动图和与压力传感器相连的充满液体的导管分别获得左心室功能/结构和全身/心内压测量值。与载体处理的 OVX 大鼠相比，GPER 或丙基吡唑三苯激动剂治疗可改善雌激素丢失后的舒张功能。尽管各组之间的平均动脉血压没有明显差异，但慢性 G1，而不是其他 ER 配体，增强了主动脉环对乙酰胆碱的体外血管舒张反应性。G1 的这些有利作用进一步与心脏血管紧张素转换酶活性、AT1R 蛋白表达和 Ang II 免疫反应性降低相关。与载体处理的 OVX SHR 相比，ERβ 的激活对心脏功能没有影响，也没有改变经典心脏 RAS 的成分。这些数据表明，在 3 种 ER 中，GPER 在维持舒张功能和有利调节心脏 RAS 方面具有独特的作用，而与动脉压无关。具体而言，如果 GPER 被药理学激活，它可能为限制雌激素丢失后高血压女性舒张功能障碍的发展和/或进展提供治疗机会。
