Brosnihan K Bridget, Li Ping, Figueroa Jorge P, Ganten Detlev, Ferrario Carlos M
Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-0132, USA.
Am J Physiol Heart Circ Physiol. 2008 May;294(5):H1995-2001. doi: 10.1152/ajpheart.01193.2007. Epub 2008 Mar 14.
Clinical trials revealed that estrogen may result in cardiovascular risk in patients with coronary heart disease, despite earlier studies demonstrating that estrogen provided cardiovascular protection. It is possible that the preexisting condition of hypertension and the ability of estrogen to activate the renin-angiotensin system could confound its beneficial effects. Our hypothesis is that the attenuation of estrogen to agonist-induced vasoconstrictor responses through the activation of nitric oxide (NO) synthase (NOS) is impaired by hypertension. We investigated the effects of 17beta-estradiol (E(2)) replacement in normotensive Sprague-Dawley (SD) and (mRen2)27 hypertensive transgenic (TG) rats on contractile responses to three vasoconstrictors, angiotensin II (ANG II), serotonin (5-HT), and phenylephrine (PE), and on the modulatory role of vascular NO to these responses. The aorta was isolated from ovariectomized SD and TG rats treated chronically with 5 mg E(2) or placebo (P). The isometric tension of the aortic rings was measured in organ chambers, and endothelial NOS (eNOS) in the rat aorta was detected using Western blot analysis. E(2) treatment increased eNOS expression in the SD and TG aorta and reduced ANG II- and 5-HT- but not PE-induced contractions in SD and TG rats. The inhibition of NOS with N(omega)-nitro-L-arginine methyl ester enhanced ANG II-, 5-HT-, and PE-induced contractions in P-treated and ANG II and PE responses in E(2)-treated SD and TG rats. Only the responses to 5-HT were augmented in hypertensive rats. In conclusion, this study shows that the preexisting condition of hypertension augmented the vascular responsiveness of 5-HT, whereas the attenuation of estrogen by ANG II and 5-HT vascular responses was not impaired by hypertension. The adrenergic agonist was unresponsive to estrogen treatment. The contribution of NO as a factor contributing to the relative refractoriness of the vascular responses is dependent on the nature of the vasoconstrictor and/or the presence of estrogen.
临床试验表明，尽管早期研究显示雌激素具有心血管保护作用，但它可能会给冠心病患者带来心血管风险。高血压的预先存在状态以及雌激素激活肾素 - 血管紧张素系统的能力可能会混淆其有益效果。我们的假设是，高血压会损害雌激素通过激活一氧化氮（NO）合酶（NOS）来减弱激动剂诱导的血管收缩反应的能力。我们研究了在正常血压的斯普拉格 - 道利（SD）大鼠和（mRen2）27高血压转基因（TG）大鼠中，17β - 雌二醇（E₂）替代对三种血管收缩剂（血管紧张素II（ANG II）、5 - 羟色胺（5 - HT）和去氧肾上腺素（PE））收缩反应的影响，以及血管NO对这些反应的调节作用。从长期接受5mg E₂或安慰剂（P）治疗的去卵巢SD和TG大鼠中分离出主动脉。在器官浴槽中测量主动脉环的等长张力，并使用蛋白质免疫印迹分析检测大鼠主动脉中的内皮型NOS（eNOS）。E₂治疗增加了SD和TG大鼠主动脉中eNOS的表达，并减少了SD和TG大鼠中ANG II和5 - HT诱导的收缩，但对PE诱导的收缩无影响。用N（ω） - 硝基 - L - 精氨酸甲酯抑制NOS会增强P处理组中ANG II、5 - HT和PE诱导的收缩，以及E₂处理的SD和TG大鼠中ANG II和PE的反应。只有高血压大鼠对5 - HT的反应增强。总之，本研究表明，预先存在的高血压状态增强了血管对5 - HT的反应性，而高血压并未损害雌激素对ANG II和5 - HT血管反应的减弱作用。肾上腺素能激动剂对雌激素治疗无反应。NO作为导致血管反应相对不应性因素的作用取决于血管收缩剂的性质和/或雌激素的存在。
