CIRCUMVENTRICULAR ORGANS: GENDER AND HYPERTENSION

有人提出，雌激素延迟和/或预防高血压的发作，并可能起到使女性比同龄男性“心血管年轻”的作用。在实验性高血压动物中也有类似的观察结果，然而，雌激素保护作用的潜在机制还不完全清楚。鉴于雌激素替代疗法在女性健康中的重要性，很明显，了解雌激素心血管保护作用的细胞机制对于继续开发治疗女性高血压的临床疗法至关重要。血管紧张素II（AngII）是临床和实验性高血压的重要因子。在实验动物中长期静脉输注低水平的血管紧张素II导致血压升高，这涉及神经源性对维持血压的贡献增加，而这可以通过预先损伤最后区来预防（3，6，33，57，95）。 认为循环中血管紧张素Ⅱ作用于最后区神经元以维持高血压。拟开展的研究将检验雌激素通过抑制Ang II对最后区神经元的作用而保护免受Ang II诱导的高血压的一般假设。为了验证这一假设，并表征雌激素（17 β-雌二醇）对最后区神经元的作用，Ang II诱导的血压升高和压力反射调制，本提案将利用来自分离的最后区神经元的全细胞膜片钳记录，在清醒动物中的最后区神经元的体内单单位记录和血流动力学测量来解决以下4个主要和不同的目标。1)评价暴露于17 β-雌二醇后最后区膜的性质。2)确定急性和慢性17 β-雌二醇对最后区钙处理的影响。3)确定17 β-雌二醇对最后区神经元激活的影响。4)评价急性和慢性17 β-雌二醇对血管紧张素II型高血压的影响。确定雌激素对血管紧张素II依赖性高血压的中枢神经系统机制的影响，将对我们理解雌激素替代治疗的心血管益处产生重大影响。

It has been proposed that estrogen delays and or prevents the onset of hypertension and may function to keep women "cardiovascularly younger" than men of the same age. Similar observations have been made in experimental hypertensive animals, however, the underlying mechanisms of estrogen's protective effects are incompletely understood. Given the importance of estrogen replacement therapy in women's health, it is clear that an understanding of the cellular mechanisms underlying estrogen's cardiovascular protective effects is critical for continuing development of clinical therapies for the treatment of hypertension in women. Angiotensin II (Ang II) is an important factor in some forms of both clinical and experimental hypertension. Chronic intravenous infusions of low levels of Ang II in experimental animals result in an increase in blood pressure that involves an increased neurogenic contribution to the maintenance of blood pressure which is prevented by prior lesioning of the area postrema (3,6,33,57,95). It is thought that circulating Ang II acts on area postrema neurons to maintain the hypertension. The proposed studies will test the general hypothesis that estrogen protects against the Ang II induced hypertension by inhibiting the actions of Ang II on area postrema neurons. To test this hypothesis and to characterize the effects of estrogen (17beta-estradiol) on area postrema neurons, Ang II induced increases in blood pressure and baroreflex modulation, this proposal will utilize whole-cell patch clamp recordings from isolated area postrema neurons, in vivo single unit recordings of area postrema neurons and hemodynamic measurements in conscious animals to address the following 4 major and distinct aims. 1) To evaluate area postrema membrane properties following exposure to 17beta-estradiol. 2) To determine the effects of acute and chronic 17beta-estradiol on area postrema calcium handling. 3) To determine the effect of 17beta-estradiol on activation of area postrema neurons. 4) To evaluate the effects of acute and chronic 17beta-estradiol on Ang II hypertension. Determination of the effects of estrogen on CNS mechanisms underlying Ang II dependent hypertension will have a significant impact on our understanding of the cardiovascular benefits of estrogen replacement therapy.