SEX HORMONES, ION CHANNELS, & CORONARY ARTERY REACTIVITY

女性冠心病（CHD）发病率在2000年急剧上升， 更年期，因为雌激素水平下降。 部分有益效果 雌激素对冠心病的作用可能是通过影响冠状动脉， 保护心脏免受缺血性损伤 冠状动脉张力和 反应性由电压依赖性Ca通道调节， Ca2+进入去极化，和K+通道，当激活时， 超极化 我们提供了第一次直接测量， 两种类型的K+通道的平滑肌可能发挥作用， 在冠状动脉对雌激素的反应中的重要作用， 缺血：1）ATP敏感性K+（Katp）通道和2）内向 整流器K=（K）通道。 缺氧、腺苷和合成试剂（例如 lemakalim）激活K通道，并通过血管舒张，可能是 参与增加冠状动脉血流量，以抵消 心肌缺血 细胞外K+的小幅增加， 在缺血期间，可能激活K通道，这也可能导致 有益地增加冠状动脉血流量。 我们的初步结果 这表明了一种令人兴奋的可能性，雌激素通过改变 冠状动脉离子通道的活性增加动脉直径， 对血管舒张信号的反应。 因此，我们建议测试 假设性别和性类固醇，特别是雌激素， 冠状动脉通过调节K+和 钙通道。 我们初步的证据来支持这一假设的形式 我们的4个具体目标的基础：1）我们发现女性冠状动脉 动脉收缩血管内压力比男性或 切除卵巢的雌性大鼠冠状动脉。 在具体目标1中， 将研究膜电位（K+通道）、Ca 通道，和细胞内游离Ca2+在这个响应。2)我们发现 雌激素而不是孕激素扩张冠状动脉并抑制 钙通道 在具体目标2中，我们将探讨 急性雌激素和其他性类固醇对动脉张力，膜 电位，离子通道。3)我们发现外部的小隆起 K+扩张女性冠状动脉，但不扩张男性冠状动脉，表明性别和 性类固醇对：甜菜碱和对外部K+的超极化，腺苷 K+通道在女性中的作用更大。 具体目标 3，我们将描述性别和性类固醇对以下方面的影响： 对外部K+、腺苷和K+通道的扩张和超极化 开放器和K和K通道。4)在具体目标4中，我们将探讨 内皮细胞在所有这些反应中的作用。 我们将使用一个 获得冠状动脉综合图像的技术组合 动脉功能：在不同时间测量冠状动脉直径 水平的跨壁压，膜电位记录从平滑 完整动脉中的肌细胞、全细胞和单离子通道 在来自冠状动脉的新鲜分离的平滑肌细胞中的测量 动脉和细胞内Ca2+测量。 拟议的研究应 为冠状动脉反应性的控制提供了重要的见解 由雌激素，其他性类固醇和性别决定 这项研究还应 加深我们对离子调节冠状动脉张力的理解 渠道，推进我们对可能的反应机制的理解， 女性冠状动脉血管缺血。 最后，建议 该项目应提出治疗冠心病的新策略 女性的疾病。

Coronary heart disease (CHD) in women increases dramatically at menopause, as estrogen levels drop. Part of the beneficial effect of estrogen on CHD may be through effects on the coronary arteries in ways that protect the heart from ischemic injury. Coronary artery tone and reactivity are regulated by voltage-dependent Ca channels, which allow Ca2+ entry on depolarization, and K+ channels, which when activated cause hyperpolarization. We have provided the first direct measurements in smooth muscle of two types of K+ channels that are likely to play important roles in the response of coronary arteries to estrogen and ischemia: 1) The ATP-sensititive K+ (Katp) channel and 2) The inward rectifier K= (K) channel. Hypoxia, adenosine, and synthetic agents (e.g. lemakalim) activated K channels, and through vasodilation, may be involved in the increase in coronary blood flow to counteract periods of cardiac ischemia. Small increases in extracellular K+, which can occur during ischemia, may activate K channels which may also lead to a beneficial increase in coronary blood flow. Our preliminary results suggest the exciting possibility that estrogen, through alteration in the activity of coronary artery ion channels increases arterial diameter and response to vasodilating signals. We, therefore propose to test the hypothesis that gender and sex steroids, particularly estrogen, affect the reactivity of coronary arteries through their regulation of K+ and Ca channels. Our preliminary evidence to support this hypothesis forms the basis of our 4 Specific Aims: 1) We found that female coronary arteries constrict less to intravascular pressure than male or ovariectomized female coronary arteries from rat. In Specific Aim 1, we will investigate the role of membrane potential (K+ channels), Ca channels, and intracellular free Ca2+ in this response. 2) We found that estrogen but not progesterone dilates coronary arteries and inhibits calcium channels. In specific Aim 2, we shall explore the effects of acute estrogen and other sex steroids on arterial tone, membrane potential, an ion channels. 3) We found that small elevations in external K+ dilate female but not male coronary arteries, suggesting gender and sex steroids on: dilatins and hyperolarizations to external K+, adenosine and K+ channels play a more important role in females. In Specific Aim 3, we shall characterize the effects of gender and sex steroids on: dilations and hyperpolarization to external K+, adenosine and K+ channel openers, and K and K channels. 4) In Specific Aim 4, we will explore the role of the endothelium in all of these responses. We will use a combination of techniques to obtain an integrated picture of coronary artery function: diameter measurements of coronary arteries at different levels of transmural pressure, membrane potential recordings from smooth muscle cells in intact arteries, whole cell and single ion channel measurements in freshly dissociated smooth muscle cells from coronary arteries, and intracellular Ca2+ measurements. The proposed study should provide important insights into the control of coronary artery reactivity by estrogen, other sex steroids and gender. This study should also deepen our understanding of the regulation of coronary artery tone by ion channels, advancing our understanding of possible response mechanism of the female coronary vasculature to ischemia. Finally, the proposed project should suggest new strategies for treatment of coronary heart diseases in women.