SEX HORMONES, ION CHANNELS, & CORONARY ARTERY REACTIVITY

女性的冠心病(CHD)发病率在 更年期，随着雌激素水平的下降。的部分有益效果 雌激素对冠心病的作用可能是通过以下途径影响冠状动脉的 保护心脏免受缺血损伤。冠状动脉紧张度和 反应性由电压依赖的钙通道调节，这允许 钙离子进入去极化，以及K+通道，当激活时引起 超极化。我们在#年提供了第一批直接测量数据 可能发挥作用的两种K+通道的平滑肌 在冠状动脉对雌激素和雌激素反应中的重要作用 缺血：1)ATP敏感性K+(KATP)通道；2)内向 整流器K=(K)通道。低氧、腺苷和合成剂(例如 Lemakalim)激活的K通道，并通过血管扩张，可以 参与冠状动脉血流量的增加，以抵消 心脏缺血。细胞外K+的小幅增加，这可能发生 在缺血期间，可能激活K通道，这也可能导致 有益增加冠脉血流量。我们的初步结果 暗示了一种令人兴奋的可能性，即雌激素通过改变 冠状动脉离子通道的活动增加了动脉内径和 对血管扩张信号的反应。因此，我们建议测试 假设性别和性激素，特别是雌激素，会影响 冠状动脉对钾离子和钙离子的调节与反应性 CA频道。我们支持这一假设的初步证据形成 我们4个具体目标的基础：1)我们发现女性冠状动脉 动脉对血管内压的收缩程度比男性或 摘除大鼠卵巢的雌性冠状动脉。在具体目标1中，我们 将研究膜电位(K+通道)的作用， 通道，以及细胞内游离钙离子在此反应中的作用。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激素对动脉张力、膜的影响 电势，一个离子通道。3)我们发现外部的小海拔 K+扩张女性冠状动脉，但不扩张男性冠状动脉，提示性别和 性激素：扩张素和外源性K+、腺苷的超极化 K+通道在女性中起着更重要的作用。以特定的目标 3，我们将描述性别和性类固醇对以下方面的影响： 外源性K+、腺苷和K+通道的扩张和超极化 开场白，以及K频道和K频道。4)在具体目标4中，我们将探索 内皮细胞在所有这些反应中的作用。我们将使用 多种技术相结合获得完整的冠状动脉图像 冠状动脉功能：不同时间段冠状动脉内径测量 跨壁压力水平，膜电位记录从平滑 完整动脉、全细胞和单离子通道中的肌细胞 新鲜分离的冠脉平滑肌细胞的测量 动脉和细胞内钙离子的测量。拟议的研究应 为控制冠状动脉反应性提供重要见解 由雌激素、其他性激素和性别决定。这项研究也应该 加深对离子调节冠状动脉张力的认识 渠道，促进我们对可能的反应机制的理解 女性冠状动脉血管对缺血的保护作用。最后，提出了 该项目应为冠心病的治疗提出新的策略 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.