ION CHANNELS OF UTERINE MUSCLE DURING PREGNANCY

怀孕期间子宫肌肉的离子通道

• 批准号: 3327544
• 负责人: NICHOLAS SPERELAKIS
• 金额: $ 17.41万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-01 至 1992-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3327544
• 关键词: beta adrenergic agent; electrophysiology; estrogens; hormones; human pregnant subject; human tissue; ischemia; leukotrienes; magnesium; membrane channels; membrane potentials; muscle contraction; muscle relaxants; myometrium; platelet activating factor; pregnancy disorder; progesterone; reproductive system pharmacology; single cell analysis; smooth muscle; stretch receptors

Preterm labor occurs due to various causes, such as multiple gestation, infection, polyhydramnios, and uterine anomalies. However, often its etiology is unknown ("idiopathic"). Management of preterm labor depends on inhibition of contraction of uterine smooth muscle. The ion channel (e.g., voltage-dependent Ca2+ channels, various K+ channels, stretch- activated channels, and C1-channels) of myometrial cell membrane play an important role in excitation-contraction coupling. The ion channels control the cytosolic Ca2+ level, and hence the contractile sate of the myometrial cells. During pregnancy, these ion channels are modified by chronic exposure to various hormones, such as estrogen, progesterone or hCG. Resting membrane potential and spike formation of myometrium change during pregnancy. We will first investigate the change in the properties of ion channels of rat uterine smooth muscle cells during pregnancy and during chronic treatment with estrogen and/or progesterone. Then we will examine the effects of various substances and conditions, which are considered to be related to the etiology of preterm labor (e.g., leukotrienes, platelet activating factor, ischemia, mechanical stretch), on the ion channels. These studies will facilitate our understanding of the prevention and treatment of preterm labor. Further, they may provide a clue as to the cause of idiopathic preterm labor. We will also examine the effects of tocolytic agents on the activity of the myometrial ion channels. In management of preterm labor, beta-adrenergic agonists (such as ritodrine and terbutaline) have been widely used for uterine tocolytic therapy. The resulting increase in cAMP within the myometrial cell is believed to mediate the inhibition of uterine contraction, by decreasing the availability of free Ca2+. However, the mechanism of the tocolytic action of beta-agonists is still unknown at the subcellular and membrane level. It has been suggested that cAMP; (a) activates the Ca2+ pump, (b) inhibits the myosin-light chain kinase by phosphorylation, (c) inhibit Ca2+ channels, and/or (d) enhances K+ channel activity. The tocolytic agent, Mg2+,, is thought to act on the Ca2+ channel to prevent Ca2+ entry into the cell. Some of these proposed mechanisms will be clarified in our electrophysiological experiments on isolated single myometrial cells. Although the beta- adrenergic tocolytic agents are selected for beta 2 specificity, they do possess some beta 1 activity, which give rise to cardiovascular side effects. therefore, we will also test the effects of the beta- adrenergic tocolytic agents on cardiac muscle, to provide comprehensive information about their cardiovascular side effects. Finally, studies will also be done on isolated human myometrial tissue, to compare with the results on animal tissue, in order to provide new information for better management of preterm labor in humans.

早产的发生有多种原因，例如多胎妊娠、 感染、羊水过多和子宫异常。 然而，往往其 病因不明（“特发性”）。 早产的管理取决于 对子宫平滑肌收缩有抑制作用。 离子通道 （例如，电压依赖性 Ca2+ 通道、各种 K+ 通道、拉伸通道 子宫肌细胞膜的激活通道和 C1 通道）发挥着 在兴奋-收缩耦合中发挥重要作用。 离子通道 控制细胞质 Ca2+ 水平，从而控制细胞的收缩状态 子宫肌细胞。 在怀孕期间，这些离子通道被修改 长期接触各种激素，如雌激素、黄体酮或 人绒毛膜促性腺激素。 静息膜电位和子宫肌层尖峰形成 怀孕期间的变化。 我们首先要调查一下变化 大鼠子宫平滑肌细胞离子通道特性的研究 怀孕期间和长期接受雌激素治疗期间和/或 黄体酮。 然后我们将检查各种物质的影响 和条件，被认为与病因有关 早产（例如白三烯、血小板激活因子、缺血、 机械拉伸），在离子通道上。 这些研究将有助于 我们对早产的预防和治疗的理解。 此外，它们可能提供有关特发性早产原因的线索 劳动。 我们还将检查宫缩抑制剂对胎儿的影响 子宫肌层离子通道的活性。 在早产管理中 分娩时，β-肾上腺素能激动剂（如利托君和特布他林）有 广泛用于子宫保胎治疗。 由此产生的增加 子宫肌细胞内的 cAMP 被认为介导了抑制作用 通过减少游离 Ca2+ 的可用性来抑制子宫收缩。 然而，β-受体激动剂的宫缩作用机制仍不清楚。 在亚细胞和膜水平上未知。 已建议 环磷酸腺苷； (a) 激活 Ca2+ 泵，(b) 抑制肌球蛋白光 通过磷酸化链激酶，(c)抑制Ca2+通道，和/或(d) 增强K+通道活性。 宫缩剂 Mg2+ 被认为 作用于Ca2+通道，阻止Ca2+进入细胞。 一些 这些提出的机制将在我们的电生理学中得到澄清 对分离的单个子宫肌细胞进行的实验。 虽然测试版- 肾上腺素能宫缩药物是针对 β2 特异性而选择的，它们确实 具有一定的 β1 活性，可引起心血管副作用 影响。 因此，我们还将测试 beta 的效果- 肾上腺素能宫缩剂对心肌，提供全面的 有关其心血管副作用的信息。 最后，学习 还将在分离的人类子宫肌组织上进行，以与 动物组织的结果，以便提供新的信息 更好地管理人类早产。