ION CHANNELS OF UTERINE MUSCLE DURING PREGNANCY

怀孕期间子宫肌肉的离子通道

• 批准号: 3327549
• 负责人: NICHOLAS SPERELAKIS
• 金额: $ 17.01万
• 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/3327549
• 关键词: beta adrenergic agent; electrophysiology; estrogens; female; hormones; human pregnant subject; human tissue; ischemia; leukotrienes; magnesium; membrane channels; membrane potentials; muscle contraction; muscle relaxants; myometrium; myosin light chain kinase; platelet activating factor; premature labor; progesterone; reproductive system pharmacology; single cell analysis; smooth muscle; stretch receptors; tocolytic agents

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 Cl-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.

早产的发生是由于各种原因，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 抑制子宫平滑肌收缩。 离子通道（例如， 电压依赖性Ca 2+通道，各种K+通道，牵张激活 通道和Cl-通道）在子宫肌层细胞膜上起着重要的作用。 在兴奋-收缩偶联中的作用。 离子通道控制着 胞浆Ca 2+水平，因此子宫肌层的收缩状态 细胞 在怀孕期间，这些离子通道被慢性炎症改变。 暴露于各种激素，如雌激素、孕酮或hCG。 子宫肌层静息膜电位和峰电位的变化 怀孕 我们将首先研究离子性质的变化， 大鼠子宫平滑肌细胞在怀孕期间和 用雌激素和/或孕酮长期治疗。 然后我们将检查 各种物质和条件的影响，被认为是 与早产的病因有关（例如，血小板白细胞三烯 激活因子、局部缺血、机械拉伸）对离子通道的影响。 这些研究将有助于我们了解预防和 早产的治疗 此外，它们还可能提供一条线索， 特发性早产的原因 我们还将研究 宫缩抑制剂对子宫肌层离子通道活性的影响。 在 早产的管理，β-肾上腺素能激动剂（如利托君 和特布他林）已广泛用于子宫保胎治疗。 的 子宫肌层细胞内cAMP的增加被认为 通过减少子宫收缩， 游离Ca 2+的有效性。 然而，宫缩抑制作用的机制 β-受体激动剂在亚细胞和膜水平上的作用仍是未知的。 已经表明cAMP;（a）激活Ca 2+泵，（B）抑制 磷酸化肌球蛋白轻链激酶，（c）抑制Ca 2 + 通道，和/或（d）增强K+通道活性。 宫缩抑制剂， Mg 2+被认为作用于Ca 2+通道以阻止Ca 2+进入细胞内。 cell. 其中一些建议的机制将在我们的 电生理实验分离的单个子宫肌细胞。 虽然β-肾上腺素能宫缩抑制剂被选择用于β 2 特异性，它们确实具有一定的β 1活性，这会引起 心血管副作用 因此，我们还将测试 β-肾上腺素能宫缩抑制剂， 全面了解其心血管副作用。 最后，还将对分离的人类子宫肌层组织进行研究， 与动物组织的结果进行比较，以提供新的 更好地管理人类早产的信息。