ION CHANNELS OF UTERINE MUSCLE DURING PREGNANCY

怀孕期间子宫肌肉的离子通道

• 批准号: 3327548
• 负责人: NICHOLAS SPERELAKIS
• 金额: $ 3.97万
• 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/3327548
• 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; 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 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 (e.g.,电压依赖性Ca 2+通道，各种K+通道，拉伸- 激活的通道和C1-通道）在子宫肌层细胞膜上发挥作用， 在兴奋-收缩偶联中起重要作用。 的离子通道 控制胞质Ca 2+水平，从而控制细胞的收缩状态。 子宫肌层细胞 在怀孕期间，这些离子通道被修改， 长期暴露于各种激素，如雌激素、孕酮或 hCG。 静息膜电位与子宫肌层峰电位的形成 怀孕期间的变化。 我们将首先调查 大鼠子宫平滑肌细胞离子通道特性 妊娠和长期雌激素治疗期间和/或 孕酮 然后我们将研究各种物质的影响 和条件，这被认为是有关的病因， 早产（例如，白三烯，血小板活化因子，局部缺血， 机械拉伸）。 这些研究将有助于 我们对早产的预防和治疗的认识。 此外，他们可能会提供一个线索，特发性早产的原因， 劳动 我们还将研究宫缩抑制剂对 子宫肌层离子通道的活性。 早产儿的管理 分娩时，β-肾上腺素能激动剂（如利托君和特布他林） 广泛用于子宫保胎治疗。 随而增加 子宫肌层细胞内的cAMP被认为介导了抑制 子宫收缩，通过减少游离Ca 2+的可用性。 然而，β-激动剂的保胎作用的机制仍然是未知的。 在亚细胞和膜水平上未知。 有人建议 cAMP;（a）激活Ca 2+泵，（B）抑制肌球蛋白光 （c）抑制Ca 2+通道，和/或（d） 增强K+通道活性。 保胎剂Mg 2+被认为 作用于Ca 2+通道，阻止Ca 2+进入细胞。 一些 这些提出的机制将在我们的电生理学中阐明。 在分离的单个子宫肌层细胞上进行的实验。 虽然beta- 肾上腺素能宫缩抑制剂是针对β 2特异性选择的，它们确实 具有一定的β 1活性，这会引起心血管方面 方面的影响. 因此，我们也将测试beta的效果， 肾上腺素能宫缩抑制剂对心肌的作用，提供全面的 心血管副作用的信息。 最后，研究 也将在离体人子宫肌层组织上进行，以与 动物组织上的结果，以便为 更好地管理人类早产。