ION CHANNELS OF UTERINE MUSCLE DURING PREGNANCY

怀孕期间子宫肌肉的离子通道

基本信息

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
项目类别：
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

项目摘要

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”）。早产的管理取决于抑制子宫平滑肌的收缩。离子通道（例如，电压依赖性 Ca2+ 通道、各种 K+ 通道、拉伸激活子宫肌细胞膜的通道和 Cl 通道）发挥着重要作用兴奋-收缩耦合中的作用。离子通道控制细胞质 Ca2+ 水平，从而影响子宫肌层的收缩状态细胞。在怀孕期间，这些离子通道会被慢性改变接触各种激素，例如雌激素、黄体酮或 hCG。静息膜电位和子宫肌层尖峰形成过程中的变化怀孕。我们首先研究离子性质的变化妊娠期间和妊娠期间大鼠子宫平滑肌细胞的通道用雌激素和/或黄体酮进行长期治疗。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（例如白三烯、血小板激活因子、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，他们还可以提供有关特发性早产的原因。我们还将研究以下影响宫缩抑制剂对子宫肌层离子通道活性的影响。在早产管理，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。这据信，由此导致的子宫肌细胞内 cAMP 增加介导抑制子宫收缩，通过减少游离 Ca2+ 的可用性。然而，保胎作用的机制 β-激动剂在亚细胞和膜水平上的作用仍然未知。有人建议cAMP； (a) 激活 Ca2+ 泵，(b) 抑制通过磷酸化肌球蛋白轻链激酶，(c) 抑制 Ca2+ 通道，和/或(d)增强K+通道活性。保胎剂， Mg2+,, 被认为作用于 Ca2+ 通道，阻止 Ca2+ 进入细胞。其中一些拟议机制将在我们的报告中得到澄清对分离的单个子宫肌细胞进行电生理实验。虽然β-肾上腺素能宫缩剂被选择为β2 特异性，它们确实具有一些 beta 1 活性，从而产生心血管副作用。因此，我们还将测试以下效果 β-肾上腺素能宫缩剂作用于心肌，以提供有关其心血管副作用的全面信息。最后，还将对分离的人类子宫肌组织进行研究，以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。