β3 Receptor Signaling in Pregnant Human Myometrium Suggests a Role for β3 Agonists as Tocolytics.
β3 Receptor Signaling in Pregnant Human Myometrium Suggests a Role for β3 Agonists as Tocolytics.
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DOI：
10.3390/biom13061005
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发表时间：
2023-06-17
期刊：
影响因子：
5.5
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中科院分区：
文献类型：
--
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早产临产导致早产是婴儿发病和死亡的首要原因。目前，一旦分娩开始，没有什么方法能可靠地阻止它。已知β2肾上腺素能受体激动剂可松弛气道平滑肌且对治疗哮喘有效，这导致人们认为β2拟似剂可通过松弛子宫平滑肌来预防早产。β2受体激活环磷腺苷酸（cAMP）依赖性蛋白激酶无法提供有意义的宫缩抑制作用。利托君和特布他林等β2激动剂未能预防早产，这表明子宫平滑肌的调节与气道不同。其他平滑肌静止介导分子，如一氧化氮，以环鸟苷酸 - 蛋白激酶G依赖性方式松弛血管平滑肌；然而，一氧化氮激活蛋白激酶G无法解释子宫肌层对一氧化氮的松弛反应。此外，一氧化氮介导的松弛在早产临产中减弱，因此，由于这个原因以及母体血压下降，一氧化氮不能用作宫缩抑制剂。据称人子宫肌层的β3肾上腺素能受体介导的松弛是环磷腺苷酸依赖性蛋白激酶依赖性的。鉴于β2激动剂作为宫缩抑制剂的失败，这在科学上是不合理的，并表明β3肾上腺素能受体（β3AR）在子宫肌层中具有非经典的信号传导作用。在组织浴中向怀孕人子宫肌条添加β3激动剂米拉贝隆可松弛催产素诱导的收缩。米拉贝隆刺激子宫肌层微血管内皮细胞产生一氧化氮，并且添加内皮型一氧化氮合酶阻断剂Nω - 硝基 - L - 精氨酸可部分阻断体外子宫组织的松弛。近期数据表明，内皮细胞和平滑肌细胞都对β3刺激有反应，并通过不同的信号通路促进松弛。将已批准的药物如米拉贝隆（Mybetriq™）在人子宫肌层中进行重新利用作为子宫宫缩抑制剂，可以推进早产的预防。
Preterm labor leading to preterm birth is the leading cause of infant morbidity and mortality. At the present time, nothing can reliably halt labor once it begins. The knowledge that agonists of the β2 adrenergic receptor relax airway smooth muscle and are effective in the treatment of asthma led to the notion that β2 mimetics would prevent preterm birth by relaxing uterine smooth muscle. The activation of cAMP-dependent protein kinase by β2 receptors is unable to provide meaningful tocolysis. The failure of β2 agonists such as ritodrine and terbutaline to prevent preterm birth suggests that the regulation of uterine smooth muscle is disparate from that of airway. Other smooth muscle quiescent-mediating molecules, such as nitric oxide, relax vascular smooth muscle in a cGMP-protein kinase G-dependent manner; however, nitric oxide activation of protein kinase G fails to explain the relaxation of the myometrium to nitric oxide. Moreover, nitric oxide-mediated relaxation is blunted in preterm labor, and thus, for this reason and because of the fall in maternal blood pressure, nitric oxide cannot be employed as a tocolytic. The β3 adrenergic receptor-mediated relaxation of the human myometrium is claimed to be cAMP-dependent protein kinase-dependent. This is scientifically displeasing given the failure of β2 agonists as tocolytics and suggests a non-canonical signaling role for β3AR in myometrium. The addition of the β3 agonist mirabegron to pregnant human myometrial strips in the tissue bath relaxes oxytocin-induced contractions. Mirabegron stimulates nitric oxide production in myometrial microvascular endothelial cells, and the relaxation of uterine tissue in vitro is partially blocked by the addition of the endothelial nitric oxide synthase blocker Nω-Nitro-L-arginine. Recent data suggest that both endothelial and smooth muscle cells respond to β3 stimulation and contribute to relaxation through disparate signaling pathways. The repurposing of approved medications such as mirabegron (Mybetriq™) tested in human myometrium as uterine tocolytics can advance the prevention of preterm birth.
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DOI：
10.1111/micc.12046
发表时间：
2013-05
期刊：
Microcirculation (New York, N.Y. : 1994)
影响因子：
--
作者：
Amberg GC;Navedo MF
通讯作者：
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DOI：
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发表时间：
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DOI：
10.1124/jpet.110.171934
发表时间：
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影响因子：
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影响因子：
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作者：
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DOI：
10.1016/j.bbamcr.2016.10.022
发表时间：
2017-06-01
影响因子：
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作者：
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