Myometrial Function Group, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA.
Biomolecules. 2023 Jun 17;13(6):1005. doi: 10.3390/biom13061005.
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.
早产导致的早产是婴儿发病率和死亡率的主要原因。目前，一旦分娩开始，没有任何方法可以可靠地阻止分娩。β2 肾上腺素能受体激动剂可松弛气道平滑肌，并可有效治疗哮喘，这一知识促使人们认为β2 拟交感神经药可通过松弛子宫平滑肌来预防早产。β2 受体激活 cAMP 依赖性蛋白激酶无法提供有意义的保胎作用。利托君和特布他林等β2 激动剂未能预防早产表明，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 cGMP-蛋白激酶 G 依赖的方式松弛血管平滑肌；然而，一氧化氮激活蛋白激酶 G 并不能解释子宫平滑肌对一氧化氮的松弛作用。此外，早产时一氧化氮介导的松弛作用减弱，因此，由于这个原因和由于母体血压下降，一氧化氮不能用作保胎药。据称，β3 肾上腺素能受体介导的人子宫平滑肌松弛是 cAMP 依赖性蛋白激酶依赖性的。鉴于β2 激动剂作为保胎药的失败，这在科学上令人不快，并表明β3AR 在子宫平滑肌中具有非典型信号作用。在组织浴中向妊娠人子宫带中添加β3 激动剂米拉贝隆可松弛催产素诱导的收缩。米拉贝隆刺激子宫微血管内皮细胞中一氧化氮的产生，并且在体外添加内皮型一氧化氮合酶抑制剂 Nω-硝基-L-精氨酸可部分阻断子宫组织的松弛。最近的数据表明，内皮细胞和平滑肌细胞均对β3 刺激作出反应，并通过不同的信号通路对松弛作出贡献。在人子宫中测试的已批准药物（如米拉贝隆（Mybetriq™））的重新定位作为子宫保胎药，可以促进预防早产。
