Prostaglandin E2-mediated relaxation of the ductus arteriosus -: Effects of gestational age on G protein-coupled receptor expression, signaling, and vasomotor control
Prostaglandin E2-mediated relaxation of the ductus arteriosus -: Effects of gestational age on G protein-coupled receptor expression, signaling, and vasomotor control
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DOI：
10.1161/01.cir.0000145159.16637.5d
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发表时间：
2004-10-19
期刊：
影响因子：
37.8
通讯作者：
Clyman, RI
中科院分区：
文献类型：
--
作者：
Waleh, N;Kajino, H;Clyman, RI
背景 - 在早产儿中，动脉导管未闭很大程度上是由于未成熟的导管对前列腺素 E-2 (PGE(2)) 敏感性增加的结果。 PGE(2) 通过 3G 蛋白偶联受体（EP2、EP3 和 EP4）发挥作用，激活腺苷酸环化酶和 K-ATP 通道。我们探索了这些途径，以确定未成熟导管对 PGE(2) 敏感性增加的机制。方法和结果 - 我们测量了取自未成熟（65% 妊娠）和成熟（95% 妊娠）绵羊和狒狒胎儿的导管环中的 EP 受体含量（mRNA 和蛋白质）、受体结合、cAMP 产生和等长张力。未成熟导管中对选择性 EP 受体激动剂的反应增强了导管松弛和 cAMP 生成。 8-Br-cAMP 是一种稳定的 cAMP 类似物，可在未成熟的导管中产生更大的松弛作用。在存在选择性蛋白激酶 A 抑制剂 Rp-8-CPT cAMPS 的情况下，无法再证明对 PGE(2) 敏感性的发育差异。尽管 2 个胎龄的受体 mRNA 和蛋白质含量相似，但未成熟导管中 EP2、EP3 和 EP4 受体密度较高。相比之下，毛喉素和NaF分别是腺苷酸环化酶和G(s)的直接激活剂，在两个年龄组中引起cAMP的类似增加。 K-ATP 通道抑制对两个年龄组的 PGE(2) 诱导的松弛也有类似的影响。结论 - 有两种机制解释了未成熟导管对 PGE(2) 敏感性的增加：(1) 由于 PGE(2) 与单个 EP 受体的结合增加而增加了 cAMP 的产生，以及 (2) cAMP 对蛋白激酶 A 调节途径的效力增加。
Background - In the preterm newborn, a patent ductus arteriosus is in large part a result of the increased sensitivity of the immature ductus to prostaglandin E-2 (PGE(2)). PGE(2) acts through 3 G protein - coupled receptors (EP2, EP3, and EP4) that activate both adenyl cyclase and K-ATP channels. We explored these pathways to identify the mechanisms responsible for the increased sensitivity of the immature ductus to PGE(2).Methods and Results - We measured EP receptor content (mRNA and protein), receptor binding, cAMP production, and isometric tension in rings of ductus taken from immature (65% gestation) and mature (95% gestation) sheep and baboon fetuses. Ductus relaxation and cAMP generation were augmented in response to selective EP receptor agonists in the immature ductus. 8-Br-cAMP, a stable cAMP analogue, produced greater relaxation in the immature ductus. In the presence of a selective protein kinase A inhibitor, Rp-8-CPT cAMPS, the developmental differences in sensitivity to PGE(2) could no longer be demonstrated. EP2, EP3, and EP4 receptor densities were higher in immature ductus, despite similar receptor mRNA and protein contents at the 2 gestational ages. In contrast, forskolin and NaF, direct activators of adenyl cyclase and G(s), respectively, elicited comparable increases in cAMP in both age groups. K-ATP channel inhibition also had similar effects on PGE(2)-induced relaxation in both age groups.Conclusions - Two mechanisms explain the increased sensitivity of the immature ductus to PGE(2): ( 1) increased cAMP production because of increased binding of PGE(2) to the individual EP receptors and ( 2) increased potency of cAMP on protein kinase A - regulated pathways.