Heymann M A
Cardiovascular Research Institute, University of California, San Francisco, 94143-0544, USA.
Eur J Obstet Gynecol Reprod Biol. 1999 Jun;84(2):127-32. doi: 10.1016/s0301-2115(98)00321-2.
During fetal life and the transition to extra-uterine air breathing, pulmonary vascular tone is regulated by a complex, interactive group of mechanisms. Arachidonic acid metabolites play an important role in this regulation. Although prostaglandins may not be central to regulation of the resting fetal pulmonary circulation, PGI2 acts to modulate tone and thereby maintain pulmonary vascular resistance relatively constant. PGI2 also may play an important role as one of the components involved in the major changes that occur with the onset of air breathing. Leukotrienes, also metabolites of arachidonic acid and potent smooth muscle constrictors, may play an active role in maintaining the normally high fetal pulmonary vascular resistance, because leukotriene receptor blockade or synthesis inhibition increases pulmonary blood flow about eight-fold; the presence of leukotrienes in fetal tracheal fluid further supports this. In addition to PGI2, vascular endothelial cells produce other vasoactive factors. These include potent vasodilators, such as endothelium-derived relaxing factor (EDRF). EDRF, known to be nitric oxide (NO) and often called endothelium-derived nitric oxide (EDNO), is produced by endothelial cells in response to varied stimuli, generally involving specific receptors and the activation of endothelial NO synthetase (eNOS); subsequent smooth muscle relaxation is produced by a NO/guanylyl cyclase/cGMP-mediated mechanism. NO clearly is involved in regulation of vascular tone in the fetal pulmonary circulation, although it plays a far more important role in the postnatal transition to air breathing. Superfused fetal sheep pulmonary arteries release NO when stimulated with bradykinin. In fetal lambs the vasodilating effects of bradykinin are attenuated by methylene blue and resting tone falls with N(omega)-nitro-L-arginine, an inhibitor of NO synthesis, suggesting that a NO/cGMP-dependent mechanism continuously modulates or offsets the increased tone of the resting fetal pulmonary circulation. Inhibition of NO synthesis blocks the pulmonary vasodilation with oxygenation of fetal lungs in utero. Shear stress-induced NO production as well as the relationship of oxygenation to NO production further support the important function of NO in the transition. Although endothelin-1 (ET-1) has potent vasoactivity as well as ontogenetic differences in effect on pulmonary vascular resistance, its exact physiological role has not been defined. Adrenomedullin and calcitonin gene-related peptide (CGRP), two additional vasoactive substances, have profound, and prolonged, vasodilating effects in the fetal pulmonary circulation. Their physiological roles have not yet been established.
在胎儿期以及向宫外空气呼吸的过渡阶段，肺血管张力受一组复杂且相互作用的机制调节。花生四烯酸代谢产物在这种调节中起重要作用。尽管前列腺素可能并非胎儿静息肺循环调节的核心，但前列环素（PGI2）可调节张力，从而使肺血管阻力相对保持恒定。PGI2作为空气呼吸开始时发生的主要变化所涉及的成分之一，也可能发挥重要作用。白三烯也是花生四烯酸的代谢产物，是强效的平滑肌收缩剂，可能在维持胎儿正常的高肺血管阻力方面发挥积极作用，因为白三烯受体阻断或合成抑制可使肺血流量增加约8倍；胎儿气管液中存在白三烯进一步支持了这一点。除了PGI2，血管内皮细胞还产生其他血管活性因子。这些包括强效血管舒张剂，如内皮源性舒张因子（EDRF）。EDRF已知为一氧化氮（NO），通常称为内皮源性一氧化氮（EDNO），由内皮细胞对各种刺激作出反应而产生，一般涉及特定受体和内皮型一氧化氮合酶（eNOS）的激活；随后的平滑肌舒张是由NO/鸟苷酸环化酶/cGMP介导的机制产生的。NO显然参与胎儿肺循环中血管张力的调节，尽管它在出生后向空气呼吸的过渡中发挥着更为重要的作用。用缓激肽刺激时，灌注的胎儿羊肺动脉会释放NO。在胎儿羔羊中，缓激肽的血管舒张作用会被亚甲蓝减弱，静息张力会随着NO合成抑制剂N（ω）-硝基-L-精氨酸降低，这表明一种依赖NO/cGMP的机制持续调节或抵消胎儿静息肺循环增加的张力。抑制NO合成会阻断子宫内胎儿肺氧合时的肺血管舒张。剪切应力诱导的NO产生以及氧合与NO产生的关系进一步支持了NO在这一过渡中的重要作用。尽管内皮素-1（ET-1）具有强大的血管活性以及对肺血管阻力的个体发育差异影响，但其确切的生理作用尚未明确。肾上腺髓质素和降钙素基因相关肽（CGRP）这两种额外的血管活性物质在胎儿肺循环中具有深刻且持久的血管舒张作用。它们的生理作用尚未确定。
