Thébaud Bernard, Petit Thierry, De Lagausie Pascal, Dall'Ava-Santucci Josette, Mercier Jean-Christophe, Dinh-Xuan A Tuan
Service de Physiologie-Explorations Fonctionnelles, CHU Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris V, France.
Am J Respir Cell Mol Biol. 2002 Jul;27(1):42-7. doi: 10.1165/ajrcmb.27.1.4712.
Nitric oxide (NO) plays a major role in the modulation of perinatal pulmonary vascular tone. Congenital diaphragmatic hernia (CDH), a major cause of severe persistent pulmonary hypertension of the newborn (PPHN), is often refractory to inhaled NO. Alterations in NO/cyclic guanosine 3',5' monophosphate (cGMP)-mediated pulmonary vasodilatation may contribute to PPHN in CDH. We assessed NO/cGMP-mediated pulmonary vasorelaxation in vitro in 140-d gestational lamb fetuses with surgically created left CDH (term = 147 d) to age-matched controls. Relaxation of fourth generation intralobar pulmonary artery rings in response to the endothelium-dependent vasodilator, acetylcholine (ACh), and to the specific inhibitor of cGMP-phosphodiesterase (PDE), zaprinast, did not differ between the two groups. By contrast, relaxation in response to the calcium ionophore A23187 was impaired in CDH as compared with control animals. Relaxation in response to the NO donor sodium nitroprusside (SNP) (a direct activator of soluble guanylyl cyclase [sGC]) was also impaired in CDH animals as compared with controls. Repeating the challenge increased vasorelaxation in response to SNP in CDH as compared with control animals. Immunohistochemistry revealed the presence of endothelial NO-synthase in the endothelium of pulmonary arteries from both control and CDH animals. We conclude that endothelium-dependent vasodilatation in response to ACh and A23187 was differently affected in the fetal surgical CDH-lamb model. Furthermore, activity of sGC but not that of PDE was impaired in CDH animals. PPHN and decreased inhaled NO responsiveness in CDH may involve decreased sGC activity.
一氧化氮（NO）在围产期肺血管张力的调节中起主要作用。先天性膈疝（CDH）是新生儿严重持续性肺动脉高压（PPHN）的主要原因，通常对吸入NO治疗无效。NO/环磷酸鸟苷（cGMP）介导的肺血管舒张功能改变可能导致CDH患儿发生PPHN。我们评估了140日龄（足月为147日龄）经手术造成左膈疝的胎羊与年龄匹配的对照胎羊体外NO/cGMP介导的肺血管舒张功能。两组对内皮依赖性血管舒张剂乙酰胆碱（ACh）和cGMP磷酸二酯酶（PDE）特异性抑制剂扎普司特的反应，第四代叶内肺动脉环的舒张功能无差异。相比之下，与对照动物相比，CDH胎羊对钙离子载体A23187的反应性舒张功能受损。与对照动物相比，CDH动物对NO供体硝普钠（SNP）（可溶性鸟苷酸环化酶[sGC]的直接激活剂）的反应性舒张功能也受损。重复刺激后，与对照动物相比，CDH胎羊对SNP的血管舒张反应增强。免疫组织化学显示，对照和CDH动物肺动脉内皮中均存在内皮型一氧化氮合酶。我们得出结论，在胎儿手术CDH-胎羊模型中，对ACh和A23187的内皮依赖性血管舒张受到不同影响。此外，CDH动物的sGC活性受损，但PDE活性未受损。CDH患儿的PPHN和吸入NO反应性降低可能与sGC活性降低有关。
