Coceani F, Kelsey L, Seidlitz E
Research Institute, Hospital for Sick Children, Toronto, ON, Canada.
Can J Physiol Pharmacol. 1994 Jan;72(1):82-8. doi: 10.1139/y94-013.
To determine whether the ductus arteriosus can form endothelium-derived relaxing factor--nitric oxide, we used isolated ductal strips from near-term fetal lamb and examined their response to bradykinin (a nitric oxide stimulator), L-arginine (a nitric oxide precursor), and agents interfering with the synthesis (N omega-nitro-L-arginine) and action (methylene blue) of nitric oxide. Bradykinin relaxed the indomethacin-contracted ductus dose dependently from a threshold of about 10(-10) M, and peak relaxation was greater at high (176-210 mmHg; 1 mmHg = 133.3 Pa) than low (15-25 mmHg) PO2. Bradykinin relaxation was nearly completely or completely abolished in endothelium-denuded preparations and, in its place, there was often a small contraction. Pretreatment with nitric oxide inhibitors also prevented, in part (methylene blue, 1 microM) or in full (N omega-nitro-L-arginine, 100 microM), the relaxant effect of bradykinin. Paradoxically, L-arginine (10 microM) had an inhibiting rather than an enhancing effect on the bradykinin relaxation. N omega-Nitro-L-arginine (100 microM) and methylene blue (1-100 microM) contracted by themselves the untreated ductus, and their action persisted after removal of the endothelium. These findings indicate the presence in the ductus arteriosus of a nitric oxide based relaxing mechanism, which may supplement prostaglandin E2 in keeping the vessel patent in the fetus. This mechanism may, on one hand, afford protection against nonsteroidal anti-inflammatory drugs in utero and may, on the other hand, complicate the management of prematures with persistent ductus and account for failures of the indomethacin therapy.
为了确定动脉导管是否能生成内皮源性舒张因子——一氧化氮，我们使用了来自足月胎羊的离体导管条，并检测了它们对缓激肽（一种一氧化氮刺激剂）、L-精氨酸（一种一氧化氮前体）以及干扰一氧化氮合成（Nω-硝基-L-精氨酸）和作用（亚甲蓝）的药物的反应。缓激肽能使吲哚美辛收缩的导管剂量依赖性舒张，阈值约为10^(-10)M，在高氧分压（176 - 210 mmHg；1 mmHg = 133.3 Pa）时的最大舒张幅度大于低氧分压（15 - 25 mmHg）时。在内皮剥脱的标本中，缓激肽的舒张作用几乎完全或完全消失，取而代之的是常出现轻微收缩。用一氧化氮抑制剂预处理也部分（1 μM亚甲蓝）或完全（100 μM Nω-硝基-L-精氨酸）阻断了缓激肽的舒张作用。矛盾的是，10 μM的L-精氨酸对缓激肽的舒张作用具有抑制而非增强作用。100 μM的Nω-硝基-L-精氨酸和1 - 100 μM的亚甲蓝能使未处理的导管自身收缩，且在内皮去除后其作用仍持续存在。这些发现表明动脉导管中存在基于一氧化氮的舒张机制，这可能在维持胎儿血管开放方面补充前列腺素E2。一方面，这种机制可能为胎儿提供针对子宫内非甾体抗炎药的保护，另一方面，可能使持续性动脉导管未闭的早产儿管理复杂化，并解释吲哚美辛治疗失败的原因。
