Clyman R I, Waleh N, Black S M, Riemer R K, Mauray F, Chen Y Q
Cardiovascular Research Institute, Department of Pediatrics, University of California, San Francisco 94143-0544, USA.
Pediatr Res. 1998 May;43(5):633-44. doi: 10.1203/00006450-199805000-00012.
We hypothesized that nitric oxide (NO) production by the fetal ductus arteriosus is limited because of low fetal PO2, but that at neonatal PO2, NO might be an important regulator of ductus arteriosus tone. We exposed isolated rings of fetal lamb ductus arteriosus to elevated PO2. L-NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), and methylene blue and 6-anilino-5,8-quinolinedione (LY83583), inhibitors of guanylate cyclase, produced constriction of the ductus arteriosus. When ductus arteriosus rings were exposed to low PO2, L-NAME had no effect, and methylene blue and LY83583 had only a small effect on ductus arteriosus tone. Sodium nitroprusside and calcium ionophore A23187 relaxed ductus arteriosus rings more than aortic rings, and relaxed ductus arteriosus rings from immature fetuses more than those from late gestation fetuses. In contrast, ductus arteriosus rings from both early and late gestation were equally sensitive to 8-bromo-cGMP. By both reverse transcriptase-polymerase chain reaction and immunohistochemistry, endothelial cell NOS and inducible calcium-independent NOS, but not nerve cell NOS, were detected in the ductus arteriosus. Inducible NOS was expressed only by endothelial cells lining the ductus arteriosus lumen; in contrast, endothelial cell NOS was expressed by both luminal and vasa vasorum endothelial cells. The role of inducible NOS in the ductus arteriosus is uncertain because the potency of a specific inducible NOS inhibitor in constricting the ductus arteriosus was negligible compared with that of an endothelial cell NOS inhibitor. We speculate that NO may be an important regulator of ductus arteriosus tone at high but not low PO2. The endothelial cell NOS isoform found in vasa vasorum may be an important source of NO because removal of ductus arteriosus luminal endothelium only partially blocks the effects of L-NAME, methylene blue, and LY83583.
我们推测，由于胎儿血氧分压较低，胎儿动脉导管一氧化氮（NO）的生成受限，但在新生儿血氧分压水平下，NO可能是动脉导管张力的重要调节因子。我们将分离出的胎羊动脉导管环暴露于升高的血氧分压下。一氧化氮合酶（NOS）抑制剂L-NG-硝基-L-精氨酸甲酯（L-NAME）、鸟苷酸环化酶抑制剂亚甲蓝和6-苯胺基-5,8-喹啉二酮（LY83583）可使动脉导管收缩。当动脉导管环暴露于低血氧分压时，L-NAME无作用，亚甲蓝和LY83583对动脉导管张力仅有轻微影响。硝普钠和钙离子载体A23187使动脉导管环的舒张程度大于主动脉环，且使未成熟胎儿的动脉导管环舒张程度大于妊娠晚期胎儿的动脉导管环。相比之下，妊娠早期和晚期的动脉导管环对8-溴-cGMP的敏感性相同。通过逆转录聚合酶链反应和免疫组织化学方法，在动脉导管中检测到内皮细胞型NOS和诱导型钙非依赖性NOS，但未检测到神经细胞型NOS。诱导型NOS仅在动脉导管管腔内衬的内皮细胞中表达；相反，内皮细胞型NOS在管腔和滋养血管内皮细胞中均有表达。诱导型NOS在动脉导管中的作用尚不确定，因为与内皮细胞型NOS抑制剂相比，一种特异性诱导型NOS抑制剂对动脉导管收缩的效力可忽略不计。我们推测，在高血氧分压而非低血氧分压时，NO可能是动脉导管张力的重要调节因子。在滋养血管中发现的内皮细胞型NOS同工型可能是NO的重要来源，因为去除动脉导管管腔内皮层仅部分阻断L-NAME、亚甲蓝和LY83583的作用。
