Izumi H, Makino Y, Shirakawa K, Garfield R E
Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston 77555-1062, USA.
Am J Obstet Gynecol. 1995 May;172(5):1477-84. doi: 10.1016/0002-9378(95)90481-6.
Endothelium-derived relaxing factor (or nitric oxide) is thought to play an important role in control of blood flow in umbilical blood vessels at midgestation compared with term. Previous studies suggest that histamine releases endothelium-derived relaxing factor from umbilical arteries. In this study we intended to clarify the mechanism by which histamine releases endothelium-derived relaxing factor and causes vasorelaxation in human umbilical artery at the midstage (18 to 22 weeks) of gestation.
By means of very thin muscle strips that allow rapid diffusional access of applied drugs (in a few seconds), contractile properties of human umbilical artery were examined. Isometric tensions were measured in response to potassium chloride (39 mmol/L) or caffeine and inhibitory effects of histamine, A23187, glyceryl trinitrate, and 8-bromo-cyclic guanosine monophosphate on these contractions were also examined.
Histamine (0.01 to 0.1 mumol/L) did not inhibit 39 mmol/L K(+)-induced contractions of tissues taken at the terminal (38 to 41 weeks) stage of gestation. However, at midgestation histamine (0.01 to 0.1 mumol/L), A23187 (10 mumol/L), and 8-bromo-cyclic guanosine monophosphate (membrane-permeable analog of cyclic guanosine monophosphate, 0.1 mmol/L) inhibited 39 mmol/L K(+)-induced contractions. The inhibitory effects of histamine were antagonized by mepyramine (an H1 antagonist), L-NG-nitro arginine, methylene blue, and Ca++ depletion of the extracellular space but not by cimetidine (an H2 antagonist). Caffeine produced contractions both in the presence and absence of extracellular Ca++ possibly because of the release of Ca++ from intracellular storage sites. Glyceryl trinitrate and 8-bromo-cyclic guanosine monophosphate reduced the caffeine-induced contractions in Ca(++)-free solution. In addition, 10 mumol/L cyclic guanosine monophosphate did not attenuate the Ca++ sensitivity for contractile elements.
These results suggest that (1) histamine coupled to the histamine H1 receptor increases intracellular Ca++ concentration to stimulate nitric oxide synthase in human umbilical endothelial cells, (2) nitric oxide from endothelial cells activates guanylate cyclase to produce cyclic guanosine monophosphate in the umbilical smooth muscle cells, and (3) cyclic guanosine monophosphate relaxes the umbilical tissues, perhaps as a result of the activation of a Ca++ extrusion system.
与足月时相比，内皮源性舒张因子（或一氧化氮）被认为在妊娠中期脐血管血流控制中起重要作用。先前的研究表明，组胺可从脐动脉释放内皮源性舒张因子。在本研究中，我们旨在阐明组胺在妊娠中期（18至22周）释放内皮源性舒张因子并导致人脐动脉血管舒张的机制。
通过非常细的肌条，使应用的药物能在几秒钟内快速扩散进入，以此检测人脐动脉的收缩特性。测量对氯化钾（39 mmol/L）或咖啡因的等长张力，并检测组胺、A23187、硝酸甘油和8-溴环鸟苷单磷酸对这些收缩的抑制作用。
组胺（0.01至0.1 μmol/L）不抑制妊娠末期（38至41周）取材组织的39 mmol/L钾离子诱导的收缩。然而，在妊娠中期，组胺（0.01至0.1 μmol/L）、A23187（10 μmol/L）和8-溴环鸟苷单磷酸（环鸟苷单磷酸的膜通透性类似物，0.1 mmol/L）抑制39 mmol/L钾离子诱导的收缩。组胺的抑制作用被美吡拉敏（一种H1拮抗剂）、L-NG-硝基精氨酸、亚甲蓝和细胞外空间钙离子耗竭所拮抗，但不被西咪替丁（一种H2拮抗剂）所拮抗。咖啡因在有或无细胞外钙离子存在时均产生收缩，这可能是由于钙离子从细胞内储存部位释放所致。硝酸甘油和8-溴环鸟苷单磷酸在无钙溶液中降低咖啡因诱导的收缩。此外，10 μmol/L环鸟苷单磷酸并未减弱收缩元件对钙离子的敏感性。
这些结果表明：（1）与组胺H1受体偶联的组胺增加人脐内皮细胞内钙离子浓度以刺激一氧化氮合酶；（2）内皮细胞产生一氧化氮激活鸟苷酸环化酶，在脐平滑肌细胞中产生环鸟苷单磷酸；（3）环鸟苷单磷酸使脐组织舒张，这可能是由于激活钙离子外排系统的结果。
