Westendorp R G, Draijer R, Meinders A E, van Hinsbergh V W
Gaubius Laboratory, IVVO-TNO, Leiden, The Netherlands.
J Vasc Res. 1994 Jan-Feb;31(1):42-51. doi: 10.1159/000159030.
Endothelial cell contraction plays a pivotal role in the increased extravasation of fluid and macromolecules in vascular leakage. Previous studies have indicated that elevation of the adenosine 3',5'-cyclic monophosphate (cAMP) concentration can improve the endothelial barrier function. In analogy with smooth muscle cell contraction, which is inhibited by both cAMP and guanosine 3',5'-cyclic monophosphate (cGMP), we have compared the role of cAMP and cGMP in the regulation of the permeability of human endothelial cell monolayers. The cellular cGMP concentration was elevated 3- to 5-fold after addition of 10(-7) M atrial natriuretic peptide (ANP) or 10(-4) M sodium nitroprusside (SNP), both under basal and thrombin-stimulated conditions. After exposure to thrombin, cGMP generation by ANP or SNP or addition of 8-bromo-cGMP significantly suppressed the increase in permeability. Inhibition of nitric oxide production with 10(-4) M NG-nitro-L-arginine methyl ester increased the permeability of endothelial monolayers in the majority of the tested cultures, an effect that could be counteracted by addition of 8-bromo-cGMP or ANP. An increase of cAMP upon the addition of forskolin reduced the permeability in all endothelial cell strains under basal conditions and after exposure to thrombin. The forskolin- and 8-bromo-cGMP-mediated decreases in permeability were accompanied by increases in transendothelial electrical resistance. These in vitro data indicate that, in addition to cAMP, cGMP can act as a potent fine-regulator of endothelial permeability.
内皮细胞收缩在血管渗漏时液体和大分子物质外渗增加过程中起关键作用。先前的研究表明，3',5'-环磷酸腺苷（cAMP）浓度升高可改善内皮屏障功能。与受cAMP和3',5'-环磷酸鸟苷（cGMP）抑制的平滑肌细胞收缩类似，我们比较了cAMP和cGMP在调节人内皮细胞单层通透性中的作用。在基础条件和凝血酶刺激条件下，加入10(-7) M心钠素（ANP）或10(-4) M硝普钠（SNP）后，细胞内cGMP浓度升高3至5倍。暴露于凝血酶后，ANP或SNP产生的cGMP或添加8-溴-cGMP可显著抑制通透性增加。用10(-4) M NG-硝基-L-精氨酸甲酯抑制一氧化氮生成，在大多数测试培养物中增加了内皮单层的通透性，添加8-溴-cGMP或ANP可抵消这一作用。加入福司可林后cAMP增加，在基础条件下以及暴露于凝血酶后，降低了所有内皮细胞株的通透性。福司可林和8-溴-cGMP介导的通透性降低伴随着跨内皮电阻增加。这些体外数据表明，除了cAMP外，cGMP可作为内皮通透性的有效精细调节因子。
