Cyclic-GMP-mediated decrease in permeability of human umbilical and pulmonary artery endothelial cell monolayers.
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.
Westendorp
R G
RG
Gaubius Laboratory, IVVO-TNO, Leiden, The Netherlands.
Draijer
R
R
Meinders
A E
AE
van Hinsbergh
V W
VW
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000502:physiology*; D004553:Electric Conductivity; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D013917:Thrombin / Q000494:pharmacology; D014469:Umbilical Arteries / Q000187:drug effects / Q000502:physiology
D009599:Nitroprusside; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D009569:Nitric Oxide; D009320:Atrial Natriuretic Factor; D001120:Arginine; D000242:Cyclic AMP; D013917:Thrombin; D000262:Adenylyl Cyclases; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester