title: Endothelin-1 attenuates increases in hydraulic conductivity due to platelet-activating factor via prostacyclin release.
abstract: We previously showed that endothelin-1 (ET-1) and prostacyclin (PGI(2)) similarly attenuate increases in microvascular permeability induced by platelet-activating factor (PAF). This led us to hypothesize that ET-1 attenuates trans-endothelial fluid flux during PAF through PGI(2) release. We tested this hypothesis in three phases. First, bovine pulmonary artery endothelial cells were exposed to 0.008-8 μM ET-1 and assayed for PGI(2) release. Second, to determine whether increased transmonolayer flux after PAF could be attenuated by ET-1 or PGI(2) and reversed by PGI(2) synthesis inhibition or PGI(2) receptor blockade, we measured endothelial cell transmonolayer flux after cells were exposed to 10 nM PAF plus 10 μM PGI(2) or 80 pM ET-1, with or without 500 μM tranylcypromine (PGI(2) synthase inhibitor) or 20 μM CAY-10441 (PGI(2) receptor blocker). Finally, hydraulic conductivity (L(p)) was measured in rat mesenteric venules in vivo after exposure to 10 nM PAF and 80 pM ET-1 with or without tranylcypromine (100 and 500 μM) or CAY-10441 (2 and 20 μM). We found that in vitro, ET-1 stimulated a dose-dependent increase in PGI(2) production (from 126 to 217 pg/ml, P < 0.01). Compared with PAF alone, PGI(2) plus PAF and ET-1 plus PAF decreased transmonolayer flux similarly by 52 and 46%, respectively (P < 0.01), while tranylcypromine and CAY-10441 reversed these effects by 92 and 47%, respectively (P < 0.05). In vivo, PAF increased L(p) fourfold (P < 0.01) and ET-1 attenuated this effect by 83% (P < 0.01). Tranylcypromine and CAY-10441 reversed the ET-1 attenuation in L(p) during PAF by 55 and 45%, respectively (P < 0.01). We conclude that ET-1 may stimulate endothelial cell PGI(2) release to attenuate the increases in transmonolayer flux and hydraulic conductivity secondary to PAF.
authors.affiliation: University of California, San Francisco-East Bay, Dept. of Surgery, 1411 East 31st St., Oakland, CA 94602, USA.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Cureton
authors.forename: Aaron
authors.initials: A
authors.lastname: Strumwasser
authors.forename: Rita O
authors.initials: RO
authors.lastname: Kwan
authors.forename: Kristopher C
authors.initials: KC
authors.lastname: Dozier
authors.forename: Brian
authors.initials: B
authors.lastname: Curran
authors.forename: Javid
authors.initials: J
authors.lastname: Sadjadi
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Victorino
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D002417:Cattle; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D019332:Endothelin-1 / Q000494:pharmacology*; D011464:Epoprostenol / Q000096:biosynthesis*; D010972:Platelet Activating Factor / Q000378:metabolism*; D051381:Rats
chemical_list: D019332:Endothelin-1; D010972:Platelet Activating Factor; D011464:Epoprostenol