Arachidonic acid release and permeability changes induced by endothelins in human cerebromicrovascular endothelium.
The vasoactive peptide endothelin-1 (ET-1) dose-dependently increased release of 51Cr from human cerebromicrovascular endothelial cells (HBEC), without affecting cell viability as assessed by lactate dehydrogenase release. ET-1 also induced transient accumulation of inositol triphosphate (IP3) and release of [3H] arachidonic acid (AA) from HBEC. The ET-1-induced 51Cr release, formation of IP3, and AA release from HBEC were competitively inhibited by selective ETA subtype receptor antagonist BQ-123. ET-1-stimulated 51Cr- and AA release from HBEC were potentiated by proteinkinase C (PKC) activator phorbol-myristate ester, and abolished by H7, an inhibitor of PKC. Dexamethasone, indomethacin, acetylsalicylic acid, imidazole, as well as the inhibitor of protein kinase A, H8, had no effect on 51Cr release. The results suggest that ETA-receptor mediated activation of PKC and increase in the HBEC 'permeability' for low molecular weight molecules in response to excessive release of endothelins from either HBEC or surrounding tissues during pathologic conditions may contribute to the formation of cerebral edema.
Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
D B
DB
Stanimirovic
N
N
Bertrand
R
R
McCarron
S
S
Uematsu
M
M
Spatz
D016718:Arachidonic Acid / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000098:blood supply*; D001929:Brain Edema / Q000503:physiopathology*; D002470:Cell Survival / Q000502:physiology; D002857:Chromium / Q000378:metabolism; D046508:Culture Techniques; D016232:Endothelins / Q000502:physiology*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D006801:Humans; D008833:Microcirculation / Q000503:physiopathology; D011493:Protein Kinase C / Q000502:physiology; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000502:physiology; D013702:Temporal Lobe / Q000503:physiopathology
D016232:Endothelins; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D002857:Chromium; D016718:Arachidonic Acid; D011493:Protein Kinase C