Role of phosphoinositides in the regulation of endothelial prostacyclin production.
To elucidate the role of the phosphoinositide signal transduction system in endothelial endothelial prostacyclin production, endothelial cells from human umbilical veins previously labelled with 3H-inositol were incubated with thrombin or histamine. Water-soluble inositol phosphates were separated on anion exchange columns. Both agonists evoked transient bursts of inositol phosphate production with inositol trisphosphate peaking at 15 seconds in histamine-stimulated cells and at 60 seconds in thrombin-stimulated cells. The inositol phosphate production was closely linked to prostacyclin production. After stimulation, there was concurrent desensitization to prostacyclin production and formation of inositol phosphates. Arachidonic acid and the Ca2+-ionophore A23187 did not affect inositol phosphate production in concentrations sufficient to increase prostacyclin production 20-fold, and they did not affect desensitization to a subsequent thrombin stimulation. The phorbol ester 12-o-tetradecanoyl phorbol 13-acetate, a stimulator of protein kinase C, inhibited thrombin-induced generation of inositol phosphates, enhanced A23187-mediated prostacyclin production, and had complex effects on thrombin-mediated prostacyclin production, but had no effect on its production from extrinsic arachidonic acid. The current data suggest that production of inositol phosphates is a link in receptor stimulation of endothelial cells to produce prostacyclin and that associated activation of protein kinase C affects both the generation of second messengers and the release of arachidonic acid.
Halldórsson
H
H
Department of Pharmacology, University of Iceland, Reykjavík.
Kjeld
M
M
Thorgeirsson
G
G
D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000502:physiology; D000001:Calcimycin / Q000502:physiology; D004727:Endothelium / Q000378:metabolism; D011464:Epoprostenol / Q000096:biosynthesis*; D006632:Histamine / Q000502:physiology; D006801:Humans; D010716:Phosphatidylinositols / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000502:physiology; D013917:Thrombin / Q000502:physiology; D014471:Umbilical Veins / Q000378:metabolism
D001095:Arachidonic Acids; D010716:Phosphatidylinositols; D016718:Arachidonic Acid; D000001:Calcimycin; D006632:Histamine; D011464:Epoprostenol; D013917:Thrombin; D013755:Tetradecanoylphorbol Acetate