Glucocorticoids regulate both phorbol ester and calcium ionophore-induced endothelial prostacyclin synthesis.
The respective roles of protein kinase C (PKC) and intracellular calcium concentration ([Ca2+]i) in glucocorticoid (GC) action on prostacyclin (PGl2) production by bovine aortic endothelial cells (BAEC) were investigated. Twenty-four hours' pretreatment with dexamethasone (DEX, 10(-6) diminished the response of BAEC to calcium ionophore A23187 (0.001-1 micrograms/ml) and ionomycin (3 microM) by about 50%, as assessed by both PGl2 release and [Ca2+]i elevation. Contrary to control cells, in DEX-penetrated cells short treatment with 12-O-tetradecanoyl phorbol 13-acetate (100 nM) significantly decreased PGl2 production without affecting cyclooxygenase activity. The data suggest that the mechanism of action of GC involves both pathways of intracellular signal transduction, namely the rises in both [Ca2+]i and PKC activity. These actions of DEX may be attributed to a phospholipase A2-inhibiting protein, such as lipocortin, which accumulates during exposure to DEX. Binding of a sufficient fraction of calcium ions and phosphorylation by PKC might be the events needed fro lipocortin activation.
Rosenstock
M
M
Department of Clinical Pharmacology, Corob Center of Health Sciences, Ben-Gurion University, Beer Sheva, Israel.
Katz
S
S
Danon
A
A
D015121:6-Ketoprostaglandin F1 alpha / Q000032:analysis; D000818:Animals; D017302:Annexins / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016718:Arachidonic Acid / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D011464:Epoprostenol / Q000096:biosynthesis*; D016257:Fura-2 / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011863:Radioimmunoassay; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D017302:Annexins; D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D007476:Ionophores; D016718:Arachidonic Acid; D000001:Calcimycin; D015759:Ionomycin; D015121:6-Ketoprostaglandin F1 alpha; D003907:Dexamethasone; D011464:Epoprostenol; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D010741:Phospholipases A; D054467:Phospholipases A2; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D016257:Fura-2