Studies on the roles of phospholipase A2 and eicosanoids in the regulation of corticotrophin secretion by rat pituitary cells in vitro.
Dispersed anterior pituitary cells were used to investigate the possible roles of phospholipid metabolites released by phospholipase A2 (PLA2) in the control of immunoreactive ACTH (ir-ACTH) secretion in vitro. PLA2 (15,600-62,500 U/l), the PLA2 activator melittin (0.5-20 mg/l) and arachidonic acid (1 mmol/l) all produced increases in ir-ACTH release from the cells, whilst platelet-activating factor (PAF), prostaglandin F2 alpha (PGF2 alpha), the prostacyclin analogues iloprost and BW245C, the thromboxane A2 (TXA2) analogue U46619, and the leukotrienes LTB4 and LTC4 were ineffective in this respect. PGF2 alpha (100 nmol/l and 1 mumol/l), iloprost (1 mumol/l) and BW245C (100 nmol/l and 1 mumol/l) depressed corticotrophin-releasing factor-41-induced ir-ACTH secretion, while the PAF antagonist BN52021 (10 and 100 mumol/l) and LTC4 (100 nmol/l and 1 mumol/l) had no discernable effects. The secretory responses of the cells to hypothalamic extracts (0.2 hypothalami/ml) and arachidonic acid (1 mmol/l) were generally unaffected by the cyclooxygenase inhibitors ibuprofen (10 and 100 mumol/l) and indomethacin (10 mumol/l), the TXA2 synthetase inhibitor imidazole (10 mumol/l-1 mmol/l), the lipoxygenase inhibitor nordihydroguaiaretic acid (10 and 100 mumol/l) and the dual cyclo-oxygenase/lipoxygenase inhibitors phenidone (1-100 mumol/l) and BW755C (10 and 100 mumol/l). They were, however, inhibited by the dual cyclo-oxygenase/lipoxygenase inhibitor eicosatetraynoic acid (10 and 100 mumol/l), which also blocks epoxygenase and PLA2 activity and by the cytochrome P450 inhibitor SKF-525A (1 mmol/l). The results suggest that the stimulatory effects of PLA2 and arachidonic acid on ir-ACTH secretion are not effected by products generated by the cyclo-oxygenase or lipoxygenase pathways but may be mediated by metabolites generated by the cytochrome P450 pathway.
Cowell
A M
AM
Department of Pharmacology, Charing Cross and Westminster Medical School, London.
Flower
R J
RJ
Buckingham
J C
JC
D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D001095:Arachidonic Acids / Q000502:physiology; D002478:Cells, Cultured; D015777:Eicosanoids / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D010741:Phospholipases A / Q000502:physiology*; D054467:Phospholipases A2; D010903:Pituitary Gland, Anterior / Q000378:metabolism*; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains
D001095:Arachidonic Acids; D015777:Eicosanoids; D004791:Enzyme Inhibitors; D000324:Adrenocorticotropic Hormone; D010741:Phospholipases A; D054467:Phospholipases A2