Oligomers of prostaglandin B1 inhibit arachidonic acid mobilization in human neutrophils and endothelial cells.
The previous paper (Biochim. Biophys. Acta 1006 (1989) 272-277) has demonstrated that oligomers of prostaglandin B1 are effective in vitro inhibitors of a wide range of both cell-derived and extracellular phospholipases A2. The present study has investigated the effects of prostaglandin oligomers on agonist-stimulated phospholipase activity on intact human cells. PGBx, an oligomer (n = 6) or PGB1, and PGB-trimer inhibit as much as 95% of the A23187-stimulated release of arachidonic acid from human neutrophils. The effect is dose-dependent, with an IC50 of 4-5 microM; near maximal inhibition is obtained with as little as 1 min of preincubation with PGB-trimer. Consistent with its role as a phospholipase A2 inhibitor, PGB-trimer also inhibits the A23187-stimulated incorporation of [3H]acetate into platelet-activating factor. PGBx and PGB-trimer also inhibit the release of arachidonic acid from human umbilical vein endothelial cells stimulated with histamine, thrombin, or ionophore A23187; inhibition of the basal or unstimulated turnover of both arachidonic acid and oleic acid is also observed. Inhibition by PGB-trimer can be blocked by simultaneous addition of 50 microM albumin; cells preincubated with PGB-trimer are not affected by albumin. Furthermore, removal of exogenous PGB-trimer prior to challenge with A23187 does not reverse the inhibition of either endothelial cells and neutrophils. Thus, prostaglandin B1 oligomers are taken up by human neutrophils and vascular endothelial cells and serve as potent inhibitors of arachidonic acid mobilization. One mechanism for the pharmacological effects of PGBx may be inhibition of cell-associated and extracellular phospholipase A2.
Rosenthal
M D
MD
Department of Biochemistry, Eastern Virginia Medical School, Norfolk 23501.
Franson
R C
RC
D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D007700:Kinetics; D007975:Leukotriene B4 / Q000378:metabolism; D046911:Macromolecular Substances; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D010743:Phospholipids / Q000378:metabolism; D010972:Platelet Activating Factor / Q000096:biosynthesis; D011108:Polymers / Q000494:pharmacology*; D011453:Prostaglandins / Q000494:pharmacology*; D011456:Prostaglandins B / Q000494:pharmacology*; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014471:Umbilical Veins
D001095:Arachidonic Acids; D006893:Hydroxyeicosatetraenoic Acids; D046911:Macromolecular Substances; D010743:Phospholipids; D010972:Platelet Activating Factor; D011108:Polymers; D011453:Prostaglandins; D011456:Prostaglandins B; D007975:Leukotriene B4; C034467:prostaglandin B1; D012710:Serum Albumin, Bovine; D016718:Arachidonic Acid; D000001:Calcimycin; C024303:prostaglandin Bx; D010741:Phospholipases A; D054467:Phospholipases A2