title: Synergistic inhibition of human polymorphonuclear function by prostaglandin E1 and linsidomine.
abstract: Polymorphonuclear cells (PMN) are the dominating inflammatory cell population in acute tissue injury and contribute to host-defence mechanisms by formation and release of chemical mediators. The aim of the present study was to investigate whether chemoattractant-induced PMN stimulation can be synergistically antagonized by vasodilatory prostaglandins and nitric oxide (NO), both being formed by the vasculature in inflamed areas. PGE1 (10 nM-10 microM) inhibited concentration-dependently formyl-methionyl-leucyl-phenylalanine (fMLP)-induced beta-glucuronidase and oxygen radical (O2.) release from human PMN. The NO donor linsidomine (100 microM) was ineffective, but significantly enhanced PGE1 effects on oxygen radical generation and enzyme release. The non-selective phosphodiesterase inhibitor 3-isobutyl-l-methylxanthine (IBMX) (0.5 mM) potentiated PGE1 effects on all parameters measured. The combination linsidomine (100 microM) plus IBMX (0.5 mM) did not additionally reduce beta-glucuronidase release, but abolished fMLP-stimulated O2. generation. There was a stimulation of cAMP formation by PGE1 but not by linsidomine, both in the absence and presence of IBMX. It is concluded that the effects of linsidomine on PMN function and its synergism with PGE1 are not tightly correlated with total cAMP accumulation. Alternatively, the inhibition of O2. generation by linsidomine may be related to its ability to modulate the activation of the NADPH oxidase system or to scavenge free oxygen radicals.
authors.affiliation: Institut für Pharmakologie, Heinrich-Heine-Universität Düsseldorf, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Gladis-Villanueva
authors.forename: K
authors.initials: K
authors.lastname: Schrör
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000527:Alprostadil / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D004357:Drug Synergism; D006801:Humans; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D016897:Respiratory Burst / Q000187:drug effects*
chemical_list: D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D009240:N-Formylmethionine Leucyl-Phenylalanine; C002385:linsidomine; D008981:Molsidomine; D000242:Cyclic AMP; D000527:Alprostadil; D015056:1-Methyl-3-isobutylxanthine