Characterization of the inhibitory prostanoid receptors on human neutrophils.
1. We have evaluated the effects of various prostanoid agonists on the release of leukotriene B4 (LTB4) and superoxide anions (O2-) from human neutrophils stimulated with opsonized zymosan (OZ) and formyl-methionyl-leucyl-phenylalanine (FMLP), respectively. 2. Prostaglandin E2 (PGE2) and PGD2 inhibited both OZ-induced LTB4 release (EC50 0.72 microM and 0.91 microM respectively), and FMLP-induced O2- release (EC50 0.42 microM and 0.50 microM respectively). PGF2 alpha, the TP-receptor agonist, U46619, and the IP-receptor agonist, iloprost, were also active, but were all at least an order of magnitude less potent than PGE2 and PGD2. 3. The EP2/EP3-receptor agonist, misoprostol, and the selective EP2-agonist, AH13205, were both effective inhibitors of LTB4 release, being approximately equipotent with and 16-times less potent than PGE2, respectively. In contrast, the EP1/EP3-receptor agonist, sulprostone, had no inhibitory activity at concentrations of up to 10 microM. 4. The selective DP-receptor agonist, BW245C, inhibited LTB4 release, (EC50 0.006 microM) being approximately 50 times more potent than PGD2. BW245C also inhibited O2- release, and this inhibition was antagonized competitively by the DP-receptor blocking drug, AH6809 (pA2 6.6). 5. These data indicate the presence of both inhibitory EP- and DP-receptors on the human neutrophil. The rank order of potency of EP-receptor agonists suggest that the EP-receptors are of the EP2-subtype.
Department of Cardiovascular and Respiratory Pharmacology, Glaxo Group Research Ltd. Ware, Hertfordshire.
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Wheeldon
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CJ
Vardey
D006801:Humans; D006827:Hydantoins / Q000494:pharmacology; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000378:metabolism; D016595:Misoprostol / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D011448:Prostaglandin Antagonists; D011453:Prostaglandins / Q000494:pharmacology; D011466:Prostanoic Acids / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000187:drug effects / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014966:Xanthenes / Q000494:pharmacology; D044004:Xanthones; D015054:Zymosan / Q000494:pharmacology
D006827:Hydantoins; D011448:Prostaglandin Antagonists; D011453:Prostaglandins; D011466:Prostanoic Acids; D011982:Receptors, Prostaglandin; D014966:Xanthenes; D044004:Xanthones; D016595:Misoprostol; D013481:Superoxides; C081039:AH 13205; D007975:Leukotriene B4; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; D009240:N-Formylmethionine Leucyl-Phenylalanine; C030669:BW 245C; D015054:Zymosan