Characterization of the prostanoid receptors mediating inhibition of PAF-induced aggregation of guinea-pig eosinophils.
1. Prostanoids induce a wide range of biological actions which are mediated by specific membrane-bound receptors. We have recently shown that the E-type prostaglandins, PGE1 and PGE2, effectively inhibit eosinophil aggregation induced by platelet-activating factor (PAF). In an attempt to determine which prostanoid receptor(s) were involved, we investigated the effects of a range of selective prostanoid agonists and antagonists on eosinophil homotypic aggregation induced by PAF. 2. Both PGE1 and PGE2 (10(-10) to 10(-6) M) induced a concentration-related inhibition of the aggregation response induced by PAF. PGE1 was more effective than PGE2 but PGE2 was slightly more potent than PGE1 (approximate IC50 values for PGE1 and PGE2 of 1.5 x 10(-8) M and 5 x 10(-9) M, respectively). 3. The EP2-selective agonists, 11-deoxy-PGE1, butaprost and AH13205, and the EP2/EP3-selective agonist, misoprostol, also inhibited PAF-induced aggregation. The rank order of potency for EP2-selective agonists was 11-deoxy-PGE1 > misoprostol > butaprost = AH13205. The protein kinase A inhibitor, KT5720 (10(-6) M), reversed the inhibitory effects of 11-deoxy-PGE1 (10(-6) M) and AH13205 (10(-5) M). 4. The EP1/EP3-selective agonist, sulprostone, and the EP1-selective agonist, 17-phenyl-omega-trinor PGE2, had no significant inhibitory activity when tested at concentrations up to 10(-6) M. The EP4-receptor antagonist, AH23848B, had no effect on PAF-induced aggregation and did affect the inhibitory activity of PGE1. 5. The IP-selective agonist, cicaprost (up to 10(-6) M), and the IP/EP1-receptor agonist, iloprost (up to 10(-5) M), had no significant effect on PAF-induced eosinophil aggregation. However, iloprost significantly augmented the inhibitory effects of a maximally inhibitory concentration of PGE2. 6. PGD2 (10(-5) M) had no effect on eosinophil aggregation and the inhibitory activity of PGE1 on PAF-induced eosinophil aggregation was not altered by the DP-selective receptor antagonist, BWA868C. 7. The results presented here suggest that the inhibition of PAF-induced eosinophil aggregation by prostanoids is mediated by the occupation of EP2-receptors. It is important to note that the effects of naturally occurring prostanoids, such as PGE2, on eosinophil aggregation occur at low concentrations highlighting a potential role for EP2 receptors in regulating eosinophil function in vivo.
Teixeira
M M
MM
Imperial College of Medicine, National Heart and Lung Institute, London.
al-Rashed
S
S
Rossi
A G
AG
Hellewell
P G
PG
D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D002227:Carbazoles; D002449:Cell Aggregation / Q000187:drug effects; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects*; D005260:Female; D006168:Guinea Pigs; D007211:Indoles / Q000633:toxicity; D016595:Misoprostol / Q000494:pharmacology; D010120:Oxytocics / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000494:pharmacology; D011459:Prostaglandins E, Synthetic / Q000494:pharmacology*; D011466:Prostanoic Acids / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000633:toxicity; D011982:Receptors, Prostaglandin / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000897:Anti-Ulcer Agents; D002227:Carbazoles; D007211:Indoles; D010120:Oxytocics; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D011459:Prostaglandins E, Synthetic; D011466:Prostanoic Acids; D011758:Pyrroles; D011982:Receptors, Prostaglandin; D016595:Misoprostol; C081039:AH 13205; C057416:KT 5720; D011493:Protein Kinase C; D000527:Alprostadil; C048491:butaprost; D015232:Dinoprostone; D015230:Prostaglandin D2; C034008:11-deoxyprostaglandin E1