Different responsiveness of prostaglandin D₂‐sensitive systems to prostaglandin D₂ and its analogues

Abstract

1 Prostaglandin D2 (PGD2) and six PGD2 analogues were used to classify responsiveness of several PGD2-sensitive systems. The analogues used were 9P-PGD2, 5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin (BW245C), 19,, PGD2 amide, PGD2 N-monomethylamide and 1 l-keto-I5o-hydroxy-A59"12-prostenoic acid (9-deoxy-A9"12-PGD2). The PGD2-sensitive systems examined were human platelets, rat peritoneal mast cells, rabbit transverse stomach strip, guinea-pig tracheal ring chain and helical strip of the dog cerebral artery.2 PGD2, 9p-PGD2 and BW245C inhibited the aggregation of human platelets, increased adenosine 3':5'-cyclic monophosphate (cyclic AMP) in rat mast cells and relaxed the rabbit stomach strip. The rank order of potency was BW245C> PGD2>9p-PGD2. PGD2 amide and PGD2 N-monomethylamide were inactive in the former two systems but elicited relaxant activity on the rabbit stomach strip. 17-Phenyl-PGD2 was virtually inactive in the above three systems. 3 PGD2 and 1 7-phenyl-PGD2 contracted the guinea-pig tracheal ring chain and the helical strip of dog cerebral arteries with almost equal potency. 9l-PGD2 and BW245C antagonized competitively the contractile action of PGD2. PGD2 amide and PGD2 N-monomethylamide showed weak agonistic actions in the tracheal preparation. 4 9-Deoxy-A9 I2-PGD2, showing stronger growth inhibition than PGD2 on cultured tumour cells, was inactive in human platelets, rat mast cells and guinea-pig trachea, and elicited contractile response in the rabbit stomach strip. 5 These results indicate the presence of three groups of PGD2-sensitive systems that respond differently to PGD2 and its analogues. IntroductionProstaglandin D2 (PGD2) is one of the prostaglandin which is ubiquitously formed and present in mammalian tissues (Nugteren & Hazelhof, 1973;Ikai et al., 1984). Various actions ofthis prostaglandin have been reported, which include the anti-aggregatory activity on platelets of several species (Whittle et al., 1978), the contraction of airway smooth muscle (Hamberg et al., 1975;Schneider & Drazen, 1980), inflammatory effects (Flower et al., 1976;Soter et al., 1983), and the action on mast cells (Holgate et al., 1980). PGD2 also induces either contractions or relaxations in several vascular and gastrointestinal smooth muscle preparations (Horton & Jones, 1974;Whittle et al., 1979;Toda, 1982a). Recently CNS effects ofthis prostaglan-'Author for correspondence. din such as hypothermia and induction of sleep have been reported in rodents (Ueno et al., 1982a, b). In addition, inhibition of tumour cell proliferation by PGD2 and its dehydration derivatives, 9-deoxy-A9-PGD2 and 9-deoxy-A9"2-PGD2 has also been described (Fukushima et al., 1982a,b;Kikawa et al., 1984). However, whether these actions are mediated via a single and identical PGD2 receptor or several PGD2 receptors exist for each action has remained unclarified. It is also likely that PGD2 acts on other prostaglandin or thromboxane receptors to elicit responses in some of the systems. A specific PGD2 receptor was identifi...

Dominant Expression of Rat Prostanoid DP Receptor mRNA in Leptomeninges, Inner Segments of Photoreceptor Cells, Iris Epithelium, and Ciliary Processes

“…2), whereas it was the strongest in human retina, among other tissues examined (Boie et al, 1995). Species-specific functions of PGD 2 have been reported in a variety of pharmacological assays (Narumiya and Toda, 1985), which is likely due to diversity of the tissue distribution profile of the reception system for PGD2, as shown here.…”

Essential role for hematopoietic prostaglandin D2 synthase in the control of delayed type hypersensitivity

“…Therefore, inguinal lymph nodes were excised from mBSA-sensitized and -challenged animals and lymph-node-derived cells incubated with BW245C (DP1 agonist), 15R-PGD 2 (DP2 agonist), or 15d-PGJ 2 for 24 h, followed by a determination of lymphocyte proliferation and IL-2 production. The concentrations of BW245C used were based on those shown to activate the DP1 receptor (0.9-2.5 nM) (14,15), whereas those for 15R-PGD 2 were of a concentration shown to activate the DP2 receptor (1 M) (16). The 15d-PGJ 2 was used at levels known to alter various proinflammatory signaling pathways and protein expression (17).…”

Prostaglandin D2 is a potent chemoattractant for human eosinophils that acts via a novel DP receptor

“…Similarly, the existence of a second PGD 2 receptor may clarify some of the discrepant reports in the literature documenting various effects of PGD 2 that were not readily explained by its interaction with DP 1 receptors accompanied by activation of adenylyl cyclase. 48 Some of these effects may be due to interaction with receptors for other prostanoids, as PGD 2 has a relatively high affinity for FP receptors 32,49 and PGD 2 -mediated bronchoconstriction has been reported to be due to stimulation of TP receptors. 33,34 In contrast, some other effects of PGD 2 , such as those on epithelial cell ion transport, 50 are difficult to explain on the basis of classic prostanoid receptors and may be due to stimulation of DP 2 receptors.…”