Antagonism of PGD2 vasodepressor responses in the rat in vivo by the novel, selective antagonist, BW A868C.
1. Bolus intravenous injection of prostaglandin D2 (PGD2, 1-160 micrograms kg-1), the hydantoin prostanoid BW245C (0.25-160 micrograms kg-1) or prostacyclin (PGI2, 0.05-0.5 microgram kg-1) caused a dose-dependent fall in systemic arterial blood pressure (BP) in the anaesthetized rat, lasting 2-4 min. 2. Intravenous infusion of the novel 3-benzyl substituted hydantoin, BW A868C (1-10 micrograms kg-1 min-1), in doses that had no direct effect on BP, dose-dependently reduced the vasodepressor action of PGD2. 3. Bolus injection of BW A868C (30 and 100 micrograms kg-1, i.v.) likewise dose-dependently antagonized the vasodepressor responses to PGD2, causing a 3.4 and 13.2 fold rightward shift of the dose-response curve. 4. The thromboxane-receptor antagonist, BM 13.177 (2.5 mg kg-1 i.v.) had little effect on the PGD2 vasodepressor responses, suggesting minimal contribution of a PGD2 interaction at thromboxane receptor-sites in the systemic vasculature of this species. 5. BW A868C (10 micrograms kg-1 min-1 i.v.) caused a rightward shift (59 fold) of the dose-response relationship for BW245C, the putative PGD2-receptor agonist. This antagonism lasted for at least 1h after termination of the BW A868C infusion. Higher doses of BW A868C (20-100 micrograms kg-1 min-1) caused no further antagonism of the vasodepressor responses to BW245C, suggesting that this prostanoid also acts at vascular receptors other than of the DP-type. 6. BW A868C (10 micrograms kg-1 min-1, i.v.) failed to alter the vasodepressor actions of prostacyclin. 7. These findings in the rat in vivo support the characterization of BW A868C as a potent and selective antagonist of the cardiovascular actions of PGD2 at the DP-receptor.
Hamid-Bloomfield
S
S
Department of Pharmacology, Wellcome Research Laboratories, Beckenham, Kent.
Whittle
B J
BJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D011464:Epoprostenol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006827:Hydantoins / Q000494:pharmacology*; D007262:Infusions, Intravenous; D008297:Male; D015230:Prostaglandin D2 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology
D006827:Hydantoins; D011982:Receptors, Prostaglandin; D013449:Sulfonamides; C058848:BW A868C; C040624:sulotroban; C030669:BW 245C; D011464:Epoprostenol; D015230:Prostaglandin D2