title: The role of prostanoid TP- and DP-receptors in the bronchoconstrictor effect of inhaled PGD2 in anaesthetized guinea-pigs: effect of the DP-antagonist BW A868C.
abstract: 1. In anaesthetized, pump-ventilated guinea-pigs, bolus intravenous injection of prostaglandin D2 (PGD2 5-160 micrograms kg-1) caused a dose-dependent rise in both heart rate and systemic mean arterial blood pressure with only a small monophasic rise in pulmonary inflation pressure (PIP). 2. In contrast, inhaled PGD2 (0.1-1 mg ml-1, 30s) provoked a substantial concentration-dependent biphasic rise in PIP. The bronchoconstrictor action of inhaled PGD2 was accompanied by minimal cardiovascular effects. 3. The 3-benzyl substituted hydantoin BW A868C (0.1-1 mg kg-1 i.v.) a novel prostanoid DP-receptor antagonist, had no significant effect on the cardiovascular or bronchoconstrictor effects of intravenously administered or inhaled PGD2. 4. However, BW A868C (0.1-1 mg kg-1 i.v.) did inhibit the hypotensive actions of the DP-receptor agonist, BW 245C (1-3 micrograms kg-1 i.v.). 5. The prostanoid TP-receptor antagonist BM 13.177 (2.5 mg kg-1 i.v.) strongly inhibited the bronchoconstrictor effect of inhaled PGD2, abolishing the first phase of this response and reducing the peak increase in PIP provoked by PGD2 (0.1 or 1 mg ml-1 for 30 s), by 67 +/- 16% and 44 +/- 5% respectively. 6. A combination of BW A868C (0.1 or 1 mg kg-1 i.v.) with BM 13.177 (2.5 mg kg-1 i.v.) produced no greater inhibition of the bronchoconstrictor effect of inhaled PGD2 than that seen with BM 13.177 (2.5 mg kg-1 i.v.) alone. 7. Neither bilateral vagotomy, nor selective inhibition of arachidonate cyclo-oxygenase with indomethacin or 5-lipoxygenase with the novel acetohydroxamic acid BW A4C, significantly reduced the bronchoconstrictor effect of inhaled PGD2. 8. These findings indicate that the bronchoconstrictor effect of inhaled PGD2 in guinea-pigs in vivo is mediated primarily through direct TP-receptor activation and not through actions on DP-receptors.
authors.affiliation: Department of Pharmacology, Wellcome Research Laboratories, Beckenham, Kent.
authors.forename: S
authors.initials: S
authors.lastname: Hamid-Bloomfield
authors.forename: A N
authors.initials: AN
authors.lastname: Payne
authors.forename: A A
authors.initials: AA
authors.lastname: Petrovic
authors.forename: B J
authors.initials: BJ
authors.lastname: Whittle
mesh_terms: D000280:Administration, Inhalation; D000758:Anesthesia; D000818:Animals; D044482:Benzeneacetamides; D001980:Bronchi / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors; D006168:Guinea Pigs; D006827:Hydantoins / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000008:administration & dosage / Q000494:pharmacology*; D011457:Prostaglandins D; D011982:Receptors, Prostaglandin / Q000502:physiology*; D012129:Respiratory Function Tests; D013449:Sulfonamides / Q000494:pharmacology; D013928:Thromboxane A2; D014628:Vagotomy
chemical_list: D044482:Benzeneacetamides; D016861:Cyclooxygenase Inhibitors; D006827:Hydantoins; D006877:Hydroxamic Acids; D016859:Lipoxygenase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011457:Prostaglandins D; D011982:Receptors, Prostaglandin; D013449:Sulfonamides; C056614:N-(3-phenoxycinnamyl)acetohydroxamic acid; C058848:BW A868C; D013928:Thromboxane A2; C040624:sulotroban; D015230:Prostaglandin D2; D007213:Indomethacin