1 In anaesthetized, pump-ventilated guinea-pigs, bolus intravenous injection of prostaglandin D2 (PGD2 5-160jg kg-') 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 mgml-', 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 mgkg-' 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 (0.1-1mgkg-' i.v.) did inhibit the hypotensive actions of the DP-receptor agonist, BW 245C (1-3 pg kg-' i.v.). 5 The prostanoid TP-receptor antagonist BM 13.177 (2.5mgkg-' 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 mgml-'1 for 30s), by 67 + 16% and 44 + 5% respectively. 6 A combination of BW A868C (0.1 or 1 mg kg' i.v.) with BM 13.177 (2.5mg kg ' i.v.) produced no greater inhibition of the bronchoconstrictor effect of inhaled PGD2 than that seen with BM 13.177 (2.5 mg kg'-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.

1 The anti-aggregatory prostanoid, prostaglandin D2 (PGD2) does not completely inhibit ADPinduced aggregation ofguinea-pig platelets and thus produces a bell-shaped dose-inhibition curve. The nature of this bell-shaped curve has now been investigated in guinea-pig platelet-rich plasma.2 Two selective thromboxane receptor antagonists, 13-aza-prostanoic acid (13-AZA; 16-64.4tiM) and BM 13.177 (5.9-29.8 pM), converted PGD2 to a full inhibitor of aggregation in a dose-related manner.3 The putative platelet PGD2 receptor antagonist, N-0164 (75 lM) also converted PGD2 to a full inhibitor of platelet aggregation. In contrast to 13-AZA and BM 13.177, higher concentrations of N-0164 (380 and 760 gM) caused a dose-related rightward shift of the PGD2 dose-inhibition curve.4 The thromboxane receptor antagonism of N-0164 was confirmed in studies in which the doseaggregation curve to U-46619, a thromboxane mimetic, was competitively antagonized with a pA2 value of 4.67 and a slope of 1. 13, comparable to that of 13-AZA. 5The results show that N-0164 acts as both a platelet PGD2 and thromboxane-receptor antagonist in both human and guinea-pig platelet-rich plasma. 6 The results further indicate that PGD2 can interact at thromboxane receptors in guinea-pig platelets.

1 Bolus intravenous injection of prostaglandin D2 (PGD2, 1-160pgkg-1), the hydantoin prostanoid BW245C (0.25-160 pg kg 1) or prostacyclin (PG12, 0.05-0.5 pgkg-1) caused a dose-dependent fall in systemic arterial blood pressure (BP) in the anaesthetized rat, lasting 2-4 min. 4 The thromboxane-receptor antagonist, BM 13.177 (2.5mgkg-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.gkg-1min-' 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 1 h after termination of the BW A868C infusion. Higher doses of BW A868C (20-100pgkg-1 min-) caused no further antagonism of the vasodepressor responses to BW245C,gesting that this prostanoid also acts at vascular receptors other than of the DP-type. 6 BWA868C(l0pgkg-1min- ',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.