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

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Abstract
1 In anaesthetized, pump-ventilated guinea-pigs, bolus intravenous injection of prostaglandin D2 (PGD2 5–160 μg 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 Diphasic 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 μg 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 30s), 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.