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Anaphylactic bronchoconstriction provoked by aerosol challenge, and its pharmacological modulation, has been investigated in anaesthetized pump‐ventilated guinea‐pigs actively sensitized to ovalbumin (OA). Aerosol challenge (OA 0.03–10 mg ml−1) provoked immediate bronchoconstriction, the degree of which, and its rate of development, was directly related to antigen concentration. Concomitant changes in heart rate and systemic arterial blood pressure following aerosol challenge were reduced compared with systemic (OA, 1 mg kg−1 i.v.) challenge. Unlike systemic challenge, aerosol challenge did not cause a concomitant fall in either circulating leukocyte or platelet count. When a submaximal (microshock) aerosol challenge stimulus (OA, 0.3 mg ml−1, 5 s) was employed, bronchoconstriction was markedly reduced by mepyramine (2 mg kg−1 i.v.). The residual component of bronchoconstriction was enhanced by indomethacin (10 mg kg−1 i.v.), an effect which was reversed by either BW755C (30 mg kg−1 i.v.) or FPL55712 (10 mg kg−1 i.v.). When a supramaximal (macroshock) aerosol challenge stimulus (OA, 10 mg ml−1, 5 s) was employed, bronchoconstriction was also markedly reduced by mepyramine. Residual bronchoconstriction was not altered by indomethacin, slowed but not reduced by indomethacin plus BW755C, and substantially reduced by indomethacin plus FPL55712. The successive incremental antagonism of anaphylactic bronchoconstriction by mepyramine and mepyramine plus indomethacin and FPL55712 indicates that the predominant mediators involved are histamine and leukotrienes, respectively. The failure of indomethacin plus BW755C to inhibit the mepyramine‐resistant bronchoconstriction provoked by OA macroshock may reflect the increased generation of leukotrienes via a 5‐lipoxygenase isoenzyme resistant to inhibition by BW755C. Aerosol challenge of actively sensitized anaesthetized guinea‐pigs by this method may be a useful model of human allergic bronchoconstriction, particularly when the effects of a drug given itself as an aerosol are being evaluated.

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.