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 The effect of a novel series of orally-active acetohydroxamic acid inhibitors of arachidonate 5-lipoxygenase on 'leukotriene-dependent' anaphylactic bronchoconstriction has been investigated in anaesthetized, pump-ventilated guinea-pigs actively sensitized to ovalbumin (OA). In a complementary series of experiments, the pharmacokinetics of these compounds in the plasma compartment following oral administration to guinea-pigs has also been investigated. 2 In animals pretreated with mepyramine (2mgkg-, i.v.) and indomethacin (10mgkg-, i.v.) and challenged with antigen aerosol (OA 10mgmlP1; 5s) compounds BW A4C, BW A137C and BW A797C (10-200mgkg-1, p.o., 1 h pre-challenge) markedly reduced that component of anaphylactic bronchoconstriction shown to be 'leukotriene-dependent'. 3 The maximum degree of inhibition (up to 75%) of 'leukotriene-dependent' anaphylactic bronchoconstriction by these three compounds was equivalent to that seen with the leukotriene antagonist FPL 55712 (10 mg kg-', i.v.).4 The peak levels of unchanged acetohydroxamic acids in the plasma compartment occurred 0.5 h after their oral administration and were as follows: BW A4C: 11.3 + 3.9; BW A137C: 7.6 + 2.4; BW A797C: 3.9 + 1.3 yg ml -1 plasma. 5 The inhibition by BW A4C and BW A137C (5Omgkg, p.o.) of 'leukotriene-dependent' anaphylactic bronchospasm persisted for up to 3 and 4 h respectively but did not extend to 6 h. The decline in inhibitory activity paralleled the fall in the concentration of unchanged drug in the plasma compartment over this time period. 6 The results of the present study are consistent with BW A4C, BW A137C and BW A797C attenuating 'leukotriene-dependent' bronchial anaphylaxis in anaesthetized guinea-pigs by selective inhibition of arachidonate 5-lipoxygenase.

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1 The possible acute occurrence of airway hyperreactivity after immediate-type bronchial anaphylaxis has been investigated in anaesthetized guinea-pigs actively sensitized to ovalbumin (OA). 2 Aerosol challenge (OA 10 mgml-1, 5s) provoked immediate bronchoconstriction which was substantially, although incompletely, reversed by isoprenaline (Iso) infusion (1 ,igkg1 min 1) for 10 min). 3 Bronchoconstrictor responses to 5-hydroxytryptamine (5-HT) were enhanced in challenged animals when compared to those in non-challenged animals that had also received Iso. This was seen as a leftward shift in the location of the dose-response curve for the bronchoconstrictor effect of 5-HT (dose-ratio 2.45, 95% confidence limits 1.77-3.38; P < 0.01). This phenomenon was associated with pulmonary infiltration of polymorphonuclear leukocytes, which was not modified by Iso treatment.4 Iso infusion alone caused a slight enhancement of airway reactivity seen as a small leftward shift of the dose-response curve for the bronchoconstrictor effect of 5-HT (dose-ratio 1.51, 95% confidence limits 1.07-2.13; P < 0.05). 5 These results support a causal relationship between acute pulmonary inflammation and airway hyperreactivity in an animal model of human allergic asthma.