Guinea‐pigs were sensitized with 3 injections of ovalbumin (OA) (1 or 10 μg per animal) using Al(OH)3 and pertussis vaccine as adjuvants at two week intervals. Sensitized guinea‐pigs were challenged with an aerosol of OA (0.1%) over a one hour period and both airway reactivity and cellular content of bronchoalveolar lavage (BAL) fluid were assessed at intervals for up to 7 days. Guinea‐pigs sensitized with 1 μg of ovalbumin responded to an aerosol of OA with increased pulmonary airway eosinophilia, which was evident 1 day after challenge and was present for up to 7 days. Airway hyperreactivity was not detectable in these animals. Guinea‐pigs sensitized with 10 μg of ovalbumin responded to an aerosol of OA with increased pulmonary airway neutrophilia and eosinophilia and with increased airway reactivity which was maximal between 8 and 24 h after exposure to OA. Depletion of circulating platelets or neutrophils, by use of selective antisera, did not alter either the magnitude of eosinophilia or the intensity of airway reactivity in sensitized guinea‐pigs (10 μg) exposed to an aerosol of OA. Pretreatment of sensitized guinea‐pigs (10 μg) for 6 days with AH 21–132, aminophylline, dexamethasone or ketotifen inhibited pulmonary airway eosinophilia, but did not diminish airway hyperreactivity. Neither eosinophil accumulation nor development of airway hyperreactivity was influenced by treatment with mepyramine or salbutamol over a 6 day period before OA inhalation. Although eosinophilia may occur in association with increased airway reactivity in this animal model, there is no evidence of a causal relationship.

1. Intravenous infusion of (+/‐) isoprenaline (1‐100 micrograms kg‐1 h‐1) enhanced airway responses (resistance, RL; and compliance, Cdyn) to histamine (1.0‐1.8 micrograms kg‐1) and bombesin (100‐240 ng kg‐1), whereas airway responses to vagal stimulation remained unchanged. 2. Bilateral vagotomy before intravenous infusion of (+/‐)isoprenaline (100 micrograms kg‐1 h‐1) prevented development of airway hyperreactivity to histamine or bombesin, yet vagotomy after infusion of isoprenaline was without effect. 3. Prior treatment with atropine (1 mg kg‐1) did not influence the capacity of (+/‐)isoprenaline (100 micrograms kg‐1 h‐1) to increase airway reactivity to bombesin. 4. Despite a 500‐fold difference in spasmolytic potency in vivo, infusion of (+)isoprenaline (100 micrograms kg‐1 h‐1) or (‐)isoprenaline (100 micrograms kg‐1 h‐1) increased reactivity of the airways to histamine or bombesin to a comparable extent. 5. Neither adrenaline (100 micrograms kg‐1 h‐1) nor forskolin (600 micrograms kg‐1 h‐1) increased reactivity of the airways to histamine or bombesin. 6. Intravenous infusion of dopamine (100 micrograms kg‐1 h‐1) or noradrenaline (100 micrograms kg‐1 h‐1) increased reactivity of the airways to histamine or bombesin. 7. Intravenous infusion of (+/‐) propranolol (100 micrograms kg‐1 h‐1) increased reactivity of the airways to histamine or bombesin which was partially inhibited by bilateral vagal section. 8. Depletion of circulating platelets by lytic anti‐platelet serum or concomitant infusion of an antagonist of platelet‐activating factor (PAF), ginkgolide B (1 mg kg‐1 h‐1) did not diminish the capacity of (+/‐)isoprenaline (100 micrograms kg‐1 h‐1) to induce hyperreactivity of the airways to histamine or bombesin. 9. These observations indicate that (+/‐)isoprenaline can induce airway hyper‐reactivity by a mechanism unrelated to beta‐adrenoceptor activation, but which is dependent upon intact vagus nerves.

Subcutaneous or intraperitoneal injection of recombinant human granulocyte-macrophage colony-stimulating factor, interleukin 3, or mouse tumour necrosis factor alpha, but not recombinant human interferon gamma, platelet-derived growth factor, or transforming growth factor beta caused selective eosinophilia of the pulmonary airways in the guinea pig. Unlike responses to latelet-activating factor, there was no attendant detectable airway hyperreactivity, but in common with responses to platelet-activating factor, eosinophilia of the airways was prevented by pretreatment with ketotifen or AH 21–132. Cytokines or lymphokines may contribute to pulmonary eosinophilia in diseases such as asthma.

Abstract-Intravenous injection of platelet activating factor (PAF) in anesthetized guinea pigs induces non-selective airway hyperreactivity. This response to PAF was reduced in a dose-dependent manner by systemic administration of established prophylactic anti-asthma drugs (ketotifen, cromoglycate, aminophylline and gluco corticosteroids) and by competitive antagonists of PAF. These inhibitory effects could not be accounted for by antagonism of histamine (H1), serotonin or peptido leukotrienes receptors; parasympatholytic activity; cyclo-oxygenase or lipoxy genase inhibition; mast cell stabilization; or bronchodilatation.Infusion or injection of PAF to induce airway hyperreactivity in the guinea pig may provide a prospective test for prophylactic anti-asthma drugs.

SDZ PCO 400 evoked dose‐related relaxation of isolated airway smooth muscle. For human bronchus precontracted by endogenous tone or addition of carbachol (10−5 m), IC50 values were 1.74 μm and 1.82 μm respectively. With guinea‐pig trachea contracted by endogenous tone, a comparable IC50 (1.79 μm) was observed, but no IC50 (< 100 μm) could be determined following contraction by carbachol (10−6 m). Airway obstruction induced by intravenous bombesin in the anaesthetized ventilated guinea‐pig was diminished by intravenous injection of SDZ PCO 400 (ID50 54 μg kg−1) or by introduction into the duodenum (ID50 1.0 mg kg−1). Inhalation of nebulized SDZ PCO 400 (0.1 mg kg−1) diminished airway obstruction due to intravenous injection of histamine (3.2–5.6 μg kg−1) for up to 20 min. Increased bronchoconstrictor responses to bombesin (180–240 ng kg−1) following intravenous infusion of platelet activating factor (PAF) or (±)‐isoprenaline, or to histamine (1.0–3.2 μg kg−1) following intravenous injections of immune complexes, were suppressed following concomitant intravenous infusion of SDZ PCO 400 (ID50 0.3 mg kg−1 h−1, 1.0 mg kg−1 h−1 and 0.1 mg kg−1 h−1 respectively). Intravenous injection of SDZ PCO 400 (0.1 mg kg−1) effected transient (< 10 min) inhibition of histamine‐induced bronchospasm, yet diminished, for prolonged periods [up to 40 min] the enhanced bronchoconstrictor responses to histamine that followed intravenous injections of immune complexes. The capacity of SDZ PCO 400 to resolve such established airway hyperreactivity was prevented by prior intraduodenal instillation of a potassium channel antagonist, glibenclamide (30 mg kg−1). In sensitized guinea‐pigs, SDZ PCO 400 inhaled as a dry powder (5.7 mg kg−1) suppressed development of allergic airway hyperreactivity to histamine (1.8–3.2 μg kg−1, i.v.), but failed to diminish accumulation of eosinophils or other inflammatory cells within the airway lumen 24 h after inhalation of ovalbumin. Preincubation (30 min) of isolated sensitized trachea of guinea‐pig with SDZ PCO 400 (10−5−10−4 m) did not influence contractile responses to ovalbumin. However in anaesthetized sensitized guinea‐pigs, insufflation of SDZ PCO 400 (1.25 mg) as a powder substantially diminished airway obstruction that followed inhalation of ovalbumin. This effect was prevented by prior vagal section. It is concluded that SDZ PCO 400 reduces airway obstruction not only through direct actions on airway smooth muscle but also by impairing the expression of airway hyperreactivity, without directly influencing inflammatory events in the airways.