We have examined the protective actions of
RP 58802B, a novel beta 2-adrenoceptor agonist, administered by the inhaled and oral routes in the anaesthetized and conscious guinea-pig against
bronchospasm induced by
histamine or
antigen (
ovalbumin). We have also examined the effects of
RP 58802B on airway reactivity and inflammatory cell infiltration in
platelet-activating factor (PAF) (
aerosol)-induced
bronchial hyperreactivity and on PAF (tracheal instillation)-induced microvascular leakage in the guinea-pig. Nebulized
RP 58802B produced a rapid onset and long lasting inhibition of
histamine-induced
bronchospasm in the anaesthetized guinea-pig (EC50 = 3.2 +/- 0.9 micrograms/ml; duration greater than 90 min). Given orally,
RP 58802B (5 mg/kg, 60 min before challenge) produced a greater than three-fold shift to the right of the dose-response curve and depressed the maximum response to
histamine by 39 +/- 11%. Increasing the concentration to 25 mg/kg had no futher effect. Similar protection was still seen 4 h after oral dosing. In conscious guinea-pigs,
RP 58802B (5 or 25 mg/kg, p.o. 60 min before challenge) significantly attenuated
antigen-induced dyspnoea with the time to severe dyspnoea increasing from 170 +/- 32 to 325 +/- 32 s at the higher dose of
drug.
RP 58802B (10 or 25 mg/kg, p.o. 60 min before exposure to PAF) prevented the development of
bronchial hyperreactivity. Although PAF-induced
bronchial hyperreactivity was not accompanied by an increase in the number of pulmonary eosinophils,
RP 58802B (25 mg/kg p.o.) reduced the numbers of eosinophils recovered by lavage.
RP 58802B (10 mg/kg p.o.) significantly inhibited PAF-induced microvascular leakage into guinea-pig lung. These data suggest that
RP 58802B, in addition to being a potent and long acting
bronchodilator, may have a prophylactic role in preventing
bronchial hyperreactivity and in reducing plasma exudation into the lungs.