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The effect of an atypical beta-adrenoceptor agonist, BRL-35135 on leukotriene B4-induced-guinea pig eosinophil chemotaxis was studied. BRL-35135 and SC-41930 (leukotriene B4-antagonist) inhibited the chemotaxis in a concentration-dependent manner (IC50 = 9.0 x 10(-6) and 2.6 x 10(-7) M, respectively). However, isoproterenol, fenoterol and another atypical beta-agonist, BRL-37344 had no effects. The inhibitory effect of BRL-35135 was not affected by (+/-)-propranolol (10(-4) M). In contrast, the nonselective beta-adrenoceptor antagonist, (-)-alprenolol (10(-4) M) dextrally shifted the inhibitory curve of BRL-35135. The response to BRL-35135 was antagonized in a competitive manner by (-)-alprenolol, with the slope of the Schild plot close to unity, and a pA2 value of 5.62. These findings suggest that guinea pig eosinophils possess an "atypical receptor", which differs from either beta 1-, beta 2- or atypical beta-adrenoceptor on guinea pig ileum, and through which eosinophil chemotaxis can be modulated by BRL-35135.

The effect of a selective platelet-activating factor (PAF) receptor antagonist, SM-10661, on antigen-induced dual asthmatic response and leukocyte infiltration into the airways of actively sensitized conscious guinea pigs was investigated. The animals were pretreated with mepyramine maleate (10 mg/kg i.p.) and then challenged with ovalbumin. The inhalation of ovalbumin caused an immediate decline in specific airway conductance (sGaw) which peaked at 5 min after the challenge. sGaw gradually returned to the baseline 6 hr after the challenge. After the early asthmatic response (EAR), a second phase change, a late asthmatic response (LAR) in sGaw peaking at 17-20 hr was observed. When 1% w/v disodium cromoglycate was inhaled for 2 min on two occasions, EAR was not affected, but LAR was significantly inhibited. Oral administration of 50 mg/kg fenoterol (30 min before challenge) significantly inhibited EAR, but had no significant effect on LAR. SM-10661 administered orally 1 hr before the challenge inhibited EAR dose-dependently (50% inhibitory dose (ID50); 59 mg/kg, but was even more effective against the LAR (ID50); 13-16 mg/kg). When 30 mg/kg of SM-10661 was administered orally 6 hr after ovalbumin challenge, LAR was completely inhibited. The number of total cells, macrophages and eosinophils in bronchoalveolar lavage fluids rose significantly 17 hr after antigen challenge compared to that observed after saline challenge. The number of neutrophils and lymphocytes also increased in response to the ovalbumin challenge, but not significantly. SM-10661 (30 mg/kg) administered orally 1 hr before the challenge significantly inhibited the increase in total cells, macrophages and eosinophils.(ABSTRACT TRUNCATED AT 250 WORDS)

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