Effects of CIS-19, a novel PAF receptor antagonist, on PAF-induced eosinophil recruitment and enhancement of superoxide anion generation in guinea-pigs

We examined the effects of a novel plateletactivating factor (PAF) receptor antagonist, CIS-19 [cis-2-(3,4-dimethoxyphenyl)-6-isopropoxy-7-methoxyl-1-(N-methylformamido)-1,2,3,4-tetrahydronaphthalene], on PAF-induced inflammatory cells recruitment into airways and enhancement of superoxide anion (O_inf2^sup-) generation from cells retrieved by bronchoalveolar lavage (BAL) in urethane-anesthetized guinea-pigs. Administration of PAF (30 ng/kg, Lv.) produced a selective increase of eosinophils into airways, but no significant increase of the number of macrophages, neutrophils or lymphocytes. CIS-19 (2.5 and 5 mg/kg, Lv.) significantly inhibited the eosinophil recruitment induced by PAF. In vitro, PAF, phorbol 12-myristate 13-acetate (PMA) and N-formyl-methionyl-leucyl-phenylalanine (FMLP) directly stimulated generation of O_inf2^sup-from BAL cells in a concentration-dependent manner. CIS-19 (10^-7 - 10^-4 M) inhibited production of O_inf2^sup-induced by PAF (10^-7 M) in a concentration-dependent manner with an EC₅₀ value of 0.84 μM, but not induced by PMA (0.5 μg/ml) or FMLP (10^-7 M). Administration of PAF (5 ng/kg, i.v.) enhanced markedly PMA (0.5 μg/ml) and FMLP (10^-7 M)-induced generation of O_inf2^sup-by 80.2% and 51.3%, respectively. The enhancing effect of PAF was maximal in cells harvested 5 min after the addition of PAF and then declined to baseline level at 60 min. These responses were inhibited by administration of CIS-19 (0.5-2.5 mg/kg, i.v.) or BN 52021(5 mg/kg, i.v.). The results indicate that CIS-19 is potent in inhibition of PAF-induced airway inflammatory response and may have therapeutic potential as an anti-inflammatory drugs.