Pharmacological studies of platelet-activating factor (PAF)-induced augmentation of response to histamine in guinea-pigs

An acute increase in airway response to histamine produced by platelet activating factor (PAF) was investigated pharmacologically in guinea-pigs. (1) The airway response to histamine (3 micrograms/kg) measured as pulmonary pressure was increased 8 min after injection of PAF at a dose of 25 ng/kg without affecting the numbers of leukocytes (macrophages, eosinophils, neutrophils and lymphocytes) in bronchoalveolar lavage fluid and airway capillary permeability. (2) To investigate the mechanism responsible for the PAF (25 ng/kg)-induced airway hyperresponsiveness to histamine, the effects of CV-3988 (a PAF-antagonist), ONO-1078 (a leukotriene (LT) antagonist), AA-861 (a 5-lipoxygenase inhibitor), indomethacin (a cyclooxygenase inhibitor), OKY-046 (a thromboxane A2 (TXA2) synthetase inhibitor) and S-1452 (a TXA2 receptor antagonist) were examined. Simultaneously, to investigate the direct antagonistic effects of these drugs on PAF-induced response, the effects of above agents on PAF (150 ng/kg) induced bronchoconstriction were examined. CV-3988 completely inhibited both reactions, while ONO-1078 and AA-861 had no effect on both reactions. OKY-046, S-1452 and indomethacin inhibited PAF-induced bronchoconstriction more potently than PAF-induced airway hyperresponsiveness. These results indicate that inflammatory response is not involved in the onset of PAF-induced acute airway hyperreactivity. Results also suggest that TXA2 but not LT may play a role in the onset of this airway hyperreactivity and the role of TXA2 in hyperreactivity is less important than in PAF-induced bronchoconstriction.