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.
Department of Pharmacology, Gifu Pharmaceutical University, Japan.
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Sakurai
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Yamaguchi
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Iwama
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Nagai
D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016084:Bronchoconstriction / Q000187:drug effects; D002199:Capillary Permeability; D002867:Chromones / Q000494:pharmacology; D004347:Drug Interactions; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D007958:Leukocyte Count; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors; D008297:Male; D008689:Methacrylates / Q000494:pharmacology; D010742:Phospholipid Ethers / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011312:Pressure; D012143:Respiratory Physiological Phenomena; D012137:Respiratory System / Q000098:blood supply / Q000187:drug effects*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors
D016227:Benzoquinones; D001643:Bridged Bicyclo Compounds; D002867:Chromones; D005229:Fatty Acids, Monounsaturated; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors; D008689:Methacrylates; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; C056566:S 145; D013928:Thromboxane A2; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; D006632:Histamine; C037913:CV 3988; C034364:ozagrel; C047681:pranlukast; D007213:Indomethacin