Contributions of thromboxane and leukotrienes to PAF-induced impairment of lung function in the rat.
This study was carried out to further clarify the role of eicosanoids in platelet-activating factor (PAF)-induced pulmonary vasoconstriction, bronchoconstriction, and edema formation in the isolated perfused rat lung. Infusion of PAF into the isolated perfused rat lung caused vasoconstriction [mean effective concn (EC50) = 0.88 nmol], caused bronchoconstriction (EC50 = 0.71 nmol), and increased the capillary filtration coefficient (EC50 = 1.4 nmol). Two minutes after injection of 50 nmol PAF, a high thromboxane concentration (3,000 pg/ml) and a low peptidoleukotriene concentration (150 pg/ml) were found in the effluent perfusate. PAF-induced vaso- and bronchoconstriction were unaffected by the non-redox 5-lipoxygenase inhibitor ZM-230,487 but were markedly attenuated by inhibition of cyclooxygenase with acetylsalicylic acid or thromboxane-receptor antagonism with BM-13177. Dual inhibition of cyclooxygenase and 5-lipoxygenase had the most pronounced inhibitory effect on PAF-induced vaso- and bronchoconstriction. None of the inhibitors tested prevented the increase in vascular permeability. We conclude that thromboxane is the major vasoconstrictor and bronchoconstrictor induced by PAF, whereas leukotrienes contribute a significant but minor part in this system. PAF-induced microvascular permeability was not inhibited by blockade of arachidonate metabolism and therefore seems to be mediated by a mechanism independent of eicosanoids.
Department of Biochemical Pharmacology, University of Konstanz, Germany.
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Uhlig
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Wollin
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Wendel
D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005260:Female; D015289:Leukotrienes / Q000502:physiology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008168:Lung / Q000187:drug effects*; D009929:Organ Size / Q000502:physiology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D013931:Thromboxanes / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects
D016861:Cyclooxygenase Inhibitors; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D010972:Platelet Activating Factor; D017482:Receptors, Thromboxane; D013931:Thromboxanes