Involvement of capsaicin-sensitive nerves in the bronchomotor effects of arachidonic acid and melittin: a possible role for lipoxin A4.
1. Functional studies have been performed to evaluate the potential involvement of capsaicin-sensitive nerves in the bronchomotor responses evoked by lipid mediators produced from the metabolic breakdown of arachidonic acid (AA) in the guinea-pig bronchus. 2. In the presence of indomethacin, the exogenous administration of AA (0.01-1 mM) produced a concentration-dependent contractile response in guinea-pig isolated bronchial rings. AA-induced contractions were augmented by epithelium-removal and by thiorphan (10 microM), an inhibitor of tachykinin breakdown. A sustained downward and rightward displacement of the complete concentration-response curve to AA was observed after in vitro capsaicin desensitization. 3. BWA4C (1 microM), a selective inhibitor of 5-lipoxygenase, shifted the AA concentration-response curve to the right. In the presence of this inhibitor, capsaicin desensitization did not have any further inhibitory action. 4. A potent, concentration-dependent and capsaicin-sensitive bronchoconstrictor effect was also observed with the polypeptide, melittin (10 nM-1 microM), an activator of phospholipase A2, which therefore should generate endogenous AA. 5. In vitro capsaicin-desensitization produced a significant reduction of the bronchomotor responses evoked by lipoxin A4 (1-6 microM), but not of those elicited by other lipoxygenases products such as leukotriene D4 (1-100 nM) or by 15-hydroxyeicosatetraenoic acid (15-HETE, 1-6 microM). 6. These findings indicate that lipoxin A4 but not leukotriene D4 or 15-HETE, might be one of the lipoxygenase mediators of excitatory effects of AA on capsaicin-sensitive sensory nerves.
Manzini
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Istituto Farmacobiologico Malesci, Research Laboratories, Firenze, Italy.
Meini
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D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology*; D044482:Benzeneacetamides; D001980:Bronchi / Q000187:drug effects / Q000294:innervation; D002211:Capsaicin / Q000494:pharmacology*; D004848:Epithelium / Q000502:physiology; D006168:Guinea Pigs; D006877:Hydroxamic Acids / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology / Q000502:physiology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D044045:Lipoxins; D016859:Lipoxygenase Inhibitors; D008297:Male; D008555:Melitten / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation*; D011480:Protease Inhibitors / Q000494:pharmacology; D013189:SRS-A / Q000494:pharmacology
D001095:Arachidonic Acids; D044482:Benzeneacetamides; D006877:Hydroxamic Acids; D006893:Hydroxyeicosatetraenoic Acids; D044045:Lipoxins; D016859:Lipoxygenase Inhibitors; D011480:Protease Inhibitors; D013189:SRS-A; C040527:lipoxin A4; C056614:N-(3-phenoxycinnamyl)acetohydroxamic acid; D008555:Melitten; D016718:Arachidonic Acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D002211:Capsaicin; D007213:Indomethacin