Involvement of capsaicin‐sensitive nerves in the bronchomotor effects of arachidonic acid and melittin: a possible role for lipoxin A₄

Abstract

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 (10pM), 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 pM), 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 (10nM-lipM), an activator of phospholipase A2, which therefore should generate endogenous AA. 5In vitro capsaicin-desensitization produced a significant reduction of the bronchomotor responses evoked by lipoxin A4 (1-6,UM), but not of those elicited by other lipoxygenases products such as leukotriene D4 (1-lOOnM) or by 15-hydroxyeicosatetraenoic acid (15-HETE, 1-6pM). 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.

Effects of chronic airway inflammation on the activity and enzymatic inactivation of neuropeptides in guinea pig lungs.

“…We and others have previously shown that a variety of bronchoactive mediators release tachykinins from guinea pig lungs (39)(40)(41)(42). Therefore, the loss of NEP activity observed in antigen-exposed lungs could result in an enhanced response to tachykinins released by other bronchoactive mediators.…”

Lipoxins in asthma: potential therapeutic mediators on bronchial inflammation?

“…Capsaicin desensitization abolished subsequent motor responses to capsaicin itself or stimulation of NANC nerves, while it left unaffected cholinergic responses. Endogenously generated LXA 4 are hypothesized to act partially through the activation of capsaicin‐sensitive sensory nerve fibers (115) and explain the excitatory effects of AA on capsaicin‐sensitive sensory nerves (116). Other studies on isolated human bronchi showed afterwards that capsaicin might exert a contractile (117), relaxant (118) or biphasic action (119) as a function of capsaicin concentration.…”

A possible role of lipoxygenase in the activation of vanilloid receptors by anandamide in the guinea‐pig bronchus

“…These compounds include 12‐ and 15‐hydroperoxyeicosatetraenoic acids (HPETE) and 5‐ and 15‐hydroxyeicosatetraenoic acids (HETE) and leukotriene B 4 . It has also been shown that lipoxygenase products, including lipoxin A 4 , may be mediators of the excitatory effects of arachidonic acid on capsaicin‐sensitive sensory nerves in the guinea‐pig bronchus (Manzini & Meini, 1991). These effects were only observed in the presence of the cyclo‐oxygenase inhibitor, indomethacin.…”