Pharmacologic and neurochemical evidence for the activation of capsaicin-sensitive sensory nerves by lipoxin A4 in guinea pig bronchus.
Exogenous administration of lipoxin A4 (LXA4) to guinea pig isolated bronchus produced contractile effects in a concentration-dependent manner (1, 3, and 6 microM). These responses were potentiated when preparations were previously incubated with thiorphan (10 microM), an inhibitor of tachykinin breakdown, but were significantly depressed when sensory nerves were previously desensitized in vitro by capsaicin (10 microM for 15 min) challenge. Ruthenium red (10 microM for 20 min), a blocker of the cationic channel coupled to the capsaicin receptor, also produced, although in a weaker manner, a reduction in bronchomotor responses elicited by LXA4. On the other hand, preexposure to omega-conotoxin (0.1 microM for 45 min), a blocker of neuronal voltage-dependent Ca2+ channels, did not modify the LXA4 contractile effects. Furthermore, LXA4 (6 microM) superfusion of guinea pig bronchial tissue elicited a significant calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) release that was reduced by capsaicin (10 microM, 30 min) desensitization. Finally, LXA4 (10 microM) was unable to displace [3H]resiniferatoxin binding in dorsal root ganglion of rat and guinea pig. These findings support (1) a role for LXA4 in activating motor sensory function of capsaicin-sensitive nerves; (2) this activation mechanism is marginally ruthenium red-sensitive and omega-conotoxin-resistant; and (3) the interaction does not involve the recognized binding site on the vanilloid receptor. As a whole this study presents LXA4 as an endogenous mediator activating sensory nerves potentially involved in basic mechanisms of airway diseases.
Meini
S
S
Pharmacology Department, Istituto Farmacobiologico Malesci S.p.A., Florence, Italy.
Evangelista
S
S
Geppetti
P
P
Szallasi
A
A
Blumberg
P M
PM
Manzini
S
S
D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000294:innervation*; D016084:Bronchoconstriction / Q000502:physiology*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D006168:Guinea Pigs; D006893:Hydroxyeicosatetraenoic Acids / Q000502:physiology*; D044045:Lipoxins; D008297:Male; D008978:Mollusk Venoms / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology; D010456:Peptides, Cyclic / Q000494:pharmacology; D012430:Ruthenium Red / Q000494:pharmacology; D015244:Thiorphan / Q000494:pharmacology; D020960:omega-Conotoxins
D002121:Calcium Channel Blockers; D006893:Hydroxyeicosatetraenoic Acids; D044045:Lipoxins; D008978:Mollusk Venoms; D010456:Peptides, Cyclic; C040527:lipoxin A4; D020960:omega-Conotoxins; C053423:Conus magus toxin; D012430:Ruthenium Red; D015244:Thiorphan; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin