Role of peptidoleukotrienes in capsaicin‐sensitive sensory fibre‐mediated responses in guinea‐pig airways.

Abstract

SUMMARY1. The right bronchus with the right vagus nerve remaining intact was isolated from the guinea-pig. Stimulating the end of the right vagus nerve distal to the bronchus resulted in a biphasic contractile response with a rapid first phase and a second phase which persisted after the cessation of stimulation. The first phase was selectively sensitive to atropine, while the second phase was non-cholinergic, but abolished by pre-treatment with the sensory C fibre toxin, capsaicin. This biphasic contraction was mimicked by electrical field stimulation of the bronchus and strips of the distal aspect of the trachea.2. The capsaicin-sensitive second phase produced by either vagus nerve stimulation or electrical field stimulation, was inhibited by greater than 50% by the selective peptidoleukotriene receptor antagonist SKF 104353, whereas the inactive stereoisomer of SKF 104353, SKF 104373, was without effect. SKF 104353 did not inhibit the cholinergic first phase, nerve conduction along the vagus nerve, or contractions to exogenously added substance P and neurokinin A.3. The inhibitory effect of SKF 104353 on second-phase contractions was mimicked by two structurally unrelated selective peptidoleukotriene receptor antagonists, WY 48252 and ICI 198615, and by the 5'-lipoxygenase inhibitor REV 5901.4. Exogenously added leukotriene D4 (1 nM) potentiated the second-phase contractions in the trachea and this effect was reversed by 041 /SM-SKF 104353.Leukotriene D4 did not affect responses to exogenously added substance P or neurokinin A.5. Stimulation of the right vagus nerve produced plasma extravasation in the trachea and in the main bronchi of atropine-and propranolol-pre-treated guinea-pigs. This was inhibited by about 50% by SKF 104353 (10 mg/kg, i.v.), whereas SKF 104373 (10 mg/kg, i.v.) was without effect.6. It is suggested that endogenous peptidoleukotrienes make a significant contribution to the airway smooth muscle and vascular effects of capsaicin-sensitive nerve stimulation in the guinea-pig.

Hypertonicity, but not hypothermia, elicits substance P release from rat C-fiber neurons in primary culture.

“…While this approach has the advantage noted above, it does remove the Cfiber from extraneuronal influences that are ordinarily present within the intact airway. It is well established that various compounds can "sensitize" or inhibit C-fiber activation by other stimulants (21)(22)(23)(24). It is possible that the absence of such a m 30-50 -e compounds which might be present within intact airways altered the responses we observed in cultured DRG cells.…”

“…Perhaps mechanical coupling, rather than direct neuronal activation, explains how some or all of the mediators studied led to tachykinin release. Other studies have also concluded that administration of various inflammatory mediators (21)(22)(23)(24)(25)(26)(27) or even hypertonic saline (28) stimulate C-fibers to release tachykinins in the airways. Yet because airways contain many cell types capable of releasing their own compounds which might directly stimulate sensory g; 600-Q 400-L.. C-fibers, and because of the potential for mechanical coupling noted above, it is difficult to be sure whether or not the effect of a putative C-fiber stimulant is actually a direct one.…”

Using guinea pigs in studies relevant to asthma and COPD

“…Similarly, there is evidence for a tonic cysLT 1 receptor mediated regulation of airways in guinea pigs [58,59]. In both species, this basal tone mediated by autacoids appears to be manifest both in vivo and in vitro [58,[60][61][62].…”

Inflammation-Induced Plasticity of the Afferent Innervation of the Airways

“…Moreover, the histamine H 1 receptor-selective antagonist pyrilamine could prevent and reverse the antigen-induced potentiation. Other mast cell mediators such as the cysteinyl leukotrienes (Cys -LTs) may also contribute to allergen-induced potentiation of tachykinergic nerve-mediated responses in the airways via the activation of Cys-LT 1 receptors on afferent nerve endings (70,75,76).…”