Capsaicin-induced airway obstruction in tracheally perfused guinea pig lungs.

Abstract

The neurokinin receptors responsible for transducing the airway obstruction resulting from capsaicin infusion were defined in the tracheally perfused guinea pig lung. In this lung preparation, buffer is perfused via the trachea and allowed to exit the lung through numerous small holes in the pleural surface; airway obstruction is monitored as the backpressure (Pao) generated at a constant perfusion flow rate. Infusion of the specific NK1 receptor agonist, Sar-9 Met02(11) substance P, resulted in an increase in Pao; this effect was prevented by the NK1 receptor antagonist CP 99,994 but not by the NK2 receptor antagonist SR 48,968. Infusion of the specific NK2 receptor agonist Nle10-neurokinin A 4-10 resulted in an increase in Pao; this effect was prevented by the NK2 receptor antagonist SR 48,968 but not by the NK1 receptor antagonist CP 99,994. In the absence of NK receptor antagonists, infusion of capsaicin resulted in a significant increase in Pao, 31 +/- 4 cm H2O. In the presence of the NK1 receptor antagonist, the capsaicin response was not diminished, but in the presence of the NK2 receptor antagonist, the Pao response diminished to only 10 +/- 2 cm H2O, p < 0.001. These data indicate that when capsaicin is presented to the epithelial surface of the lung the resulting airway obstruction is mediated predominantly by NK2 receptor stimulation.

Localization of leukaemia inhibitory factor to airway epithelium and its amplification of contractile responses to tachykinins

“…In human airways, contractile responses to capsaicin and SP and NKA are thought to be mediated through the NK 2 receptor (Naline et al , 1989; Ellis et al , 1993). In guinea‐pig trachea, stimulation of both NK 2 and NK 1 receptors are thought to mediate the bronchoconstrictor response to capsaicin (Bertrand et al , 1993; Lilly et al , 1994) and the related compound resiniferatoxin (Foulon et al , 1993), although NK 2 receptor mediated pathways appear to predominate (Mizuguchi et al , 1996). In the present study, contractile responses to NKA were significantly greater than those elicited by the selective NK 1 receptor agonist, [Sar 9 ,Met(O 2 ) 11 ]‐SP.…”

Increased blocking activity of combined tachykinin NK1‐ and NK2‐receptor antagonists on tachykinergic bronchomotor responses in the guinea‐pig

“…, 1988). The predominant mechanism in capsaicin‐ or resiniferatoxin‐induced airway obstruction occurs indirectly through the stimulation of the tachykinin NK 2 ‐receptors in perfused isolated lung (Lilly, Besson, Israel, Rodger & Drazen, 1994) or intact guinea‐pig (Satoh, Lou, Lee & Lundberg, 1992; Foulon et al. , 1993; Kudlacz, Logan, Shatzer, Farrell & Baugh, 1993; Boni, Ballati & Evangelista, 1995).…”

Developmental expression of neurokinin A and functional neurokinin-2 receptors in lung

“…Tracheal perfusion assays were used to define the functional capacity of the tachykinin receptors present in our samples. Because of the limited number of samples available for study, we chose to use substantial doses of agonists that had been previously demonstrated to be effective in causing bronchoconstriction in the tracheal perfusion model (31)(32)(33). In our studies, tracheal perfusion assay of capsaicin-challenged lungs demonstrated that the midgestational (i.e., canalicular stage) developing lung can release endogenous neuropeptides that activate neurokinin receptors on smooth muscle to cause bronchoconstriction.…”

“…Because of the limited number of samples available for the tracheal perfusion studies, doses for the peptide agonists and SR-48968 were chosen from published studies examining human and animal model airway responses. Doses used in the tracheal perfusion assays were those that caused bronchoconstriction in adult guinea pig samples studied with tracheal perfusion assay (31,32) and those demonstrated to be effective bronchoconstricting doses in other models (13,48,63). At the completion of the assays, the intact capacity of the pulmonary smooth muscle to respond to agonists was demonstrated by administering 6.1 mg (0.025 mol) of the nonspecific smooth muscle agonist BaCl 2.…”