Involvement of tachykinin NK<SUB>1</SUB> and NK<SUB>2</SUB> receptors in substance P-induced microvascular leakage hypersensitivity and airway hyperresponsiveness in guinea-pigs

Abstract

Involvement of tachykinin NK 1 and NK 2 receptors in substance P-induced microvascular leakage hypersensitivity and airway hyperresponsiveness in guinea-pigs. E. Boichot, K. Biyah, N. Germain, X. Emonds-Alt, V. Lagente, C. Advenier. ©ERS Journals 1996. ABSTRACT: Tachykinins, such as substance P, might be involved in the development of airway hyperresponsiveness (AHR) and airway inflammation. However, it is unknown which tachykinin receptors mediate these biological activities. The effects of two antagonists of tachykinin neurokinin-1 (NK 1 ) and tachykinin neurokinin-2 (NK 2 ) receptors, SR 140333 and SR 48968, respectively, were investigated on substance P (SP)-induced airway hyperresponsiveness and potentiation of the histamine-induced increase in microvascular leakage, in phosphoramidon-pretreated guinea-pigs.Guinea-pigs were pretreated with phosphoramidon (0.1 mM aerosol for 15 min) and exposed 15 min later to saline solution alone or to saline solution containing SP (0.1 mg·mL -1 for 30 min). Twenty four hours later, the animals were anaesthetized and prepared for the recording of the pulmonary inflation pressure (PIP) to acetylcholine or for the investigation of microvascular leakage to histamine.Pretreatment of the guinea-pigs with a single dose of SR 48968 (1 mg·kg -1 , i.p.) 30 min before SP exposure, significantly prevented the development of AHR, whereas SR 140333 (1 mg·kg -1 , i.p.) did not. In a second set of experiments, phosphoramidon-pretreated guinea-pigs exposed to SP presented a significant potentiation of the histamine-induced increase in microvascular leakage in pulmonary airways. When the guinea-pigs were pretreated with SR 140333, an inhibition of the increased microvascular leakage to histamine was observed. In contrast, no significant inhibitory activity was noted when the guinea-pigs were pretreated with SR 48968.The present data demonstrate the importance of tachykinin NK 2 receptor stimulation in the development of airway hyperresponsiveness and that of tachykinin NK 1 receptor stimulation in microvascular leakage hypersensitivity in phosphoramidonpretreated and substance P-exposed guinea-pigs. The results also suggest a dissociation between the presence of microvascular leakage and the occurrence of airway hyperresponsiveness. Eur Respir J., 1996Respir J., , 9, 1445Respir J., -1450 Among the different inflammatory mediators suspected of playing a role in airway hyperresponsiveness (AHR) and airway inflammation, several lines of evidence suggest that tachykinins, such as substance P (SP) and neurokinin A, might be involved. Indeed, recent studies have reported that exposure of guinea-pigs to an aerosol of capsaicin or substance P, substances that release endogenous sensory neuropeptides, such as SP, elicited AHR to exogenous bronchoconstrictor agents [1][2][3][4]. Conversely, a chronic treatment with high doses of capsaicin, which depletes tachykinins from nonadrenergic noncholinergic nerves, eliminates AHR to methacholine or histamine induced by acute capsaicin [2], ovalbumin [5],...

The role of tachykinin receptor antagonists in the prevention of bronchial hyperresponsiveness, airway inflammation and cough

“…Inhaled SP in phosphoramidon-pretreated guinea-pig also induced bronchial hyperresponsiveness [49]. In this model again, SR 48968, but not SR 140333, suppressed the leftward shift of the dose-response curve to acetylcholine observed after exposure of phosphoramidon-pretreated guineapigs to SP [67], and these data also support a role for tachykinin NK 2 receptor stimulation in the development of airway hyperresponsiveness. Similar conclusions were reported by YOSHIHARA et al [68], who showed that SR 48968 prevented the potentiation of antigen-induced bronchoconstriction by cold air in guinea-pigs; and by PERRETTI et al [69], who reported that the specific and long-acting peptidic antagonist, MEN 10,627, inhibited PAF-induced airway hyperresponsiveness in the guineapig.…”

“…In these conditions, SR 140333 has been shown to markedly reduce the SP-induced potentiation of microvascular leakage induced by histamine, whereas SR 48968 had no preventative effects [67]; strengthening the role of the tachykinin NK 1 receptor in the microvascular leakage following tachykinin stimulation. Similar results were obtained in animals exposed to aerosolized citric acid and challenged 24 h later with histamine [93].…”

“…We recently showed that aerosolized SP, in addition to its direct effects, potentiates histamine-induced microvascular leakage in phosphoramidon-pretreated guineapigs 24 h later [67]. In these conditions, SR 140333 has been shown to markedly reduce the SP-induced potentiation of microvascular leakage induced by histamine, whereas SR 48968 had no preventative effects [67]; strengthening the role of the tachykinin NK 1 receptor in the microvascular leakage following tachykinin stimulation.…”

The role of the tachykinin NK1 receptor in airway changes in a mouse model of allergic asthma

“…Furthermore, antagonizing the NK 1 receptor has no influence on the increased activation status of alveolar macrophages after ovalbumin challenge in sensitized guinea pigs, suggesting no effect of the NK 1 receptor on the activation of macrophages in ovalbumin-sensitized and ovalbumin-exposed animals. 11 We did not observe any induced hyperresponsiveness in our model, although others did report allergen-induced hyperresponsiveness in mice, 21,22 guinea pigs, 23,24 and rats. 25 Therefore, no conclusions about the role of the NK 1 receptor in allergen-induced hyperresponsiveness could be made.…”

Neurokinin–1 Receptor Antagonist Inhibits Short–Term Sulfuric–Acid–Induced Airway Hyperresponsiveness in Sensitized Guinea Pigs

“…Also, NK 2 but not NK 1 antagonists have been shown to reduce allergen–induced AHR at 24 and 48 h after allergen challenge [6]. Boichot et al [16]showed that NK 1 antagonists inhibited the increase of microvascular leakage of histamine in SP–exposed guinea pigs, but did not prevent the development of AHR, and suggested a lack of association between the presence of microvascular leakage and the occurrence of AHR. Advenier et al [12]suggested that NK 1 mediated the development of microvascular leakage hypersensitivity, whille NK 2 mediated the development of AHR by exposure to SP or citric acid in guinea pigs, and that NK 2 receptor stimulation plays an important role in the development of AHR, while the effects of NK 1 receptor antagonists are still being debated.…”