A neurokinin 1-receptor antagonist improves exercise-induced airway narrowing in asthmatic patients.

Ichinose, Masakazu; Miura, M.; Yamauchi, H.; Kageyama, Natsuko; Tomaki, Masafumi; Oyake, Tatsuya; Ohuchi, Yuzuru; Hida, Wataru; Miki, Hiroshi; Tamura, Gen; Shirato, Kunio

doi:10.1164/ajrccm.153.3.8630576

Cited by 107 publications

(33 citation statements)

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“…Although this suggested that tachykinin release from airway sensory nerves is involved in responses to bradykinin, this hypothesis could not be confirmed in another study by our group, as no protective effect could be demonstrated of 4 mg of inhaled FK-224 against NKAinduced bronchoconstriction in asthmatics [38]. Inhaled FK-888 was shown to shorten the recovery phase of exercise-induced airway narrowing to some extent, albeit without influencing the maximal fall in sGaw [39]. Finally, intravenously administered CP-99994 did not significantly inhibit hypertonic saline-induced bronchoconstriction or cough in mild asthmatics [40].…”

Section: Discussionmentioning

confidence: 71%

The effect of the NK2 tachykinin receptor antagonist SR 48968 (saredutant) on neurokinin A-induced bronchoconstriction in asthmatics

Schoor¹,

Joos²,

Chasson³

et al. 1998

Eur Respir J

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Substance P (SP) and neurokinin (NK) A are members of the tachykinin peptide family and have been implicated as neurotransmitters which mediate the excitatory part of the nonadrenergic, noncholinergic (e-NANC) nervous system [1][2][3]. In the human airways, they are contained within sensory unmyelinated C nerve fibres, which are distributed beneath or within the airway epithelium, around blood vessels and glands, within the bronchial smooth muscle layer and around local ganglion cells [4][5][6][7][8]. Recent findings in both experimental animals and humans, however, suggest that non-neural cells (endothelial cells, eosinophils and macrophages), either resident or circulating, can also be a source of tachykinins and that immune stimuli can boost tachykinin production from immunocytes [9]. A reduced SP-like immunoreactivity (SP-LI) content of asthmatic airways compared with nonasthmatic subjects has been reported, suggesting an augmented SP release in asthma [10]. Supporting this hypothesis, bronchoalveolar lavage fluid [11] and induced sputum [12] from asthmatics were found to contain increased amounts of SP-LI. SP and NKA contract human airways in vitro and in vivo, NKA being more potent than SP and asthmatics being more sensitive than normal subjects [5,[13][14][15][16][17]. Other potentially important airway effects of tachykinins include mucus secretion, cough, vasodilatation, increased vascular permeability and a broad array of pro-inflammatory effects involving various types of leukocytes [1][2][3].SP and NKA interact with their target cells in the airways through specific tachykinin receptors, with SP being the preferential agonist for the tachykinin NK1 receptor and NKA the preferential agonist for the tachykinin NK2 receptor [18]. Increased expression of NK1 [19] and NK2 [20] tachykinin receptor gene messenger ribonucleic acid (mRNA) in asthmatic airways has been reported. In isolated normal human airways in vitro, tachykinin-induced bronchoconstriction is mediated predominantly by tachykinin NK2 receptors [8,[21][22][23]; recently, however, involvement of tachykinin NK1 receptors has also been noted [24,25]. Tachykinin NK1 receptor stimulation appears to be important in eliciting neurogenic inflammation [1][2][3]18]. On the screening day and during the study periods, increasing concentrations of NKA (3.3×10 -9 to 1.0×10 -6 mol·mL -1 ) were inhaled, until the forced expiratory volume in one second (FEV1) and specific airway conductance (sGaw) decreased by at least 20 and 50%, respectively. During the study periods, 100 mg SR 48968 or matched placebo was ingested in a double-blind, randomized, crossover fashion and NKA provocation was performed at 1.5 and 24 h after dosing. At 1.5 h, the mean (SEM) log10 provocative concentration of NKA causing a 20% fall in FEV1 (PC20 FEV1) was -6.25 (0.20) after SR 48968 and -6.75 (0.17) after placebo (p=0.05); the mean log10 provocative concentration of NKA causing a 35% fall in sGaw (PC35 sGaw) was -7.02 (0.28) after SR 48968 and -7.64 (0.19) after placebo (p=0.05). A...

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Section: Discussionmentioning

confidence: 71%

The effect of the NK2 tachykinin receptor antagonist SR 48968 (saredutant) on neurokinin A-induced bronchoconstriction in asthmatics

Schoor¹,

Joos²,

Chasson³

et al. 1998

Eur Respir J

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“…41 Predominant expression of the NK2 receptor in human subjects with asthma rather than the NK1 receptor 42 may explain why an NK1 receptor antagonist only partially inhibited EIB or bronchoconstriction induced by hypertonic saline. 43,44 In summary, we found that at the level of gene expression MUC5AC is the major gel-forming mucin expressed in induced sputum cells of patients with asthma with EIB, and that the EGF receptor ligands that predominate in EIB are TGF-α, HB-EGF, and AREG. Exercise challenge initiated the release of MUC5AC into the airways related to persistent airflow obstruction and post-exercise symptoms.…”

Section: Discussionmentioning

confidence: 75%

Role of MUC5AC in the pathogenesis of exercise-induced bronchoconstriction

Hallstrand¹,

Debley²,

Farin

et al. 2007

Journal of Allergy and Clinical Immunology

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“…Tachykinins produced by nonadrenergic noncholinergic (NANC) nerves influence airway smooth muscle contraction, mucus secretion, vascular leakage, and neutrophil attachment. In experimental studies, tachykinins, especially substance P, have been linked to neurogenic inflammation [24 ] and regulation of stress hormonal pathways [25] as well as being implicated in asthma [26,27] and neurogenic skin disorders [28]. Recent data from a mouse model suggested that stress-induced airway hyperreactivity and enhanced allergic inflammation (OVA sensitization) was mediated by tachykinins [29 ].…”

Section: Stress and Autonomic Control Of Airwaysmentioning

confidence: 99%