Involvement of endogenous tachykinins in LTD4-induced airway responses (original) (raw)
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European Journal of Pharmacology, 1992
Bronchospasm induced by i.v. injection of equieffective doses of acetylcholine, capsaicin or selective tachykinin receptor agonists ([Sar9]Sp sulfone or [/3-AlaS]neurokinin A (NKA-4-10)) (for NK 1 and NK 2 receptors, respectively) was studied in anaesthetized guinea-pigs. The NK 1 and NK 2 receptor antagonists, (+)-CP96,345 (3/zmol/kg i.v.) and MEN 10,376 (3/~mol/kg i.v.), selectively abolished the bronchoconstriction induced by the respective agonist, showing that both NK 1 and NK 2 receptors mediate bronchoconstriction in guinea-pig airways and that they are activated independently. Capsaicin-induced bronchospasm was inhibited by atropine (1.5/zmol/kg i.v.) and MEN 10,376 (3/zmol/kg i.v.), but unaffected by (+)-CP96,345 (3/zmol/kg i.v.). Hexamethonium (79 /zmol/kg i.v.), propranolol (17 ~mol/kg i.v.) and physostigmine (0.9 /xmol/kg i.v.) enhanced the airway constriction induced by acetylcholine, capsaicin, [Sar9]Sp sulfone or [fl-AlaS]NKA-(4-10) while guanethidine (67/xmol/kg s.c. for two days) increased only bronchoconstriction induced by capsaicin or the selective NK 2 receptor agonist. In hexamethonium-treated animals, MEN 10,376 still abolished the increase in insuffiation pressure induced by [fl-AlaS]NKA-(4-10) and reduced the increase elicited by capsaicin. In summary, in anaesthetized guinea pig i.v. capsaicin-induced bronchospasm through activation of postjunctional NK 2 (but not NK 1) receptors along with activation of cholinergic pathways. This motor response is moderated by the simultaneous stimulation of a sympathetic bronchodilating mechanism(s), possibly through activation of NK 2 receptors localized in sympathetic ganglia.
British Journal of Pharmacology, 2000
1 The aim of this study was to determine whether neurokinin B (NKB) or speci®c agonists of tachykinin NK 3 receptors, [MePhe 7 ]NKB and senktide, were able to induce airway hyperresponsiveness in guinea-pigs. The eects of these compounds were compared to those of substance P (SP), neurokinin A (NKA) and the preferential tachykinin NK 1 ([Sar 9 , Met(0 2 ) 11 ]SP) or NK 2 ([bAla 8 ]NKA (4-10)) receptor agonists. 2 In guinea-pigs pretreated with phosphoramidon (10 74 M aerosol for 10 min) and salbutamol (8.7610 73 M for 10 min), all tachykinins administrated by aerosol (3610 77 to 10 74 M) induced airway hyperresponsiveness 24 h later, displayed by an exaggerated response to the bronchoconstrictor eect of acetylcholine (i.v.). The rank order of potency was: [bAla 8 ]NKA (4-10)4NKA=NKB=senktide=[MePhe 7 ]NKB=[Sar 9 ,Met(0 2 ) 11 ]SP4SP. 3 Airway hyperresponsiveness induced by [MePhe 7 ]NKB was prevented by the tachykinin NK 3 (SR 142801) and NK 2 (SR 48968) receptor antagonists. 4 Bronchoconstriction induced by tachykinins administered by aerosol was also determined. SP, NKA, NKB and the tachykinin NK 1 and NK 2 receptor agonist induced bronchoconstriction. The rank order of potency was: NKA=[bAla 8 ]NKA (4-10)4NKB=SP=[Sar 9 ,Met(0 2 ) 11 ]SP. Under similar conditions, and for concentrations which induce airway hyperresponsiveness, senktide and [MePhe 7 ]NKB failed to induce bronchoconstriction.
Tachykinin receptors in the guinea-pig isolated bronchi
European Journal of Pharmacology, 1991
The aim of the study was to assess which tachykinin receptors mediate the contractile response in the gtiea-pig isolated bronchi. Experiments with natural tachykinins and receptor-selective tachykinin agonists were performed in the absence or presence of peptidase inhibitors and in bronchi pretreated with phenoxybenzamk Both NK-1 (substance P, substaoce P methylester and septide) and NK-2 (neurokinin A, [/3-Alas]neurokinin A-(4-10) and MDL 28,564) receptor agonists prodLmd concentration-dependent contraction. NK-3 agonists (set&tide and [hfePhe']neurokinin B) were active only at high concentrations. Ph~noxybe~ e pre~atm~t reduced the maximal response to N&l agonists and produced a ~~~~d shift of the curve to WC-2 agonists, without depression of the maximum. Five tachykinin antagonists selective for the N&l (L 668,169) o: the NK-2 (MEN 10,207, MEN 10,376, L 659,877 and R 396) receptor were tested against substance P methylester and [&4ia8]neurokinin A-(4-10). The results indicated that these receptor-selective antagonists maintain their characteristic even when tested in a multireceptor assay such as the guinea-pig bronchus. The rank order of potency of NK-2 antagonists against [/3-Ala8]neurokinin A-(4-10) was MEN 10,207 = MEN 10,376) L 659,877 = R 396. This pattern, with the observation of the full agonist activity of MDL 28,564, indicates that in addition to NK-1 receptors, NK-2 receptors also are present in the +inea-pig bronchi and belong to the same subtype INK-2A) as present in the rabbit pulmonary artery.
Pulmonary Pharmacology & Therapeutics, 1997
Aerosolized substance P (0.1 , for 30 min) induced airway hyperresponsiveness in guinea-pigs 24 h after they were pre-treated with salbutamol (8.7 m by aerosol for 10 min) and phosphoramidon (0.1 m by aerosol for 10 min). This was displayed by an exaggerated response to the bronchoconstrictor effect of acetylcholine. A microvascular leakage hypersensitivity also occurred and was demonstrated by a potentiation of the plasma protein extravasation from bronchial vessels induced by histamine. The aim of this study was to investigate the effects of the non-peptide and potent tachykinin NK 3 receptor antagonist, SR 142801 (osanetant), in comparison with those of the tachykinin NK 1 and NK 2 receptor antagonists, SR 140333 (nolpitantium) and SR 48968 (saredutant) respectively, on substance P. When given once at 1 mg/kg ip 45 min before exposure to substance P, SR 142801 prevented both hyperresponsiveness to acetylcholine and the potentiation of histamine-induced increase in microvascular permeability. SR 142801 did not exhibit any tachykinin NK 1 or NK 2 antagonistic activity in experiments on guinea-pig isolated airways, in vitro or in vivo. The results suggest that tachykinin NK 3 receptors might be involved in these substance P-induced effects on airways.
Pulmonary Pharmacology & Therapeutics, 1998
The effects of iv injections of two endogenous tachykinins, substance P (SP) and neuropeptide and the highly selective tachykinin agonists [Sar 9 ,Met(O 2 ) 11 ]-SP, [Lys 5 ,MeLeu 9 ,Nle 10 ]-NKA(4-10) and senktide, on total lung resistance (R L ), dynamic lung compliance (C dyn ) and systemic blood pressure, were compared in the anaesthetized rabbit. Senktide, the NK-3 receptor selective agonist, had no effect on R L , C dyn or blood pressure. The other four agonists caused dose-dependent increases in R L and C dyn , with [Sar 9 ,Met(O 2 ) 11 ]-SP being the most potent agonist in producing changes in the absence of phosphoramidon. This suggested that NK-1 receptors play an important role in these responses. [Sar 9 ,Met(O 2 ) 11 ]-SP, SP and neuropeptide also decreased blood pressure.
Lung, 1996
The aim of the present study was to examine the role of neuropeptides, especially substance P (SP) and neurokinin A (NKA), in toluene diisocyanate (TDI)induced airway hyperresponsiveness (AHR) to acetylcholine aerosols. Thirty parts per billion of TDI in air administered over 4 hours caused a significant increase in the airway constrictive response to acetylcholine (ACH) aerosols in rabbits (AR~: 245 + 30%, p < 0.005) without altering basic values of respiratory, cardiovascular or blood gas parameters. Inhalation of the aerosolized neuropeptides SP and NKA resulted in a similar increase in airway responsiveness (AR) to ACH as exposure to 30 ppb TDI. To determine whether neuropeptides contribute to TDI-induced AHR, we studied their effects after systemic treatment with capsaicin as well as after infusion of specific synthetic antagonists for SP and NK2 (NKA) receptors. CAPS treatment performed on 4 consecutive days as well as antagonists' infusion only moderately (p > 0.05) decreased airway responses to ACH. CAPS application prevented the TDI-induced increase in AR to ACH in all rabbits. The increase in airway resistance to ACH did not significantly change after TDI exposure (98 _+ 22% of the control response before TDI, p > 0.05). Simultaneous infusion of specific synthetic SP and NK2 receptor antagonists also abolished the TDI-induced increase in airway responses to ACH in all animals investigated (p > 0.05). The results of this study demonstrate that neuropeptides, especially the tachykinins SP and NKA, are important mediators in TDI-induced AHR in rabbits.
American Journal of Respiratory and Critical Care Medicine, 1998
Aerosolized citric acid induces several pulmonary effects including bronchoconstriction, airway inflammation, and cough. Evidence from the use of tachykinin NK 1 and NK 2 receptor antagonists, as well as chronic treatment with high doses of capsaicin, have suggested that these effects are mediated through the release of tachykinins from sensory nerve endings. In the present study, we have investigated the effects of a tachykinin NK 3 receptor antagonist, SR 142801 (osanetant), on cough, bronchoconstriction, and bronchial hyperresponsiveness induced by aerosolized citric acid (0.4 M) in guinea pigs. SR 142801, at 0.3 and 1 mg и kg Ϫ 1 by intraperitoneal route, significantly inhibited cough in conscious guinea pigs by 57 Ϯ 3 and 62 Ϯ 10% (n ϭ 8), respectively. In anaesthetized guinea pigs, it failed to inhibit the bronchoconstriction induced by citric acid when given alone but abolished it when combined with the tachykinin NK 2 receptor antagonist, SR 48968 (saredutant). In guinea pigs pretreated with thiorphan (1 mg и kg Ϫ 1), aerosolized citric acid (0.4 M, 1 h) induced airway hyperresponsiveness 24 h later, displayed by an exaggerated response to the bronchoconstrictor effect of acetylcholine. A microvascular leakage hypersensitivity also occurred and was demonstrated by a potentiation of the plasma protein extravasation from bronchial vessels induced by histamine. When given once intraperitoneally at 1 mg и kg Ϫ 1 30 min before the citric acid exposure, SR 142801 inhibited both hyperresponsiveness to acetylcholine and the potentiation of histamine-induced increase in microvascular permeability. The results suggest that tachykinin NK 3 receptors are involved in citric acid-induced effects on airways. Daoui S, Cognon C, Naline E, Emonds-Alt X, Advenier C. Involvement of tachykinin NK 3 receptors in citric acid-induced cough and bronchial responses in guinea pigs.
Journal of Autonomic Pharmacology, 1991
The NK-1 selective agonists [P-Ala4, Sar9]SP-(4-1 1) sulphone and [pGlu6, Prog]SP-(6-1 1) dose-dependently increased vascular permeability in various segments of rat and guinea-pig tracheo-bronchial region, while the NK-2 ([Nle10]NKA-(4-10) and [P-Ala8]NKA-(4-10)) or NK-3 ([MePhe'INKB and [MePhe'INKB-(4-10)) selective agonists were inactive. These findings provide evidence that the inflammatory response of the airway to intravenous tachykinins is exclusively mediated by the NK-1 receptor subtype. 2 Plasma protein extravasation induced by capsaicin was more intense in the caudal segments of the rat airways and paralleled the tissue concentration of substance P-like and calcitonin gene-related peptide-like immunoreactivity. The response to capsaicin was greatly reduced in rats pretreated with high dose of the toxin (655 pmol kg-' s.c., 3 weeks before) and was smallest in the airway regions where the depletion of neuropeptides had been more severe. 3 The depletion of transmitters from capsaicin-sensitive nerves did not affect the inflammatory response of the airway to serotonin (500 nmol kg-' i.v.), while increased responsiveness to a threshold dose (0.37 nmol kg-' i.v.) of [P-Ala4, Sar9]SP-(4-1 1) sulphone was observed. This finding gives preliminary evidence that, after depletion of transmitters from capsaicin-sensitive nerves, upregulation of NK-1 receptors may develop in rat trachea.