Regular ArticleEffects of Capsaicin, (±)-CP-96,345 and SR 48968 on the Bradykinin-induced Airways Microvascular Leakage in Guinea-pigs
Abstract
Summary: The aim of this study was to demonstrate the involvement of neuropeptides in the increase in microvascular permeability induced by bradykinin in guinea-pig airways in vivo and to determine the type of receptor involved. Extravasation of intravenously injected Evans blue dye was used as an index of vascular permeability. Increase in plasma exudation induced by bradykinin (0.3 μg/kg, iv) was reduced or abolished by capsaicin (40 mg/kg, sc, 7 days before experiments), a drug which destroys neurokinins in the NANC nerve endings. (±)-CP-96,345 (3 mg/kg, iv), an antagonist of neurokinin NK1-receptors, abolished the increase of vascular permeability induced by bradykinin and reduced or abolished the effects of substance P (0.3 μg/kg, iv). The higher dose of (±)-CP-96,345 (10 mg/kg, iv) completely blocked the effects of substance P, but it did not modify those of neurokinin A (100 μg/kg, iv). In contrast, SR 48968 (0.1 and 0.3 mg/kg, iv), an antagonist of neurokinin NK2-receptors, reduced the increase of vascular permeability induced by neurokinin A without influencing the effects of bradykinin and substance P. These results demonstrate that a stimulation of the non-adrenergic non-cholinergic (NANC) nerves and a subsequent release of neuropeptides, especially of substance P, is involved in the effects of bradykinin.
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Tachykinin NK<inf>3</inf> receptor agonists induced microvascular leakage hypersensitivity in the guinea-pig airways
2001, European Journal of PharmacologyMicrovascular leakage hypersensitivity is a main component of neurogenic inflammation and of tachykinin effects.The aim of this study was to examine the ability of neurokinin B and of the tachykinin NK3 receptor agonists, [MePhe7]neurokinin B or senktide, to potentiate when given by aerosol the microvascular leakage induced by histamine in guinea-pig airways and to compare their effects to those of tachykinin NK1 (substance P, [Sar9,Met(O2)11]substance P) or tachykinin NK2 (neurokinin A, [βAla8]neurokinin A (4–10)) receptor agonists. Guinea-pigs were pretreated successively for 10 min with aerolized salbutamol and phosphoramidon; 15 min later, they were exposed for 30 min to an aerosolized solution of tachykinin receptor agonists; 24 h later, the animals were anaesthetized and vascular permeability was quantified by extravasation of Evans blue dye. Neurokinin B, [MePhe7]neurokinin B and senktide (3×10−6–3×10−5 M) induced a potentiation of the effects of histamine on the vascular permeability in the trachea and main bronchi. Compared to other tachykinin NK1 and NK2 receptor agonists, the order of potency was: senktide>neurokinin B=[Sar9,Met(O2)11]substance P=[βAla8]neurokinin A (4–10)=[MePhe7]neurokinin B>neurokinin A>substance P. The potentiation by [MePhe7]neurokinin B of histamine-induced microvascular leakage was abolished by the tachykinin NK1 receptor antagonist SR140333 ([(S)1-{2-[3-(3,4-dichlorophenyl)-1-(3-iso-propoxyphenylacetyl)piperidin-3-yl]etyl}-4-phenyl-1-azoniabicyclo[2.2.2]octane, chloride]) or the tachykinin NK3 receptor antagonists SR 142801 ([(R)-(N)-(1-(3-(l-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl) propyl)-4-phenylpiperidin-4-yl)-N-methylacetamide]) and SB 223412 ([(S)-(−)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide]). In conclusion, these results suggest that tachykinin NK3 receptors might be involved in the potentiation of histamine-induced increase in microvascular permeability.
Airway inflammation and tachykinins: Prospects for the development of tachykinin receptor antagonists
2001, European Journal of PharmacologyThe tachykinins substance P and neurokinin A are contained within sensory airway nerves. Immune cells form an additional source of tachykinins in inflamed airways. Elevated levels of tachykinins have been recovered from the airways of patients with asthma and chronic obstructive pulmonary disease. Airway inflammation leads to an upregulation of tachykinin NK1 and NK2 receptors. Preclinical studies have indicated a role for the tachykinin NK1, NK2 and NK3 receptors in bronchoconstriction, airway hyperresponsiveness and airway inflammation caused by allergic and nonallergic stimuli. Compounds that are able to block two or three tachykinin receptors hold promise for the treatment of airways diseases such as asthma and/or chronic obstructive pulmonary disease.
Effects of selective tachykinin-receptor antagonists on tachykinin- induced airway mucus secretion in the rat
1999, NeuropeptidesTachykinins like substance P (SP), neurokinin A (NKA), neurokinin B (NKB) differentially stimulate airway mucus secretion with the following rank order of potency in rat trachea: SP>NKA>NKB. These differential actions are most likely due to different affinities to the tachykinin receptors, termed neurokinin (NK)1, NK2and NK3. In this study we characterized the receptor subtype responsible for the differential secretagogue effects in rat trachea by means of selective receptor antagonists and receptor agonists.
SR 140333 [NK1-antagonist] completely inhibited SP action (283,29±21, 12%→84,53±4, 09%;P<0,01) and significantly reduced the effects of NKA (179,08±17,34%→118,86±6,7%;P<0,01) and NKB (171,89±5,75%→109,5±4,11%;P<0,01). SR 48968 [NK2-antagonist] did not affect SP action, but reduced the effects of NKA and NKB. SR 142801 [NK3-antagonist] did not change any effect of SP, NKA or NKB. [Sar9]SP (NK1-agonist) caused strong dose-dependent secretagogue effects similar to SP, [βAla8]NKA (NK2-agonist) showed only slight and [Pro7]NKB (NK3-agonist) no effects.
The present data suggest that the secretagogue effects elicited by tachykinins in rat trachea are mediated via NK1receptors.
Comparative effects of nonpeptide tachykinin receptor antagonists on experimental gut inflammation in rats and guinea-pigs
1998, Life SciencesPrevious studies have shown tachykinins implicated in gut inflammation. The aim of this work was to evaluate the effect of treatments with tachykinin NK1, NK2, and NK3 selective receptor antagonists on the development of gut inflammation induced by trinitrobenzenesulfonic acid (TNBS) in rats and guinea-pigs. On day 0, rats and guinea-pigs received an intraluminal instillation of TNBS/ethanol (40 ). Each group was daily treated with intraperitoneally injected NK1 (SR 140333; 0.3 mg/kg/day), NK2 (SR 48968; 5 mg/kg/day), or NK3 (SR 142801; 1, 5, or 10 mg/kg/day) receptor antagonists or their vehicle. On day 4, inflammatory levels were evaluated by measuring gut permeability, myeloperoxidase activity, macro- and microscopic damage scores. In TNBS treated rats, daily administration of SR 140333 (0.3 mg/kg/day) and SR 48968 (5 mg/kg/day) reduced colonic inflammation. In TNBS treated guinea-pigs, daily administration of SR 48968 (5 mg/kg/day) and SR 142801 (at 5 and 10 mg/kg/day) attenuated significantly ileal injury. These results suggest that non-peptide tachykinin receptor antagonists are potent anti-inflammatory agents on gut inflammation in rats and guinea-pigs. However, their activity depends upon the animal species and type of receptor considered.
Role of bradykinin B<inf>2</inf> receptors and mast cells in the bradykinin-induced skin response in the rat
1996, European Journal of PharmacologyWe investigated the role of activation of bradykinin receptors and mast cells in the microvascular leakage of the vessels of the skin induced by the intracutaneous (i.c.) injection of bradykinin in the rat. We evaluated the effects of HOE140 (d-Arg-[Hyp3,Thi5,d-Tic7,Oic8]bradykinin), a bradykinin B2 receptor antagonist, and ketotifen (4-(1-methyl-4-piperidylidene)4H-benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-one hydrogen fumarate), a histamine H1 receptor antagonist with mast cell stabilizing properties, on the skin response. Evans blue dye extravasation served as an index of the increase in vascular permeability. Bradykinin (2–100 nmol/site i.c.) induced the extravasation of Evans blue dye in a dose-dependent manner. Ketotifen (20 mg/kg i.p.) significantly inhibited the leakage of dye induced by bradykinin (10 nmol/site i.c.) by 66.2%, while HOE140 (1 mg/kg i.v.) had no effect. The concomitant injection of HOE140 (0.2, 2 nmol/site) and bradykinin (10 nmol/site i.c.), also did not significantly reduce the extravasation of dye. We conclude that the extravasation of plasma induced by the i.c. injection of bradykinin is mediated mainly by stimulation of the skin mast cells, but not by bradykinin B2 receptors.
In vitro and in vivo evidence for a tachykinin NK<inf>1</inf> receptor antagonist effect of vapreotide, an analgesic cyclic analog of somatostatin
1995, European Journal of PharmacologyVapreotide, a long-acting somatostatin analog, possesses an analgesic effect. The purpose of this work was to determine a tachykinergic involvement. Vapreotide reduced substance P-induced biting and scratching in mice. This inhibitory effect of substance P action was confirmed by experiments performed on the bronchial apparatus of guinea-pigs known to possess tachykinin NK1 and NK2 receptors. (i) Vapreotide reduced the substance P-induced plasmatic exudation. (ii) It inhibited selectively the tachykinin-dependent second contractile phase induced by electrical field stimulation of isolated bronchi. (iii) It shifted to the right the concentration-effect curve of substance P-induced contraction of isolated main bronchi. The peptide displaced [3H]substance P (IC50 = 3.3 ± 1.8 × 10−7 M) from guinea-pig bronchial tachykinin NK1 sites. The displacement of [125I]neurokinin A, a specific tachykinin NK2 receptor ligand, needed higher concentrations (IC50 = 4.5 ± 0.6 × 10−6 M). It is concluded that vapreotide possesses an antagonist activity on guinea-pig tachykinin NK1 receptors; the involvement in its analgesic action is discussed.