Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P20366 (substance P)
21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the effects of capsazepine, a selective capsaicin antagonist, and SR 48968, a selective NK2 receptor antagonist, on citric acid inhalation-induced bronchoconstriction in guinea-pigs. Simultaneous inhalation of capsazepine (10 microM) significantly inhibited (by 85%) the bronchoconstriction induced by inhaled citric acid (0.4 M) but not that induced by histamine (2 mM). In capsaicin-pretreated (50 mg/kg s.c. 3 weeks earlier) guinea-pigs, citric acid failed to cause any bronchoconstriction, while the effect of histamine was uninfluenced. Furthermore, citric acid inhalation-induced bronchoconstriction was also markedly inhibited (by 65%) after pretreatment with SR 48968 (0.3 mg/kg i.v.). SR 48968 blocked the bronchoconstriction but not the hypotension evoked by neurokinin A. Therefore, these results suggest that inhalation of a low-pH solution such as citric acid can stimulate sensory neurons through a mechanism similar to that for capsaicin with regard to sensitivity to capsazepine. Tachykinins such as neurokinin A are then locally released from the terminals of sensory nerves and cause bronchoconstriction, mainly by NK2 receptor mechanisms.
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PMID:Inhibitory effects of capsazepine and SR 48968 on citric acid-induced bronchoconstriction in guinea-pigs. 839 84

In order to create a new drug for the treatment of respiratory diseases, such as asthma and chronic bronchitis, having a novel therapeutic mechanism, we have been trying to develop new compounds with neurokinin (NK)-receptor antagonistic effects. We used [3H]-substance P binding to guinea pig lung membrane for the first screening system and successfully discovered FK224 from a fermentation product and FK888 from chemical design studies using an octapeptide antagonist (D-Pro4,D-Trp7,9,10) SP4-11 as the parent compound. FK224 and FK888 showed different selectivities against the NK-receptor subtypes (NK1, NK2, NK3); FK888 was a highly potent NK1-selective antagonist, and FK224 was a NK1 + NK2 dual receptor antagonist. Neither compound had any activity on the NK3 receptor. In the in vivo experiments, FK224 and FK888 significantly inhibited the constriction and plasma extravasation in the airway induced by agonist injection. These compounds also showed inhibitory effects on the airway response induced by capsaicin and antidromic stimulation of vagus nerves. Furthermore, FK224 and FK888 were effective on the mucus secretion in the airway and the cough reflex induced by citric acid challenge. There were some differences in the effects of FK224 and FK888 in the in vivo experiments, and it was suggested that the NK1 receptor and NK2 receptor were mainly involved in neurogenic inflammation and airway constriction, respectively. FK224 and FK888 are now undergoing clinical studies to test the effectiveness of a NK antagonist in human respiratory diseases.
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PMID:[Discovery and pharmacological properties of selective neurokinin-receptor antagonists, FK224 and FK888]. 852 64

To examine the mechanisms of an angiotensin-converting enzyme (ACE) inhibitor-induced cough in perimenopausal and postmenopausal women, cough responses to aerosols of capsaicin and citric acid were examined in four groups of female guinea pigs treated orally with danazol (D) (an agent decreasing plasma estrogen levels), cilazapril (C) (an inhibitor of ACE), both danazol and cilazapril (C+D), or without either drug (control group) for 4 to 5 wk. Capsaicin caused dose-dependent increases in the number of coughs in all four groups. C or D alone shifted dose-response curves to capsaicin (from 10(-7) M to 10(-3) M) to lower concentrations compared with the control, and C+D further shifted them. Likewise, the number of coughs induced by citric acid (3 x 10(-1) M; 2 min) was highest in animals treated with C+D and significantly higher in animals treated with C or D than in the control group. Aerosols of a selective substance P (SP) receptor antagonist FK 888 (10(-5) M; 2 min) inhibited capsaicin-induced cough in all four groups, and dose-response curves to capsaicin did not differ significantly at any concentrations among the four groups in the presence of FK 888 (p > 0.10). D decreased cyclic AMP levels in the trachea, irrespective of the combination of C. A beta 2-adrenoceptor agonist, procaterol, which is thought to inhibit SP release by elevation of cyclic AMP in sensory nerves, dose-dependently inhibited the number of coughs induced by capsaicin (10(-3) M) in animals treated with D. The present study suggests that SP is a common mechanism mediating increases in the sensitivity of cough reflex induced by both ACE inhibition and a decrease in plasma estrogen levels, and the additive effects of the two events may explain the high incidence of cough during ACE inhibitor therapy in perimenopausal and postmenopausal women.
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PMID:Angiotensin-converting enzyme inhibitor and danazol increase sensitivity of cough reflex in female guinea pigs. 856 37

Fenspiride is a nonsteroidal anti-inflammatory agent, which we have previously shown to have an in vivo antibronchoconstrictor action in guinea pigs. We have currently studied this action using the constrictors Substance P, neurokinin A, citric acid and capsaicin in anaesthetized guinea-pigs. Fenspiride has also been reported to produce a subjective improvement in cough in patients. We have used a conscious guinea-pig model of cough as a more definitive method to study the effect of fenspiride on capsaicin- and citric acid-induced cough. Aerosolized fenspiride (1 mg.mL-1) caused a 58% reversal of capsaicin-induced bronchoconstriction; and i.v. fenspiride (1mg.kg-1) a 45% reversal of citric acid induced bronchoconstriction. Substance P- and neurokinin A-induced bronchoconstriction were unaffected by 1 mg.kg-1 i.v. fenspiride. Aerosolized fenspiride (1, 3 and 10 mg.mL-1) administered for 4 min reduced citric acid (300 mM) induced cough, but 0.1 mg.mL-1 was without effect. Pretreatment with aerosolized fenspiride (10 mg.mL-1) caused a shift in the citric acid dose response curve to the right. For citric acid-induced cough, the duration of action of aerosolized fenspiride (10 mg.mL-1) was found to be 5 and 15 min post-treatment. Aerosolized capsaicin (30 microM) induced cough was also reduced by 3 and 10 mg.mL-1 aerosolized fenspiride, but no significant effect was found with 1 mg.mL-1. We conclude that aerosolized fenspiride reduces capsaicin- and citric acid-induced bronchoconstriction as well as induced cough in guinea-pigs in vivo. Whether a pathway common to both cough and bronchoconstriction is the site of action of fenspiride remains to be established. We postulate that fenspiride, acting as an antitussive and antibronchoconstrictor agent, would be beneficial in the clinical situation for those patients with hyperresponsive airways.
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PMID:Antitussive and antibronchoconstriction actions of fenspiride in guinea-pigs. 858 25

Airway hyperresponsiveness is a main feature of asthma, and several lines of evidence suggest that tachykinins might be involved in the pathogenesis of airway hyperresponsiveness in rodents. We conducted a study designed to describe an original model of airway hyperresponsiveness induced by citric acid administered as aerosol to guinea pigs, and to investigate the effects of the nonpeptide neurokinin1 (NK1) and neurokinin2 (NK2)-receptor antagonists, SR 140333 and SR 48968, respectively, on the development of this airway hyperresponsiveness. Animals received thiorphan 1 mg/kg intraperitoneally and 30 min later were exposed to an aerosol of citric acid 0.4 M for 1 h. After 24 h, the animals were anesthetized and ventilated. Airway hyperresponsiveness was evidenced by significant shifts to the left of dose-response curves for intravenous acetylcholine (ACh) without a change in maximum responses to ACh. Exposure to citric acid induced an airway hyperresponsive that was abolished by chronic pretreatment with capsaicin (120 mg/kg, 5 d before citric acid exposure). SR 48968 1 mg/kg intraperitoneally, given once at 30 min before the citric acid exposure, inhibited airway hyperresponsiveness, whereas SR 140333 1 mg/kg or codeine 30 mg/kg given under similar conditions did not. The inhibition of airway hyperresponsiveness by SR 48968 did not result from functional antagonism, since SR 48968 did not affect ACh-induced bronchoconstriction, nor did it result from inhibition of tachykinin, which could have been released under the influence of ACh in hyperresponsive animals, since SR 48968 given after the exposure to aerosolized citric acid failed to inhibit airway hyperresponsiveness. In conclusion, these results show that inhaled citric acid can induce the development of an airway hyperresponsiveness in the guinea pig through a release of tachykinins, and also demonstrate that NK2-receptor stimulation plays a predominant role in the development of airway hyperresponsiveness.
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PMID:The tachykinin NK2 receptor antagonist SR 48968 inhibits citric acid-induced airway hyperresponsiveness in guinea pigs. 863 May 92

We compared the effects of a tachykinin NK1 receptor antagonist, FK888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-prolyl]-N-methy l-N -phenylmethyl-3-(2-naphthyl)-L-alaninamide), and a tachykinin NK2 receptor antagonist, SR48968 ((S)-N-methyl-N[4-(4-acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl)butyl]benzamide]), on citric acid-induced cough and bronchoconstriction in conscious guinea pigs. FK888 and SR48968 inhibited the cough dose dependently. Combination of FK888 and SR48968 showed a small additive effect compared with that of FK888 or SR48968 alone. SR48968 but not FK888 inhibited the bronchoconstriction dose dependently. These results indicate that tachykinin NK1 receptors as well as tachykinin NK2 receptors are involved in the citric acid-induced cough response. The antitussive activity of the tachykinin NK1 receptor antagonist appeared not to depend on the anti-bronchoconstrictor effects.
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PMID:Effects of specific tachykinin receptor antagonists on citric acid-induced cough and bronchoconstriction in unanesthetized guinea pigs. 873 11

Two nonpeptide tackykinin NK2 receptor antagonists have now been described, SR 48968 and GR 159897. These drugs are highly specific and very potent antagonists with affinity (binding and in vitro study) for NK2 receptors in the subnanomolar range (pKi = 9-10), without intrinsic activity. They act preferentially on the human NK2A receptor subtype. These drugs exert potent and long-acting antagonism by both i.v. and oral administration. Their use has first confirmed the preponderant role of NK2 receptors in airway smooth muscle contraction, especially in human bronchi. A role for NK2 receptor stimulation has also been clearly demonstrated in bronchoconstriction induced by various agents known to induce the release of tachykinins (capsaicin, resiniferatoxin, citric acid, sodium metabisulfite diethyl ether, serotonin, and bradykinin), in allergen-induced airway constriction in the guinea pig sensitized to ovalbumin, and in hyperpnea-induced bronchoconstriction. Inhibition of neurokinin A mediated or capsaicin-mediated dyspnea by SR 48968 has also been demonstrated in the guinea pig. SR 48968 also is very efficient in inhibiting cough induced by citric acid or capsaicin. Finally, SR 48968 is able to abolish in guinea pigs in vivo the bronchial hyperreactivity induced after 24 or 48 h by a citric acid challenge or an ovalbumin challenge, respectively. Thus, nonpeptide, long-acting NK2 receptor antagonists can be regarded as suitable tools for investigations in humans. They may shortly allow a precise determination of the role of tachykinins in asthmatic patients.
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PMID:Tachykinin NK2 receptors further characterized in the lung with nonpeptide receptor antagonists. 884 25

We here report a model of potentiation by citric acid of airway microvascular leakage induced by histamine and its modification by the tachykinin NK1 and NK2 receptor antagonists, SR 140333 ((S)1-{2-[3-(3,4-dichlorophenyl)-1-(3-iso-propoxyphenylacetyl)p iperidin- 3-yl]ethyl}-phenyl-1-azoniabicyclo[2.2.2]octane, chloride) and SR 48968 (S)-N-methyl-N-[4-(4-acetyl-amino-4-phenylpiperidino)-2-(3,4- dichlorophenyl-butyl]benzamide. Guinea-pigs exposed to an acrosol of citric acid 0.4 M for 1 h developed 24 h later a hyperresponsiveness to histamine-induced microvascular leakage measured by Evans blue dye extravasation. SR 140333, but not SR 48968 (1 mg kg-1 given each once 30 min before citric acid exposure), prevented this potentiation. These results provide further evidence of the role of tachykinin and tachykinin NK1 receptor stimulation on airway hyperresponsiveness and its neurogenic inflammatory component.
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PMID:SR 140333 prevents potentiation by citric acid of plasma exudation induced by histamine in airways. 885 7

Evidence shows that nedocromil sodium has a major inhibitory effect on sensory nerve activation. Animal models in which inhibitory effects have been demonstrated include bradykinin- or ovalbumin-induced plasma extravasation; cigarette smoke- or sulfur dioxide-induced bronchial hyperresponsiveness and increase in inflammatory cells in the airway; and bradykinin-induced airway vasodilatation and nasal mucosal edema. Nedocromil sodium has prevented the edema in human skin induced by substance P and neurokinin A, and, in the isolated rabbit trachea, has prevented substance P-induced potentiation of cholinergic neural responses at preganglionic (but not postganglionic) sites. In vitro, the drug also has inhibited nonadrenergic noncholinergic bronchoconstriction in guinea pig bronchi. Although a protective effect against citric acid-induced cough in the dog has been reported, no data are available from models of enhanced cough reflex, such as that in asthma. Inhibition of sensory nerve activation and prevention of tachykinin release by nedocromil sodium probably contribute to its beneficial effects in the treatment of asthma.
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PMID:Effects of nedocromil sodium on airway neurogenic mechanisms. 893 86

Five neuropeptides: Substance P (SP), Neurokinin A (NKA), Calcitonin Gene-Related Peptide (CGRP), Neuropeptide Y (NPY) and Vasoactive Intestinal Polypeptide (VIP), were measured in the saliva of eight subjects. The saliva was collected using different stimulation techniques: whole resting saliva, whole paraffin stimulated saliva, whole citric acid stimulated saliva and parotid saliva of different secretion rates -0.25 mL/min, 0.50 mL/min and 1.00 mL/min, also stimulated by citric acid. The neuropeptides were analysed by radioimmunoassay. The results showed that the concentration of all neuropeptides decreased significantly, two- to four-fold (CGRP up to 16-fold) in whole saliva, when the salivary secretion rates increased six- to eight-fold due to stimulation. However, the amounts of all neuropeptides released over time into the whole saliva increased two- to five-fold (ten-fold for CGRP) as the volumes of saliva increased due to chewing-stimulation as compared to resting saliva or citric acid stimulated saliva. There was also more CGRP in the resting saliva than in the citric acid stimulated saliva. The concentration of CGRP in the parotid saliva decreased three- to ten-fold when the salivary flow increased, whereas the concentration of NKA increased three- to four-fold and that of NPY almost two-fold under the same conditions. The concentrations of SP and VIP did not change in the different flows of parotid saliva. The release of all neuropeptides in the parotid saliva over time showed significant increases (3-14-fold) when the secretion rates increased except CGRP, which showed no changes at all. We concluded that neuropeptides are continuously released into the saliva. Their amounts increase with stimulation, but they are diluted by the increased volume of saliva, and they are also affected by the mode of stimulation-muscular activity leads to a greater release than citric acid stimulation. As the neuropeptides play an important role in the control of salivary secretory mechanisms, their normal occurrence and release are of fundamental importance for the understanding of the function of the salivary glands.
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PMID:Neuropeptides in the saliva of healthy subjects. 901 Apr 82


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