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)

The effect of ammonia on the cough response to citric acid and on substance P release from C-fibers involved in this reflex was assessed. For a period from one to four days, piglets were exposed, in an inhalation chamber, to ammonia at a concentration of 15 or 30 ppm. During exposure, cough induction tests were done every two days. Recovery of the cough reflex after ammonia exposure was also determined. In a separate group of piglets exposed for 2 days to 30 ppm ammonia, substance P content was determined in bronchial and tracheal lavage fluids and in the tracheal and bronchial mucosa. Ammonia (30 ppm) was found to inhibit coughing significantly (the cough frequency was reduced by 64%) after a two-day exposure. In animals exposed for 4 days to this ammonia concentration, the recovery ranged from 3 to 7 days (mean: 5 days). The same ammonia concentration also caused the substance P content to increase significantly in bronchoalveolar lavage fluid (to 432% of its initial value) and tracheal lavage fluid (to 149%) and to decrease significantly in the tracheal mucosa (-58%), however the content in bronchial mucosa was not significantly affected (-43%). Exposure to 15 ppm ammonia had no effect on the frequency of citric acid-induced coughing. In conclusion, ammonia inhibits citric acid-induced coughing in pigs at concentrations that can be detected in piggeries. This inhibitory effect may be related to substance-P depletion in C-fiber endings.
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PMID:Inhibiting effect of ammonia on citric acid-induced cough in pigs: a possible involvement of substance P. 1114 Aug 27

Angiotensin-converting enzyme (ACE) inhibitors are among the first-choice drugs for treating hypertension and congestive heart disease. It has been reported, however, that these drugs could induce chronic cough and airway hyperresponsiveness. The aim of this work was to assess in pigs the effects of bradykinin and tachykinins on citric-acid-induced coughing after ACE inhibitor pretreatment. Coughing was induced by challenging pigs with an aerosol of 0.8 M citric acid over 15 min. Coughs were counted by a trained observer for 30 min. The animals underwent two cough induction tests two days apart (days 1 and 3), the first being taken as a control. All drugs were injected intravenously 30 min before the second challenge. In the control group, no difference was observed between days 1 and 3. The ACE inhibitor enalapril (7.5 and 15 microg/kg) caused the cough frequency to increase significantly. In contrast, a dose-related decrease was observed with Hoe140 (icatibant), a bradykinin B2 receptor antagonist (0.5 and 1 mg/kg). When both drugs were administered simultaneously (15 microg/kg for enalapril and 1 mg/kg for Hoe140), a significant increase was observed as compared with the control value obtained on day 1. When enalapril was combined with the three tachykinin receptor antagonists SR 140333 (NK1 receptor antagonist), SR 48968 (NK2 receptor antagonist) and SR 142801 (NK3 receptor antagonist), a significant decrease was observed as compared with control value obtained on day 1; the percentage of variation was also significantly different as compared with those observed in enalapril groups at both doses. These data suggest that ACE-inhibitor-induced enhancement of the cough reflex is mainly due to tachykinins and not to bradykinin in our pig model. Bradykinin, however, plays a major role in coughing induced by citric acid alone.
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PMID:Role of bradykinin and tachykinins in the potentiation by enalapril of coughing induced by citric acid in pigs. 1146 10

In asthma patients, microaspiration of acid into the lower airways (ie, airway acidification) causes such respiratory responses as cough and bronchoconstriction. The mechanism of bronchoconstriction induced by airway acidification is unknown, although evidence is emerging that increasing proton concentrations in airway tissues can activate a subpopulation of primary sensory neurons, so-called capsaicin-sensitive primary sensory neurons, that contain such neuropeptides as the tachykinins substance P (SP) and neurokinin A (NKA). Protons activate a capsaicin-operated channel/receptor, located in the afferents of capsaicin-sensitive neurons, with the subsequent opening of ion channels that are permeable to sodium, potassium, and calcium ions. This event initiates a propagated action potential that antidromically depolarizes collateral fibers and triggers neuropeptide release from nerve fiber varicosities. The tachykinins SP and NKA, released from terminals of primary sensory neurons in peripheral tissues, cause all the major signs of inflammation (neurogenic inflammation) by means of activation of NK(1) and NK(2) receptors. Exposure of the airways to acidic solutions stimulates sensory nerve endings of capsaicin-sensitive sensory neurons and causes different airway responses, including bronchoconstriction. Recently, the NK(2), and to a lesser extent the NK(1), receptors have been shown to be involved with citric acid-induced bronchoconstriction in the guinea pig, which is in part mediated by endogenously released bradykinin. Tachykinins and bradykinin, released by airway acidification, could also modulate citric acid-induced bronchoconstriction by their ability to subsequently release the epithelially derived bronchoprotective nitric oxide (NO). Further study with selective tachykinin NK(1) and NK(2) agonists demonstrated that only the septide-insensitive tachykinin NK(1) receptor releases NO. Thus, bronchoconstriction induced by citric acid inhalation in the guinea pig, mainly caused by the tachykinin NK(2) receptor, is counteracted by bronchoprotective NO after activation of bradykinin B(2) and tachykinin NK(1) receptors in airway epithelium. If a similar mechanism is involved in the pathogenesis of bronchial asthma associated with gastroesophageal reflux in the respiratory tract, new therapeutic strategies should be investigated.
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PMID:Mechanisms of citric acid-induced bronchoconstriction. 1174 19

Endotheline-1 (ET-1) has been shown to enhance tachykinin-induced airway constriction. This study was designed to test whether ET-1 is involved in citric acid-induced bronchoconstriction. Forty-eight anesthetized-paralyzed guinea pigs were divided into six groups of 8 animals each: saline control; citric acid; ET-1; ET-1 + citric acid; BQ123 + ET-1 + citric acid; and BQ788 + ET-1 + citric acid. BQ123 and BQ788 are specific ETA and ETB receptor antagonists, respectively. Each animal in the saline control group received 50 breaths of 4 ml saline aerosol and in all citric acid-treated groups was given 50 breaths of 4 ml aerosol generated from 0.6 M citric acid. In all ET-1-treated groups, each animal was exposed to aerosol generated from 10(-8) M ET-1. The animal in the ET-1 + citric acid group was exposed to ET-1 5 min prior to the citric acid. For the last two groups, each animal was first exposed to aerosol generated from either 10(-5) M BQ123 or 10(-5) M BQ788. Five min later, the animal was exposed to ET-1; and then 5 min later was followed by citric acid. Dynamic respiratory compliance (Crs), forced expiratory volume in 0.1 sec (FEV(0.1)), and maximal expiratory flow at 30% total lung capacity (Vmax 30) were obtained before and 3-15 min after citric acid. Either citric acid or ET-1 inhalation caused significant decreases in Crs, FEV(0.1), and Vmax 30, indicating airway constriction. Citric acid-induced airway constriction, for most cases, was not significantly augmented by ET-1. However, either BQ123 or BQ 788 significantly attenuated the airway constriction induced by the combination of ET-1 and citric acid. Also, in an additional study, either BQ123 or BQ788 significantly attenuated citric acid-induced airway constriction. These data suggest that endogenous ET-1 plays an important role in citric acid aerosol-induced airway constriction in guinea pigs.
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PMID:Endothelin-1 in citric acid aerosol inhalation-induced airway constriction of guinea pigs. 1200 49

SSR 146977 is a potent and selective antagonist of the tachykinin NK3 receptor. In Chinese hamster ovary cells expressing the human tachykinin NK3 receptor, SSR 146977 inhibited the binding of radioactive neurokinin B to NK3 receptors (Ki = 0.26 nM), senktide (10 nM) induced inositol monophosphate formation (IC50 = 7.8-13 nM), and intracellular calcium mobilization (IC50 = 10 nM). It antagonized [MePhe7]neurokinin B induced contractions of guinea pig ileum (pA2 = 9.07). Senktide (30 nM) induced firing rate increase of noradrenergic neurons in the guinea pig locus coeruleus and dopaminergic neurons in the guinea pig substantia nigra was also blocked by SSR 146977 (50 and 100 nM, respectively). In vivo, in the respiratory system, SSR 146977 inhibited bronchial hyperresponsiveness to acetylcholine, bronchial microvascular permeability hypersensitivity to histamine (doses of 0.1-1 mg/kg i.p.), and cough (doses of 0.03-1 mg/kg i.p.) provoked by citric acid in guinea pigs. In the central nervous system, SSR 146977 inhibited turning behaviour (ID50 = 0.2 mg/kg i.p. and 0.4 mg/kg p.o.) and prevented the decrease of locomotor activity (10 and 30 mg/kg i.p) mediated by the stimulation of NK3 receptors in gerbils. In guinea pigs, SSR 146977 antagonized senktide-induced acetylcholine release in the hippocampus (0.3 and 1 mg/kg i.p) and norepinephrine release in the prefrontal cortex (0.3 mg/kg i.p.). It also prevented haloperidol-induced increase of the number of spontaneously active dopamine A10 neurons (1 and 3 mg/kg i.p.).
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PMID:Biochemical and pharmacological activities of SSR 146977, a new potent nonpeptide tachykinin NK3 receptor antagonist. 1205 57

We tested if there is a direct relationship between reactive oxygen species and citric acid-induced airway constriction. Guinea pigs were divided into two groups: control and dimethylthiourea (a hydroxyl radical scavenger). The animals in each group were further separated into four subgroups: baseline, recovery 2-3 min, recovery 10 min, and recovery 20 min. Each animal was anesthetized, cannulated, paralyzed, and artificially ventilated. Citric acid aerosol inhalation caused the following significant changes in the control group during the recovery period: airway constriction for at least 20 min, increases in luminol-amplified t-butyl hydroperoxide-initiated chemiluminescence counts in the bronchoalveolar lavage samples at 2-3 and 20 min, an increase in bronchoalveolar lavage fluid substance P level at 2-3 min, and elevations in the bronchoalveolar lavage fluid total cell and neutrophil numbers at 20 min. All citric acid-induced alterations were prevented by dimethylthiourea pretreatment. These results suggest that citric acid inhalation induces the initial release of reactive oxygen species and tachykinins, which causes further cellular infiltration and sustained airway constriction.
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PMID:Reactive oxygen species in sustained airway constriction induced by citric acid aerosol inhalation. 1235 74

The biochemical and pharmacological properties of a novel antagonist of the tachykinin neurokinin 1 (NK1) receptor, SSR240600 [(R)-2-(1-[2-[4-[2-[3,5-bis(trifluoromethyl)phenyl]acetyl]-2-(3,4-dichlorophenyl)-2-morpholinyl]ethyl]-4-piperidinyl)-2-methylpropanamide], were evaluated. SSR240600 inhibited the binding of radioactive substance P to tachykinin NK1 receptors in human lymphoblastic IM9 cells (K(i) = 0.0061 nM), human astrocytoma U373MG cells (K(i) = 0.10 nM), and human brain cortex (IC50 = 0.017 nM). It also showed subnanomolar affinity for guinea pig NK1 receptors but was less potent on rat and gerbil NK1 receptors. SSR240600 inhibited [Sar(9),Met(O2)(11)]substance P-induced inositol monophosphate formation in human astrocytoma U373MG cells with an IC50 value of 0.66 nM (agonist concentration of 100 nM). It also antagonized substance P-induced contractions of isolated human small bronchi with a pIC50 value of 8.6 (agonist concentration of 100 nM). The compound was >100- to 1000-fold more selective for tachykinin NK1 receptors versus tachykinin NK2 or NK3 receptors as evaluated in binding and in vitro functional assays. In vivo antagonistic activity of SSR240600 was demonstrated on tachykinin NK1 receptor-mediated hypotension in dogs (3 and 10 microg/kg i.v.), microvascular leakage (1 and 3 mg/kg i.p.), and bronchoconstriction (50 and 100 microg/kg i.v.) in guinea pigs. It also prevented citric acid-induced cough in guinea pigs (1-10 mg/kg i.p.), an animal model in which central endogenous tachykinins are suspected to play a major role. In conclusion, SSR240600 is a new, potent, and centrally active antagonist of the tachykinin NK1 receptor, able to antagonize various NK1 receptor-mediated pharmacological effects in the periphery and in the central nervous system.
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PMID:SSR240600 [(R)-2-(1-[2-[4-[2-[3,5-bis(trifluoromethyl)phenyl]acetyl]-2-(3,4-dichlorophenyl)-2-morpholinyl]ethyl]- 4-piperidinyl)-2-methylpropanamide], a centrally active nonpeptide antagonist of the tachykinin neurokinin-1 receptor: I. biochemical and pharmacological characterization. 1243 41

Gustatory processing within the medulla is modulated by a number of physiologic and experiential factors. Several neurotransmitters, including excitatory amino acids, GABA, and substance P, are involved in synaptic processing within the rostral portion of the nucleus of the solitary tract (NST). Endogenous opiates have been implicated in the regulation of feeding behavior and in taste palatability and gustatory responses in the parabrachial nuclei are reduced by systemic morphine. In the present experiments, extracellular recording of neuronal activity within the NST in response to taste input was combined with local microinjection of met-enkephalin (Met-ENK) and naltrexone (NLTX) to determine the effect of these agents on gustatory activity. The anterior tongue was stimulated with anodal current pulses to determine the time course of drug action (n=85 cells) and with prototypical taste stimuli (0.032 M sucrose, NaCl, and quinine hydrochloride, and 0.0032 M citric acid) to investigate the effects of these opioid compounds on taste-evoked responses (n=80 cells). Among these 165 taste-responsive neurons in the NST, the activity of 39 (23.6%) was suppressed by Met-ENK. These effects were dose-dependent and blockable by NLTX, which alone was without effect, suggesting that opiates do not maintain a tonic inhibitory influence. Immunohistochemical experiments demonstrated both micro - and delta-opioid receptors within the gustatory portion of the NST; previous studies had shown numerous fiber terminals containing Met-ENK. These data suggest that endogenous opiates play an inhibitory role in gustatory processing within the medulla.
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PMID:Opioid modulation of taste responses in the nucleus of the solitary tract. 1259 Nov 16

The noncholinergic airway constriction is mediated by tachykinins, mainly neurokinin A and substance P, and this bronchoconstriction is usually enhanced during inflammatory episodes. We demonstrated previously that reactive oxygen species play an important role in capsaicin-, hyperventilation-, and citric acid (CA) inhalation-induced noncholinergic airway constriction. For understanding cellular involvement, we further investigated the relationship between mast cells, bradykinin (BK), reactive oxygen species, and noncholinergic airway constriction. Sixty-five guinea pigs were divided into seven groups: saline control; CA; BK + CA; cromolyn sodium (CS) + CA; BK + CS + CA; compound 48/80 + CA; and compound 48/80 + BK + CA. CS was used to stabilize mast cells, whereas a secretagogue, compound 48/80, was for the depletion of mast cells. Each animal was anesthetized, cannulated, paralyzed, and ventilated artificially. In control animals, CA aerosol inhalation caused decreases in dynamic compliance and forced expiratory parameters, indicating CA-induced noncholinergic airway constriction. Either CS or compound 48/80 significantly attenuated the CA-induced airway constriction. Also, we detected a significant increase in lucigenin-initiated chemiluminescence counts of the bronchoalveolar lavage sample in the BK + CA group. Furthermore, CA exposure caused an increase in bronchoalveolar lavage substance P level. Either CS or compound 48/80 prevented the above CA-induced increases in chemiluminescence and substance P. These results suggest that mast cells play an important role in CA aerosol inhalation-induced airway constriction via perhaps releasing constricting factors.
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PMID:Mast cells and reactive oxygen species in citric acid-induced airway constriction. 1507 13

Cough is associated with plasticity of putative cough afferent fibres, but whether plasticity in the brainstem network contributes is less well understood. A key site in the CNS network is the nucleus tractus solitarius (NTS), the first synaptic contact of the primary afferent fibres. We sought to develop a conscious guinea pig model to detect enhanced cough, to focus on the NTS as a potential site for plasticity, and to test a role for substance P in the NTS since the neuropeptide has been implicated in plasticity of the vagal afferent fibres. Guinea pigs were exposed to second-hand tobacco smoke (SHS) or filtered air (FA) from 1-6 weeks of age. At 5 weeks, cannulae were implanted in the NTS. At 6 weeks, either vehicle or a neurokinin 1 (NK-1) receptor antagonist was injected into the NTS of the conscious guinea pigs who were then exposed to citric acid aerosol. SHS exposure significantly enhanced citric acid-induced cough (56%, P<0.05), an effect attenuated by NTS NK-1 receptor blockade (P<0.05). The findings suggest that one possible mechanism for plasticity in cough is related to substance P effects in the NTS. Future studies will be required to investigate the possible mechanisms underlying the role of substance P as well as other mechanisms in generating SHS-induced cough.
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PMID:Plasticity of central mechanisms for cough. 1556 91


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