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 studied the effect of epithelium removal on the contractile responses to exogenous tachykinins and to endogenous tachykinins released by capsaicin in guinea pig trachea. We also studied the effects of inhibition of endopeptidase (by phosphoramidon, 10 microM, and thiorphan, 100 microM), and of inhibition of cyclooxygenase (by indomethacin, 5 microM) on these responses. The order of potency of exogenous tachykinins was neurokinin A (NKA) greater than neurokinin B (NKB) greater than substance P (SP). Epithelium removal enhanced the sensitivity and magnitude of the contractile response to SP, and to a lesser extent NKA and NKB. Capsaicin induced only a weak contractile response in guinea pig trachea. Phosphoramidon and thiorphan increased the sensitivity to SP, but had no effect on acetylcholine responses. The leftwardshift due to epithelium removal was reduced, but not abolished, by phosphoramidon and thiorphan. NKA- and NKB-induced contractions were also enhanced significantly by phosphoramidon. The effect of epithelium removal was abolished for NKA, but not for NKB. Phosphoramidon also increased significantly the contraction to capsaicin in the presence of epithelium, without altering the response obtained in the absence of epithelium. Indomethacin potentiated the sensitivity and maximal contractile response to all the tachykinins with the greatest effect on SP responses, and to capsaicin. The combination of indomethacin with phosphoramidon or thiorphan abolished the effect of epithelium removal for all the tachykinins. We conclude that the effects of exogenous and endogenous tachykinins are enhanced by removal of epithelium and by inhibition of metalloendopeptidase and cyclooxygenase, suggesting that tachykinins may be degraded by epithelial enzymes, and may release relaxant prostanoids in airways.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Influence of epithelium on guinea pig airway responses to tachykinins: role of endopeptidase and cyclooxygenase. 246 59

Removal of epithelium from mammalian tracheae has been shown to enhance responsiveness to a variety of contractile and relaxant agents. One of the most dramatic shifts reported has been for guinea pig tracheal tissue denuded of epithelium and treated with substance P. We investigated whether this shift in responsiveness was because of 1) removal of an epithelium-associated enzyme, neutral endopeptidase, which degrades substance P and 2) loss of an epithelium-derived noncyclooxygenase relaxant factor. Using a muscle bath preparation we performed concentration-response curves with substance P and acetylcholine on indomethacin-treated tissues with and without intact epithelium and with and without pretreatment with the neutral endopeptidase inhibitor, phosphoramidon. Epithelium removal potentiated the mean agonist concentration calculated to causes 30% of the maximal contractile response by 148-fold for substance P and by 7-fold for acetylcholine. Phosphoramidon potentiated the contractile response to substance P, but not to acetylcholine, by both the epithelium-intact and denuded tissues (P less than 0.05). However, the degree of enhancement by phosphoramidon was much greater in the intact tissues. With phosphoramidon treatment, therefore, the difference in responsiveness to substance P between the intact and denuded tissues was reduced from 148-fold to 18-fold. This effect of phosphoramidon suggests that the hyperresponsiveness to substance P of epithelium-denuded airway tissue is largely because of removal of neutral endopeptidase. Because all tissues were treated with indomethacin, the leftward shifts in substance P and in acetylcholine responsiveness induced by epithelium removal further suggest that an epithelium-derived noncyclooxygenase factor other than neutral endopeptidase also modulates the contractile response to substance P and to acetylcholine.
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PMID:Epithelium removal alters responsiveness of guinea pig trachea to substance P. 246 89

We examined the effects of acute exposure to cigarette smoke on the airway responses to substance P in anesthetized guinea pigs and on the activity of airway neutral endopeptidase (NEP). After exposure to air or to cigarette smoke we measured the change in total pulmonary resistance (RL) induced by increasing concentrations of aerosolized substance P in the absence or presence of the NEP inhibitor phosphoramidon. In the absence of phosphramidon the bronchoconstrictor responses to substance P were greater in cigarette smoke-exposed guinea pigs than in air-exposed animals. Phosphoramidon did not further potentiate the responses to substance P in smoke-exposed guinea pigs, whereas it did so in air-exposed animals. In the presence of phosphoramidon, bronchoconstrictor responses to substance P in animals exposed to air or to cigarette smoke were not different. Aerosols of SOD delivered before cigarette smoke exposures dramatically reduced smoke-induced hyperresponsiveness to substance P, whereas heat-inactivated SOD had no effect on smoke-induced hyper-responsiveness to substance P. Cigarette smoke solution inhibited NEP activity from tracheal homogenate in a concentration-dependent fashion, an inhibitory effect that was mostly due to the gas phase of the smoke, but not to nicotine. The mild chemical oxidant N-chlorosuccinimide mimicked the concentration-dependent inhibitory effect of smoke solution on airway NEP activity. We conclude that cigarette smoke causes enhanced airway responsiveness to substance P in vivo by inactivating airway NEP. We suggest that cigarette smoke-induced inhibition of airway NEP is due to effects of free radicals.
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PMID:Cigarette smoke induces bronchoconstrictor hyperresponsiveness to substance P and inactivates airway neutral endopeptidase in the guinea pig. Possible role of free radicals. 247 76

Sensitive afferent nerves and the neurokinins they release upon activation are considered to be important in controlling bronchomotor tone. Human isolated bronchi respond to neurokinin A (NKA), substance P (SP), and neurokinin B (NKB) with dose-dependent contractions. The order of potency of the three natural neurokinins is NKA greater than SP greater than NKB, suggesting the presence of NK-2 receptors. To further characterize the neurokinin receptors in human bronchi, we used selective agonists for each receptor type (i.e., NK-1, NK-2, and NK-3). In fact, NK-1 selective compounds, [Pro9]SP(1-11) sulfone and [beta-ala4,Sar9]SP(4-11) sulfone, did not induce significant contractions up to 10(-5) M. Similarly, the selective agonist for the NK-3 receptor, [MePhe7]NKB(4-10), was almost inactive. However, the NK-2 selective fragment [Nle]NKA(4-10) was a potent stimulant. The negative log of the peptide concentration that caused 50% of maximal effect (pD2) was 6.99 for NKA and 6.12 for [Nle10]NKA(4-10). Removal of the epithelium significantly enhanced the contractile responses to the three neurokinins and also to the NK-2 selective agonist. Phosphoramidon, an enkephalinase inhibitor, was more potent than epithelium removal in enhancing the contractile responses to these agonists. However, epithelium removal and phosphoramidon did not increase the weak responses to the NK-1 and NK-3 selective compounds. In the presence of phosphoramidon, removal of the epithelium slightly enhanced the contractile responses to NKA and [Nle]NKA(4-10) but not to SP and NKB.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of neurokinin effects and receptor selectivity in human isolated bronchi. 247 56

We examined the effects of viral respiratory infection by Sendai virus on airway responsiveness to tachykinins in guinea pigs. We measured the change in total pulmonary resistance induced by substance P or capsaicin in the presence or absence of the neutral endopeptidase inhibitor, phosphoramidon, in infected and in noninfected animals. In the absence of phosphoramidon, the bronchoconstrictor responses to substance P and to capsaicin were greater in infected than in noninfected animals. Phosphoramidon did not further potentiate the responses to substance P and to capsaicin in the infected animals, whereas it did so in noninfected animals. Studies performed in vitro showed that nonadrenergic noncholinergic bronchial smooth muscle responses to electrical field stimulation were also increased in tissues from infected animals and that phosphoramidon increased the response of tissues from noninfected animals greatly but increased the responses of tissues from infected animals only slightly. Responses to acetylcholine were unaffected by viral infection. Neutral endopeptidase activity was decreased by 40% in the tracheal epithelial layer of the infected animals. We suggest that respiratory infection by Sendai virus causes enhanced airway responsiveness to tachykinins by decreasing neutral endopeptidase-like activity in the airway epithelium.
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PMID:Virus induces airway hyperresponsiveness to tachykinins: role of neutral endopeptidase. 247 56

In anesthetized ferrets, we cannulated the duct of the lateral nasal gland for direct collection of glandular liquid. Administration of methacholine and substance P into the internal carotid artery via a retrograde cannulation of the lingual artery produced a dose-dependent increase in glandular output. The dose-response curve to methacholine was significantly shifted to the right by atropine. The secretory response to substance P was only partially inhibited by atropine at the dose that completely blocked secretion produced by methacholine (51 nmol/kg), suggesting the involvement of noncholinergic as well as cholinergic pathways. Phosphoramidon, an inhibitor of neutral endopeptidase, significantly potentiated the action of substance P. The analyses of electrolyte contents in glandular secretion revealed the presence of Na+, K+, and Cl-. The sum of the electrolyte concentrations indicated that the secretion was close to isotonic. The anesthetized ferret is a useful in vivo model for the study of physiology and pathophysiology of nasal secretion.
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PMID:Lateral nasal gland secretion in the anesthetized ferret. 248 68

We tested the hypothesis that tachykinins mediate hyperpnea-induced bronchoconstriction (HIB) in 28 guinea pigs. Stimulus-response curves to increasing minute ventilation with dry gas were generated in animals depleted of tachykinins by capsaicin pretreatment and in animals pretreated with phosphoramidon, a neutral metalloendopeptidase inhibitor. Sixteen anesthetized guinea pigs received capsaicin (50 mg/kg sc) after aminophylline (10 mg/kg ip) and terbutaline (0.1 mg/kg sc). An additional 12 animals received saline (1 ml sc) instead of capsaicin. One week later, all animals were anesthetized, given propranolol (1 mg/kg iv), and mechanically ventilated (6 ml/kg, 60 breaths/min, 50% O2 in air fully water saturated). Phosphoramidon (0.5 mg iv) was administered to five of the noncapsaicin-treated guinea pigs. Eucapnic dry gas (95% O2-5% CO2) hyperpnea "challenges" were performed by increasing the tidal volume (2-6 ml) and frequency (150 breaths/min) for 5 min. Capsaicin-pretreated animals showed marked attenuation in HIB, with a rightward shift of the stimulus-response curve compared with controls; the estimated tidal volume required to elicit a twofold increase in respiratory system resistance (ES200) was 5.0 ml for capsaicin-pretreated animals vs. 3.7 ml for controls (P less than 0.03). Phosphoramidon-treated animals were more reactive to dry gas hyperpnea compared with control (ES200 = 2.6 ml; P less than 0.0001). Methacholine dose-response curves (10(-11) to 10(-7) mol iv) obtained at the conclusion of the experiments were similar among capsaicin, phosphoramidon, and control groups. These findings implicate tachykinin release as an important mechanism of HIB in guinea pigs.
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PMID:Tachykinins mediate bronchoconstriction elicited by isocapnic hyperpnea in guinea pigs. 249 85

We examined an endogenous substance causing cough in awake guinea pigs. An intraperitoneal injection of phosphoramidon, a selective inhibitor of neutral endopeptidase (E.C. 3.4.24.11), caused cough in a dose-dependent fashion for approximately 40 min. At a dose of 3 x 10(-3) mol/kg, phosphoramidon caused a total of 11.6 +/- 1.4 coughs in 40 min. Phosphoramidon (3 x 10(-3) mol/kg)-induced cough was significantly inhibited by systemic pretreatment with capsaicin (p < 0.01). Aerosols of FK 888 (1 min), a specific inhibitor of substance P (NK1) receptor, inhibited phosphoramidon (3 x 10(-3) mol/kg)-induced cough in a dose-dependent fashion with complete inhibition at a dose of 10(-5) M. Likewise, aerosols of FK 224 (10(-5) M; 1 min), another inhibitor of NK1 and NK2 receptors, or lidocaine (4%, 1 min) significantly inhibited phosphoramidon (3 x 10(-3) mol/kg)-induced cough (p < 0.01). Furthermore, aerosols of FK 888 (10(-5) M; 1 min) significantly inhibited cough induced by cigarette smoke in awake guinea pigs (p < 0.01). These results suggest that substance P released from sensory nerves in the airway may be an endogenous substance causing cough and the substance P antagonist may be the drug for treatment of cough in respiratory disease.
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PMID:Evidence for substance P as an endogenous substance causing cough in guinea pigs. 750 93

1. We have investigated the mechanism of capsaicin-induced mouse ear oedema compared with that of arachidonic acid (AA)-induced ear oedema, and evaluated the possible involvement of neuropeptides in the development of capsaicin-induced oedema. 2. Topical application of capsaicin (0.1-1.0 mg per ear) to the ear of mice produced immediate vasodilatation and erythema followed by the development of oedema which was maximal at 30 min after the treatment. This oedema was of shorter duration with less swelling than AA-induced oedema (2.0 mg per ear). 3. Capsaicin-induced ear oedema was unaffected when inhibitors of arachidonate metabolites including platelet activating factor (PAF) were administered before capsaicin (250 micrograms per ear) application, while these agents significantly prevented AA-induced oedema. Dexamethasone, histamine H1 and/or 5-hydroxytryptamine (5-HT) antagonists, and substance P (SP) antagonists were effective in inhibiting both models. Furthermore, a Ca(2+)-channel blocker and the capsaicin inhibitor, ruthenium red, were effective inhibitors of capsaicin oedema but had no effect on AA-induced oedema. 4. Phosphoramidon (50 micrograms kg-1, i.v.), an endopeptidase inhibitor, markedly (P < 0.001) enhanced only capsaicin-induced ear oedema, but bestatin (0.5 mg kg-1, i.v.), an aminopeptidase, failed to enhance oedema formation. 5. Neuropeptides (1-100 pmol per site) such as rat calcitonin gene-related peptide (CGRP), SP, neurokinin A (NKA), and vasoactive intestinal peptide (VIP), which are released from capsaicin-sensitive neurones, caused ear oedema by intradermal injection. Furthermore, a synergistic effect of CGRP (10 fmol per site) and SP (10 pmol per site) on oedema formation was observed. 6. The oedema induced by neuropeptides was significantly (P<0.05 or P<0.001) inhibited when cyproheptadine (20 mg kg-1, p.o.), a histamine H, and 5-HT antagonist, was administered before injection. In contrast, nifedipine (50 mg kg-1, p.o.), a Ca2+-channel blocker, and indomethacin(10 mg kg-1, p.o., except for NKA), a cyclo-oxygenase inhibitor, had little effect on neuropeptide induced oedema.7. These results suggest that the mechanism of capsaicin-induced ear oedema is different from that of AA-induced oedema and suggest that the development of capsaicin-induced ear oedema is primarily mediated by neuropeptides. The neuropeptides released after activation of sensory nerves cause an increase of vascular permeability by interactions with endothelial cells and by histamine (and 5-HT)release from mast cells.
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PMID:Profile of capsaicin-induced mouse ear oedema as neurogenic inflammatory model: comparison with arachidonic acid-induced ear oedema. 750 28

1. Phosphoramidon, a potent inhibitor of endopeptidase-24.11 (E-24.11) and thermolysin, has been shown to reduce the hypertensive effect of exogenous big endothelin-1 (big ET-1) in rats. To examine whether E-24.11 or thermolysin convert big ET-1 to endothelin-1 (ET-1) and C-terminal fragment (CTF), the effects on porcine and human big ET-1 of each of the purified enzymes were compared in vitro. 2. For E-24.11, the relative rates of hydrolysis were ET-1 > CTF >> big ET-1. The relative half-lives for hydrolysis of 3 nmol of each peptide by 200 ng enzyme were: big ET-1 > 24 h; ET-1, 37 min; CTF, 57 min. For comparison, the half-life for hydrolysis of substance P under similar conditions was 2.1 min. 3. For thermolysin the relative rates of hydrolysis were found to be big ET-1 > CTF > ET-1. The relative half-lives for hydrolysis of 3 nmol peptide by 50 ng enzyme were: big ET-1, 25 min; ET-1, 56 min; CTF, 47 min. 4. Because the low rate of conversion of big ET-1 to ET-1 by E-24.11 did not yield sufficient ET-1 for h.p.l.c. quantification a RIA specific for ET-1(16-21) was used to study further the hydrolysis of big ET-1 by E-24.11. Incubation of big ET-1 (0.2-2 nmol) with E-24.11 (4-400 ng) generated ET-1 levels of between 1.7 and 33 pmol measured by RIA. Incubation of big ET-1 (2 nmol) with E-24.11 (40 ng) for 8 h showed that steady state levels of ET-1 were achieved after 4 h indicating that the rate of ET-1 degradation was then equal to the formation of new ET-1. Characterization of the immunoreactivity by h.p.l.c. and RIA confirmed that authentic ET-1 had been produced, but the yield was insufficient for verification by mass spectrometry.5. Both ET-l-like and CTF-like peaks were detected at 214 nm when the products of big ET-1 hydrolysis by thermolysin were resolved by h.p.l.c. RIA and mass spectrometry confirmed the production of ET-1 with amounts in the range 120-160 pmol.6. The hydrolysis profile of ET-1 by E-24.11 and thermolysin shows that both enzymes have some common cleavage sites consistent with their similar specificities hydrolysing on the amino side of a hydrophobic residue.7. Thermolysin, for which 3D structural information is available, may represent a better model for endothelin converting enzyme (ECE) action than E-24.11 and could be useful for the design of ECE inhibitors. Since E-24.11 can both synthesize and hydrolyse ET-1, the presence of E-24.11 in membrane fractions or in partially purified ECE preparations may produce misleading estimates of ECE activity.
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PMID:Generation by the phosphoramidon-sensitive peptidases, endopeptidase-24.11 and thermolysin, of endothelin-1 and c-terminal fragment from big endothelin-1. 752 8


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