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 substance P (SP) and other tachykinins on respiratory glycoconjugate (RGC) release was studied in a feline tracheal organ culture system. SP in concentrations of 10(-5) and 10(-6) M stimulated an increase in RGC release of 35 +/- 8% and 18.5 +/- 5%, respectively. The addition of the protease inhibitor aprotinin or the enkephalinase inhibitor thiorphan to the cultures had no effect on the baseline secretion of RGC but markedly potentiated the activity of SP. SP in the presence of aprotinin or thiorphan was active at 10(-8) -10(-9) M concentrations and was more potent at each concentration studied (in the presence of peptidase inhibitors). Among other tachykinins studied, only physalaemin in the presence of aprotinin had a clear stimulatory effect on RGC release at 10(-6) M concentration (26% +/- 5% increase above control, n = 4, p less than 0.02); kassinin, neurokinin A, and neurokinin B had little or no effect on RGC secretion in concentrations of 10(-6) M or less. Autoradiographic studies of [125I]SP binding revealed SP receptor expression in the submucosal glands of the feline trachea. [125I]SP binding was inhibited in the presence of excess unlabeled SP. We conclude that SP receptors are present in the feline tracheal submucosal glands and that binding to SP receptors results in RGC secretion.
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PMID:Substance P receptor-mediated secretion of respiratory glycoconjugate from feline airways in vitro. 246 45

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

To determine the regulatory role of neutral endopeptidase (NEP) in the tachykinin-induced increase in vascular permeability, we examined the effects of NEP inhibitors and of other protease inhibitors on plasma extravasation induced by intradermal injection of substance P, neurokinin A, and neurokinin B in guinea pig skin. The three tachykinins induced plasma extravasation in concentration-dependent fashions. A significant NEP activity was found to be present in the guinea pig skin. The tachykinin-induced responses were increased by the NEP inhibitors phosphoramidon and thiorphan. However, other protease inhibitors, including a kininase II inhibitor, did not affect the response. We conclude that NEP modulates the tachykinin-induced increase in vascular permeability in the skin.
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PMID:Neutral endopeptidase modulates tachykinin-induced increase in vascular permeability in guinea pig skin. 247 Jun 80

The metallopeptidase enkephalinase known to participate in the inactivation of endogenous enkephalins and, possibly, other neuropeptides such as tachykinins, was visualized by autoradiography using a [125I]iodinated monoclonal antibody. A detailed mapping of the enzyme in rat brain and spinal cord was established on 10-micron serial sections prepared in a frontal plane as well as a few sections in a sagittal plane. On adjacent sections, and for the purpose of comparison, substance P-like and enkephalin-like immunoreactivities were also visualized by autoradiography using a 125I-monoclonal antibody and a polyclonal antibody detected by a secondary 125I-anti-rabbit antibody respectively. Histological structures were identified on adjacent Nissl-stained sections. Using the highly sensitive 125I-probe, enkephalinase immunoreactivity was found to be distributed in a markedly heterogeneous manner in all areas of the central nervous system. Immunoreactivity was undetectable in white matter areas, for example the corpus callosum or fornix, and had a laminar pattern in, for example, the cerebral cortex or hippocampal formation. Hence, although immunodetection was not performed at the cellular level, a major neuronal localization of the peptidase is suggested. The latter is consistent with the detection of a strong immunoreactivity in a pathway linking the striatum to the globus pallidum, the entopeduncular nucleus and the substantia nigra, as well as with a series of biochemical and lesion data. The strong immunoreactivity also present in choroid plexuses and ependymal cells as well as in the intermediate lobe and in scattered cells of the anterior lobe of the pituitary suggests that populations of glial and endocrine cells also express the peptidase. The highest density of enkephalinase immunoreactivity was observed in basal ganglia and limbic areas (caudate putamen, globus pallidus, nucleus accumbens, olfactory tubercles) as well as in areas involved in pain control mechanisms (superficial layers of the spinal nucleus of the trigeminal nerve or of the dorsal horn of the spinal cord) which also display the highest immunoreactivities for both enkephalins and substance P (except in globus pallidus for the latter). These localizations account for the opioid-like analgesic and motor effects of enkephalinase inhibitors inasmuch as a selective or predominant participation of the peptidase in enkephalin inactivation is assumed. A number of other areas appear richly endowed in both enkephalinase and enkephalins whereas substance P is hardly detectable. This is particularly the case for the olfactory bulb, bed nucleus of the accessory olfactory tract, the cerebellum (where enkephalinase mainly occurs in the molecular layer) and the hippocampal formation (namely in the molecular layer of the dentate gyrus).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Detailed immunoautoradiographic mapping of enkephalinase (EC 3.4.24.11) in rat central nervous system: comparison with enkephalins and substance P. 247 16

To determine whether recombinant enkephalinase (neutral endopeptidase, EC 3.4.24.11) prevents cough induced by exogenously applied and endogenously released neuropeptides, we measured cough responses to aerosolized solutions of substance P or of capsaicin for 2 min in random-source guinea pigs before or after exposing them to aerosolized recombinant human enkephalinase. Substance P (10(-16) M) increased coughing compared with its vehicle. Enkephalinase (120 micrograms) inhibited cough induced by subsequent exposure to substance P compared with the response to substance P alone, but after further exposure to the enkephalinase inhibitor leucine-thiorphan (10(-5) M), substance P increased cough significantly. Similar results were obtained for capsaicin-induced cough. In pathogen-free guinea pigs, after they inhaled inactive recombinant enkephalinase (33 micrograms), capsaicin (10(-13) M) increased cough significantly. In contrast, after they inhaled active recombinant enkephalinase (33 micrograms), capsaicin increased cough only slightly. These results suggest that aerosolized enkephalinase reaches the sites of release or actions of endogenous neuropeptides and, by degrading them, prevents cough induced by their release. Furthermore, these studies suggest that recombinant enkephalinase might be useful in the treatment of cough and other symptoms of diseases involving peptides cleaved by this enzyme.
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PMID:Recombinant human enkephalinase (neutral endopeptidase) prevents cough induced by tachykinins in awake guinea pigs. 247 75

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

Capsaicin-evoked release of substance P-like immunoreactivity (SP-LI) from dorsal horn slices of guinea pig spinal cord was unaffected by incubation with the converting enzyme inhibitor captopril (10 microM). However, incubation with the endopeptidase 24.11 inhibitor, thiorphan (10 microM), induced a 2.44-fold increase of capsaicin-evoked SP-LI release, leaving the capsaicin-evoked release of calcitonin gene-related peptide (CGRP)-LI unchanged. Endopeptidase-24.11 activity was higher in homogenates of the dorsal than ventral spinal cord. Endopeptidase-24.11 might be involved in the inactivation of SP released from central endings of primary sensory neurons.
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PMID:Thiorphan increases capsaicin-evoked release of substance P from slices of dorsal spinal cord of guinea pig. 247 94

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


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