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)

In some animal species substance P and neurokinin A (NKA) cause bronchoconstriction by the release of acetylcholine from postganglionic cholinergic nerve endings. The aim of the present study was to investigate the effect of an anticholinergic drug, oxitropium bromide, on bronchoprovocation with NKA in asthmatics. Eleven mild asthmatics (mean % predicted FEV1 85.5) received on 2 separate days, double blind, in a randomised order, 400 mcg oxitropium bromide or placebo, 90 min before challenge with NKA. NKA was inhaled at 3 concentrations (10(-4), 3.10(-4) and 10(-3) M). Specific airways conductance (sGaw) and forced expiratory volume in 1 s (FEV1) were used as parameters of airway calibre. Compared to the placebo-aerosol, oxitropium bromide caused a significant increase in sGaw and FEV1. On the placebo-treatment day, NKA caused a concentration-dependent decrease in sGaw and FEV1. The percentage changes in sGaw and FEV1 on the oxitropium day were not statistically different from those occurring on the placebo day. We conclude that oxitropium bromide caused a significant bronchodilation but offered no significant protection against NKA-induced bronchoconstriction in mild asthmatic subjects.
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PMID:The effect of oxitropium bromide on neurokinin A-induced bronchoconstriction in asthmatic subjects. 285 43

The effect of inhaled capsaicin, the irritant extract of pepper, on airway tone has been studied in humans. Inhaled capsaicin (2.4 X 10(-10) and 2.4 X 10(-9) mol) caused a dose-dependent fall in specific airways conductance (maximum fall 28 +/- 19 and 38 +/- 19%, respectively; means +/- SD, n = 17). This was maximal within 20 s of exposure and lasted for less than 60 s. There was no difference in the magnitude or duration of bronchoconstriction between normal, smoking, or asthmatic subjects. Capsaicin also caused coughing and retrosternal discomfort. On repeated exposure to capsaicin, there was no evidence for a reduced response (tachyphylaxis). Ipratropium bromide (0.25 mg by inhalation) significantly (P less than 0.05) reduced the bronchoconstriction (maximum falls 34 +/- 14 and 15 +/- 9% after saline and ipratropium bromide, respectively; means +/- SD n = 6), indicating that it was dependent on a cholinergic vagal reflex rather than on local release of substance P from nerves in the airway. Inhaled sodium cromoglycate (10 mg by nebulizer or 40 mg as a dry powder), however, had no significant effect on the bronchoconstrictor response. Capsaicin may be a useful tool for investigating nonmyelinated nerve reflexes in human airways.
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PMID:Bronchoconstrictor response to inhaled capsaicin in humans. 315 68

1. Topical application of capsaicin to the human nasal mucosa induced a burning sensation and sneezing. A dose-dependent seromucous nasal secretion was also observed. Capsaicin (75 micrograms) was more potent than methacholine (50 mg) in producing nasal secretion, while topical histamine (200 micrograms), substance P (135 micrograms) and calcitonin gene-related peptide (36 micrograms) did not induce rhinorrhea. 2. Pretreatment with either topical ipratropium bromide, systemic dexchlorpheniramine or indomethacin did not influence the effects induced by capsaicin. Topical pretreatment with lidocaine inhibited the painful sensation but failed to block the rhinorrhea. Desensitization to the effects of capsaicin occurred following 4-5 subsequent applications, and full recovery was observed within 30-40 days. 3. It is proposed that the effects of capsaicin in human nasal mucosa are due to excitation of primary afferent neurones that (a) convey burning and painful sensation, (b) evoke a sneezing reflex and (c) induce nasal secretion by releasing transmitter(s) from their peripheral terminals.
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PMID:Secretion, pain and sneezing induced by the application of capsaicin to the nasal mucosa in man. 337 Mar 86

Human and canine airway mucosa in vitro synthesizes and secretes mucus glycoprotein, proteoglycans and lipids which can be separated by density gradient ultracentrifugation in caesium bromide. In secretions from unstimulated explants, the small amount of mucus glycoprotein present is found in association with proteoglycans. 'Free' mucus glycoprotein of typical buoyant density is present only after stimulation of submucosal gland secretion by methacholine. Lipids are synthesized, at least in part, by the airway mucosa and occur in explant secretions as a viscoelastic gel, suggesting that they significantly influence the rheological properties of airway mucus. In addition to cholinergic and adrenergic secretomotor neurons, the airway mucosa is innervated by peptidergic fibres containing immunoreactivity to vasoactive intestinal peptide (VIP) and substance P (SP). In explants of non-bronchitic human airway, VIP inhibits baseline glycoprotein and lysozyme secretion; in canine airway mucosa, by contrast, VIP is a weak partial secretory agonist. SP is the most potent agonist of canine airway glycoprotein release described to date and appears to evoke secretion by a direct action on a stereospecific SP receptor rather than by inducing release of other endogenous secretagogues. VIP and SP have little effect on glycoprotein discharge by mucous and serous cells of the submucosal gland; SP appears to induce secretion by causing contraction of submucosal gland ducts. This may represent the most rapid way for delivering mucus into the airway in response to injury or irritation of airway epithelium.
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PMID:Airway mucus: composition and regulation of its secretion by neuropeptides in vitro. 608 50

The effects of cis-2-methyl-4-dimethylaminomethyl-1-3-dioxolane methiodide (CD), a muscarinic agonist, histamine, substance P and K+-stimulation on the mechanical responses, Ca2+-dependence and desensitization in guinea-pig ileal longitudinal smooth muscle have been studied. The mechanical responses to all four stimulants are highly dependent upon extracellular Ca2+(Ca2+EXT) and are blocked by the Ca2+ channel antagonist nicardipine. The tonic (slow) components of response are more dependent on Ca2+EXT and are more sensitive to nicardipine (IC50 values 5.0 X 10(-8) - 2.5 X 10(-9)M) than are the phasic (fast) components of response. Tissue exposure to CD (5 X 10(-7)M, 10 min) or histamine (3 X 10(-6)M and 3 X 10(-4)M, 10 min) produces short term nonspecific desensitization but substance P (5 X 10(-8)M, 10 min) produces only specific desensitization. K+-induced responses neither desensitize nor are desensitized. Desensitization is concentration- and time-dependent for both specific and nonspecific processes. Nonspecific desensitization is protected by elevation of K+ concentration (5.36mM) in the incubating medium, by dithiothreitol and by inhibitors (mepacrine,p-bromophenacyl bromide and phenylgloxal) of phospholipase A2 and is potentiated by mellitin, an activator of phospholipase A2. Desensitization produced by the muscarinic agonist CS is protected by Gpp(NH)p (10(-4)M), but histamine-induced desensitization is unaffected. There is no loss of muscarinic receptors, measured by [3H]QNB binding following tissue exposure to low concentrations of CD (5.0 X 10(-7)M) for up to 72 h. However, an apparent loss of receptors (20-30%) is measured following 10-90 min exposure of tissue to 10(-3)M CD. It is suggested that contractions of guinea-pig ileal longitudinal smooth muscle elicited by CD, histamine, substance P or K+ mobilize a common pool of Ca2+ through a Ca2+ channel antagonist (nicardipine) sensitive pathway. However, the existence of short term nonspecific desensitization (CD and histamine), specific desensitization (substance P) or no desensitization (K+ stimulation) indicates that significant differences exist in the pathways linking initial stimulus to mechanical response. The ability of elevated K+ to protect against nonspecific desensitization suggest that post stimulus membrane hyperpolarization may represent one contributing component to nonspecific desensitization. Products of phospholipid degradation may also contribute to desensitization since inhibitors or activators of phospholipase A2 prevented or potentiated respectively, nonspecific desensitization.
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PMID:Specific and non-specific desensitization of guinea-pig ileal smooth muscle. 620 87

We have used the whole cell recording technique to investigate voltage-activated outward currents in cultured ovine trachea submucosal gland cells. The cultured gland cells secreted lysozyme in response to secretagogues, methacholine (20 microM), phenylephrine (100 microM) and substance P (10 microM). Most cells in culture for 7-21 days expressed a voltage-activated outward current at potentials positive to -30 mV. This outward current inactivated slowly, by 44 +/- 6% during a 3 sec depolarization to +30 mV. The voltage-activated outward current was sensitive to the potassium channel inhibitors tetraethylammonium bromide (5 mM), 4-aminopyridine (500 microM) and glibenclamide (1 microM). These data suggest that the outward voltage-activated currents observed are due to K+ channel activity. In cells with little or no outward current present the potassium channel opener Ro 31-6930 produced an additional voltage-activated net outward current. This effect of Ro 31-6930 was sensitive to glibenclamide (1 microM). Our results suggest that some cultured submucosal gland cells express voltage-activated K+ currents with a mixed pharmacology to antagonists and that a portion of this current is sensitive to modulation by Ro 31-6930.
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PMID:Properties of K+ currents recorded from cultured ovine trachea submucosal gland cells. 805 91

In mucosa-bearing organs with inherent lymphoid populations, classical modes for control of the immune response may be augmented by products of extrinsic sensory afferent nerve endings which arborize through the lamina propria compartment containing large numbers of T and B lymphocytes. Therefore, we sought to determine the role of neuropeptides (substance P, vasoactive intestinal peptide, and somatostatin) in immune response regulation by using a homogeneous line of T lymphocytes (AO40.1 hybrid), whose activation is driven by a specific Ag (OVA) and where the end point (IL-2 release) could not be contributed to by accessory or other cells. IL-2 was quantitated by the rate of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) metabolism with the use of a murine CD4+ IL-2-dependent T lymphocyte line, and dose-response effects of each neuropeptide were examined over a broad concentration range (10(-14)-10(-6) M) encompassing that regarded as physiologic. Vasoactive intestinal peptide stimulated IL-2 release at low concentrations with a marked effect at 10(-14) M that gradually returned to control levels by 10(-7) M. Somatostatin was associated with a substantial augmentation of AO40.1 T lymphocyte IL-2 release at 10(-10) to 10(-8) M concentrations, whereas substance P demonstrated a stimulatory effect only at high concentrations (10(-9) to 10(-6) M). Concomitant [3H]thymidine uptake studies suggested that changes in cell proliferation or viability did not account for neuropeptide-induced effects in our system. With several exceptions, similar results were found with mitogen (Con A)-stimulated AO40.1 cells and human colonic lamina propria mononuclear cells. It was concluded that the three study neuropeptides, over a broad range of concentrations, have profound stimulatory (and occasionally inhibitory) effects upon the function of a cloned T lymphocyte hybrid cell responding to specific Ag and that these events may reflect those of Ag-driven mucosal T lymphocytes exposed to neuropeptides in vivo.
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PMID:Modulation of T lymphocyte function by neuropeptides. Evidence for their role as local immunoregulatory elements. 851 59

Inhibition of the reduction of the redox dye 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide by rat phaeochromocytoma PC12 cells is a specific, early response to nanomolar concentrations of the beta-amyloid peptide fragment beta (25-35), and appears to be a reliable indicator of the mechanism of beta-amyloid toxicity. Neither selective tachykinin receptor agonists, nor tachykinin receptor peptide and non-peptide antagonists elicited such a response. Furthermore, tachykinin receptor peptides did not block the effects of beta-amyloid in PC12 cells, or in two other beta-amyloid-sensitive cell lines. These experimental model systems allow the mechanism of action of beta-amyloid to be distinguished from that of tachykinin receptor peptides, and prove that the neurotoxic action of beta-amyloid, as measured by the inhibition of cellular 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide reduction is not mediated by an interaction with tachykinin receptors.
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PMID:Cellular MTT reduction distinguishes the mechanism of action of beta-amyloid from that of tachykinin receptor peptides. 877 54

We investigated the influence of the Ca(2+)-ATPase inhibitor thapsigargin (TG) on the vasorelaxant response to different endothelium-dependent and endothelium-independent relaxing agents in an isolated thoracic aorta preparation of the rabbit, precontracted by norepinephrine (NE). Pretreatment with 100 microM L-arginine methyl ester (L-NAME) an inhibitor of nitric oxide (NO) synthesis, completely prevented acetylcholine (ACh)-induced relaxation; the inactive stereoisomer D-NAME did not modify the effect of ACh. The exposure of the preparations to 1 microM TG induced a slowly developing slight increase in the basal tension during 30-min contact. The same concentration of TG also slightly reduced the response to the subsequent administration of NE. The antagonist effect of TG on the ACh response was concentration dependent in the range between 0.1 and 10 microM. A 30-min pretreatment with 1 microM TG appeared to be sufficient to induce a consistent antagonism of the ACh (0.01-10 microM) concentration-relaxant effect curve, since an increase to 60 min did not produce a further significant increment in the degree of the antagonist effect. The concentration-dependent relaxation induced by substance P (SP 0.1-3 nM) was also significantly antagonized by 1 microM TG. The effect of the calcium ionophore A23187 (0.01-1 microM) was reduced by the Ca(2+)-ATPase inhibitor only at the higher concentrations tested (0.3-1 microM). However, a 30-min contact time with 1 microM TG was completely ineffective in antagonizing the concentration-relaxant response curves to the two nitrovasodilators sodium nitroprusside (SNP 0.1-100 microM) and nitroglycerin (NTG 1-300 nM) and to the cyclic GMP analogue 8-Bromo-cyclic GMP (3-100 microM). The effects of the beta-adrenoceptor agonist isoprenaline (ISO 0.1-10 microM) and of the direct adenylate cyclase activator forskolin (FK 0.01-10 microM) were also completely unaffected by 1 microM TG. These results demonstrate that TG affects the response to agents that induce an endothelium-dependent relaxation through receptor-dependent calcium mobilization. However, they do not support the hypothesis that sarcoplasmic pump activity is essential for the development of a vasorelaxant response to endothelium-independent agents.
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PMID:Thapsigargin inhibits the response to acetylcholine and substance P but does not interfere with the responses to endothelium-independent agents. 879 40

Previously we have been able to restrict the site of covalent attachment of a photolabile and radiolabeled derivative of substance P (SP), p-benzoylphenylalanine8-SP (Bpa8-SP), to residues 178-183 located on the second extracellular loop (E2) of the SP (NK-1) receptor (Boyd, N. D., Kage, R., Dumas, J. J., Krause, J. E., and Leeman, S. E. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 433-437). To ascertain the specific amino acid in this sequence that serves as the site of covalent attachment for 125I-Bolton-Hunter reagent (BH)-Bpa8-SP, we have employed here a novel solid-phase approach to cyanogen bromide cleavage of the photolabeled receptor followed by mass spectrometric analysis of a purified labeled fragment. SP receptors on transfected Chinese hamster ovary cells were photolabeled with isotopically diluted 125I-BH-Bpa8-SP. A membrane preparation of the photolabeled receptors was adsorbed onto C-18-derivatized silica gel and cleaved with cyanogen bromide. A single radiolabeled fragment containing 63% of the photoincorporated radioactivity was generated and purified by high performance liquid chromatography. Mass spectrometric analysis identified a single molecular ion with a molecular mass of 1751.4 +/- 2, establishing that upon irradiation the bound photoligand forms a covalent link with the methyl group of a methionine residue at the peptide binding site. In view of our previous findings, this methionine is Met-181 on the primary sequence of the SP receptor.
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PMID:Identification of methionine as the site of covalent attachment of a p-benzoyl-phenylalanine-containing analogue of substance P on the substance P (NK-1) receptor. 882 8


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