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)

Injection of substance P (SP) in a rat hindpaw induced extravasation of 125I-labelled albumin in both hindpaws and salivation. Intravenous injection of SP dose-dependently increased vascular permeability. This latter effect was increased in rat paws by captopril, an inhibitor of angiotensin-converting enzyme (ACE), administered locally in combination with diprotin A, an inhibitor of an dipeptidyl(amino)peptidase IV (DAP IV) or phosphoramidon, an inhibitor of neutral endopeptidase (NEP). The increase in permeability induced by SP was inhibited by RP 67580, a NK-1-receptor antagonist. Intravenous injection of capsaicin induced labelled albumin extravasation in rat paws. This effect was increased by combination of captopril with diprotin A or phosphoramidon, but not by captopril associated with amastatin, an inhibitor of aminopeptidase M (AmM). It was suppressed by RP 67580. Injection of collagenase in rat paws triggered a swelling and a local plasma exudation. These responses were reduced by RP 67580 but not by RP 68651, its inactive enantiomer. They were increased by combination of captopril with diprotin A or phosphoramidon in normal rats. The potentiating effects of captopril and diprotin A were suppressed by RP 67580 in normal rats but did not develop in kininogen-deficient rats. The oedema induced by collagenase was also increased by lisinopril, another ACE inhibitor, administered locally in combination with apstatin, an inhibitor of aminopeptidase P (AmP). In rats pretreated by methysergide, collagenase-induced oedema was reduced and can be increased by captopril, by lisinopril, administered alone or by lisinopril associated with apstatin. It is concluded that SP is mainly inactivated in rat paws by ACE, DAP IV and NEP. In collagenase-induced oedema, a low amount of SP would be released from afferent nerve terminals by bradykinin formed in low amounts. Bradykinin is inactivated in rat paws by ACE and AmP. In collagenase-oedema, the pro-inflammatory effects of bradykinin are concealed by the effects of the other mediators.
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PMID:Influence of several peptidase inhibitors on the pro-inflammatory effects of substance P, capsaicin and collagenase. 893 67

We previously described a model of intestinal hypersensitivity in which isolated gut segments from sensitized rats demonstrated a rapid epithelial secretory response to luminal antigen that was mediated by mucosal mast cells and capsaicin-sensitive nerves. In this study, we examined the ability of the inhibitory neuropeptide, neuropeptide Y (NPY), to diminish the antigen-induced secretory response. Rats were sensitized to egg albumin (EA), and 12-14 days later, jejunal tissue was excised and mounted in Ussing chambers. NPY inhibited the short-circuit current (Isc) increase and Cl- secretion evoked by addition of EA to the luminal side of the tissue; neural blockade with tetrodotoxin (TTX) had a similar inhibitory effect. In contrast, NPY was much less effective, and TTX was completely ineffective, on the response to serosal antigen. Additional experiments examined the cell target for NPY action. NPY and TTX almost abolished the Isc response to electrical transmural stimulation of enteric nerves, suggesting a possible neural site of action. In addition, NPY significantly reduced baseline Isc; this inhibition involved both TTX-dependent and TTX-independent components. Because nerves were previously shown to facilitate antigen uptake and substance P was implicated in the response to only luminal antigen, we postulated that NPY was inhibiting nerves that facilitate antigen transport from the lumen to effector cells in the lamina propria. We therefore examined the effect of exogenous substance P added after NPY inhibition. Substance P restored the luminal antigen-induced secretory response to pretreatment values. We conclude that the neuropeptides play a significant role in immunophysiology by acting at neural and epithelial sites in the intestinal mucosa.
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PMID:Effects of neuropeptide Y and substance P on antigen-induced ion secretion in rat jejunum. 899 42

Human trials for the treatment of cystic fibrosis lung disease with adenoviral vectors have been complicated by acute inflammatory reactions of unknown etiology. Because replicating respiratory viruses can potentiate tachykinin-mediated neurogenic inflammatory responses in airways, we studied whether the endotracheal administration of a replication-deficient adenoviral vector potentiated this response. The vector Ad5CMVLacZ was administered endotracheally to rats and the leakage of Evans blue dye was used to measure the capsaicin-induced neurogenic albumin extravasation. These studies show that neurogenic albumin extravasation is significantly potentiated in the airways of rats after administration of Ad5CMVLacZ. This inflammatory response can be blocked by selective antagonists of the substance P receptor or by glucocorticoids. Therefore, (1) the acute airway inflammation observed in patients after exposure to adenoviral vectors may exhibit a neurogenic component, which can be blocked pharmacologically, and (2) preclinical adenoviral vector safety studies of other organs innervated by the tachykinin system, e.g., coronary arteries and gastrointestinal tract, should include assessment of neurogenic inflammation.
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PMID:Replication-deficient adenoviral vector for gene transfer potentiates airway neurogenic inflammation. 907 Jun 9

1. Peroxynitrite (ONOO-) is a cytotoxic species, formed by the reaction between nitric oxide and superoxide free radicals, that may be involved in inflammation. In this study we have investigated the effect of peroxynitrite on plasma extravasation and microvascular blood flow in the dorsal skin and on nociceptive responses in the hind paw of the rat. 2. Male Wistar rats were anaesthetized and their dorsal skin shaved. Plasma extravasation was measured by the extravascular accumulation of 125I-labelled albumin over 0-45 min and 0-240 min. Blood flow was measured by laser-Doppler flowmetry over 0-240 min. Studies in the hind paw were carried out in the conscious rat. Hind paw weight changes were determined by volume displacement and nociception by a mechanical hyperalgesia technique. 3. Intradermal (i.d.) peroxynitrite (100-200 nmol site-1) produced a significant (P < 0.01) dose-dependent increase in plasma extravasation in dorsal skin over 0-45 min which was not increased over 45-240 min. Plasma extravasation was significantly (P < 0.001) decreased in rats pretreated with the anti-inflammatory steroid dexamethasone (1 mg kg-1, i.v.; -180 min), but not modulated by treatment with the hydrogen peroxide deactivator catalase (2200 u site-1), or the superoxide scavenger superoxide dismutase (500 u site-1), effective doses of the tachykinin NK1 antagonist SR140333 (1 nmol site-1), the cyclo-oxygenase inhibitor indomethacin (358 mumol site-1), or combined pretreatment with mepyramine (histamine H1-receptor antagonist; 2.8 nmol site-1) and methysergide (5-HT antagonist; 1.9 nmol site-1). 4. Microvascular blood flow was significantly (P < 0.05) increased 30 and 120 min after i.d. peroxynitrite (100 nmol site-1) in dorsal skin and remained raised until the end of the recording period (240 min). The increase in blood flow was unaffected by dexamethasone (1 mg kg-1, i.v.; -180 min) or indomethacin (10 mg kg-1, s.c.; -30 min). 5. Hind paw volume was significantly (P < 0.001) increased 30 min after intraplantar peroxynitrite (87.5 and 175 nmol paw-1) and remained raised for the duration of the experiment (360 min). By comparison, nociception was not altered by intraplantar peroxynitrite. 6. These data indicate that peroxynitrite can cause an increase in both plasma extravasation and blood flow, suggesting that peroxynitrite could be of biological relevance to microvascular responses. These findings may be of importance in the pathology of inflammatory diseases in which peroxynitrite formation occurs.
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PMID:Effect of peroxynitrite on plasma extravasation, microvascular blood flow and nociception in the rat. 940 73

The role of substance P in experimental allergic conjunctivitis induced by egg albumin was investigated with guinea pigs. Increase in vascular permeability of the conjunctiva induced by antigen was significantly inhibited after repeated application of capsaicin. Substance P contents in the conjunctiva of guinea pig were decreased by topical instillation of antigen to the eyes, suggesting that substance P was released from the conjunctiva due to antigen-antibody reaction. Moreover, subconjunctival injection of substance P resulted in a dose-related conjunctivitis, and vascular permeability in the conjunctiva was also increased by substance P. In substance P-induced conjunctivitis, a significant edema was observed in the bulbar and palpebral conjunctiva, but no hyperemia was noted in all instances. Histamine contents of the conjunctiva and tears were not influenced by subconjunctival injection of substance P. However, topical application of antigen and subconjunctival injection of compound 48/80 caused a significant decrease in histamine content, and content of tear was increased by both treatments. An increase in vascular permeability induced by antigen application was significantly inhibited by intravenous injection of FK-888, which is a specific and potent NK1 receptor antagonist. From these results, it is suggested that substance P is responsible for allergic conjunctivitis to some extent, and the conjunctival hyperpermeability induced by substance P occurs through NK1 receptor on the blood vessels, rather than by the direct action on the conjunctival mast cells during allergic conjunctival reactions.
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PMID:Role of substance P in experimental allergic conjunctivitis in guinea pigs. 950 Jan 28

Neurogenic inflammation in the airways involves both mucosal oedema and plasma protein exudation into the airway lumen. We aimed to investigate the mechanism of exudation of plasma proteins into the airway lumen. Neurogenic inflammation was induced in anaesthetized Sprague-Dawley rats by electrical stimulation of both vagal nerves at 20 V, 10 Hz, 5 ms. Vascular permeability was measured as 125I-albumin extravasation into both the airway wall and tracheobronchial lavage fluid. Following vagal stimulation, tracheobronchial lavages were analysed for albumin, total protein, histamine, immunoreactive substance P (SP), and immunoreactive calcitonin gene-related peptide (CGRP). Vagal stimulation rapidly increased vascular permeability in the airway mucosa and induced exudation of plasma proteins into the tracheobronchial fluid. Pre-treatment with capsaicin inhibited both neurogenic vascular permeability and movement of albumin into the airway lumen. SP and CGRP were detectable in basal lavages (1.37+/-0.12 ng/mL and 2.17+/-0.21 ng/mL, respectively) and the concentration of SP fell by 43% following treatment with capsaicin. Following vagal stimulation, concentrations of both SP and CGRP decreased significantly. Although basal tracheobronchial lavages contained histamine, vagal stimulation did not increase the histamine concentration. These results indicate that both neurogenic vascular permeability and plasma protein exudation into the airway lumen results from activation of capsaicin-sensitive sensory nerves and the reaction is not associated with mast cell activation.
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PMID:Role of sensory innervation and mast cells in neurogenic plasma protein exudation into the airway lumen. 952 96

1. Neurogenic vasoactive responses in rat skin were investigated following 8 weeks of streptozotocin-induced diabetes to determine the effect of diabetes and of treatment with insulin and nerve growth factor (NGF) treatment. 2. Diabetic rats were divided into three groups: untreated; insulin (4 IU day(-1) by s.c. implant weeks 4-8) treated; Nerve Growth Factor, NGF, (0.2 mg kg(-1) three times weekly, weeks 4-8) treated. A fourth group served as a non-diabetic control. 3. Electrical stimulation of the saphenous nerve (10 V, 2 Hz, 1 ms for 30 s) increased blood flow in the ipsilateral paw skin, as measured by laser Doppler flowmetry. The peak increase was similar between groups, but the time taken for flow to return to a steady baseline was significantly (P < 0.01) reduced in untreated diabetic rats, when compared with non-diabetic controls, but not significantly reduced in the insulin- or NGF-treated diabetic groups. 4. A second stimulation of the saphenous nerve (10 V, 2 Hz, 1 ms for 5 min) produced plasma extravasation, measured by the extravascular accumulation of 125I-albumin, in the skin. Plasma extravasation was significantly attenuated (P < 0.001) in the untreated diabetic group, but not the insulin-treated group, compared to non-diabetic controls. Plasma extravasation was present, though reduced, in the NGF-treated group. 5. Plasma extravasation induced by intradermal injections of substance P with and without CGRP was similar in all groups indicating no decrease in vascular responsiveness to exogenously applied neuropeptides. The results suggest that release of neuropeptides is diminished in diabetes and that treatment with either insulin or NGF can restore neurogenic microvascular vasoactive responses towards normal.
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PMID:Neurogenic cutaneous vasodilatation and plasma extravasation in diabetic rats: effect of insulin and nerve growth factor. 972 73

The involvement of bradykinin and some other inflammatory mediators in formalin-induced oedema and plasma extravasation was examined. Formalin was injected in rat paws at two doses, 1.75% or 5%. The lower dose induced the development of an immediate oedema associated with a progressive accumulation of 125I-labelled albumin in the paws. These changes were suppressed by pretreatment with capsaicin or xylocaine. They were abolished by RP67580, a NK1 receptor antagonist, and increased by phosphoramidon or diprotin A. They were not affected by HOE140, a bradykinin B2 antagonist, captopril, methysergide, mepyramine, indomethacin, ketoprofen or L-N(G)-nitroarginine. The higher dose of formalin induced a swelling of the paws which took place in two phases associated with two periods of increase in vascular permeability. This oedema was reduced by pretreatment with capsaicin but not with xylocaine. It was reduced by RP67580 injected before or 30 min after formalin. It was inhibited by mepyramine, methysergide, indomethacin and NS-398, a cyclooxygenase-2 inhibitor. It was not modified by HOE140. Its development was similar in normal and kininogen-deficient rats. We concluded that formalin administered at a low dose induces an oedema which mainly results from a neurogenic inflammation mediated by neuropeptides such as substance P. At higher doses, formalin induces an oedema which mainly depends on the release of substance P, prostanoids, 5-hydroxytryptamine and histamine. Bradykinin plays no significant role in the vascular changes whereas this peptide has been reported to participate in the stimulation of nociceptive afferent neurons. This discrepancy could be explained by a difference in the threshold of stimulation of the nociceptive neurons and that of the cells of the vascular walls, or by a formation of kinins in close contact of the neurons.
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PMID:The inflammatory reaction induced by formalin in the rat paw. 1020 9

Silver nitrate stains the intercellular junctions of the endothelium and other cytoplasmic or membrane components. Two protocols are described for the silver staining of rat carotid endothelium that exclude the use of pressurized fixatives and simplify the technique previously described for rat aorta. The entire surface of the carotid endothelium was examined and several parameters (stigmata, granularity, clustering of anionic sites, transversal lines, weakening of silver lines and leukocyte adhesion) were evaluated. We studied the pattern of silver staining in two situations: (1) endothelial activation and (2) neurogenic inflammation. Endothelial activation was produced by the intravenous administration of a proinflammatory albumin or polyinosinic acid. Both products cause a marked increase in leukocyte adhesion concomitant with a decrease in argyrophilia and a weakness or loss of silver lines. Neurogenic inflammation, which is mediated by substances released from sensory nerves, was induced by the intravenous administration of substance P or capsaicin. Both stimuli produced an increase in argyrophilia and weakness or loss of silver lines. Substance P caused a clustering of anionic sites, whereas this phenomenon was more discrete with capsaicin. Nearly 80% of all examined rats (controls and inflammatory stimuli treated) showed endothelial membrane disruptions formed by clusters of cells often in the shape of streaks aligned with the long axis of the vessel. The detection of these discontinuities is important, as loss of endothelial integrity is central in the initiation of pathological events.
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PMID:Effect of inflammatory stimuli on the silver staining pattern of the rat carotid endothelium. 1042 14

The mechanisms involved in tachykinin-induced neurokinin-1 (NK(1)) receptor-mediated edema formation have been studied in anesthetized wild-type and NK(1) knockout mice. Intradermally injected substance P (30-300 pmol), NK(1) agonists septide (3-30 pmol) and GR-73632 (3-30 pmol), and the mast cell-degranulating agent, compound 48/80 induced dose-dependent edema in wild-type skin, measured by the accumulation of intravenously injected (125)I-labeled albumin. Septide was 3-10x more potent than substance P. The tachykinins were inactive in knockout mice, but compound 48/80 induced a significantly greater edema (P < 0.05) than that observed in paired wild-type mice. Capsaicin (which releases endogenous neuropeptides) and exogenous tachykinins induced edema formation, which was reduced by the mast cell amine histamine H(1) antagonist mepyramine (P < 0.05). These findings confirm that tachykinins mediate edema formation via the NK(1) receptor and provide direct evidence that the septide-sensitive binding site is on the NK(1) receptor. Furthermore, results suggest that edema induced by the tachykinins, although totally dependent on NK(1) receptor-mediated mechanism, contains a mast cell-dependent component. The evidence is in keeping with an NK(1) receptor on mast cells.
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PMID:Use of NK(1) knockout mice to analyze substance P-induced edema formation. 1044 54


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