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)

1. The effect of the inhaled alpha-adrenoceptor agonist, methoxamine (MTX), was studied on experimental airway oedema induced by injection of substance P (SP) in the rat. Sprague-Dawley rats (300-350 g) were anaesthetized with sodium thiopentone, tracheotomized and artificially ventilated. 2. MTX or its vehicle was administered by inhalation. Airway resistance and blood pressure were monitored continuously. Evans Blue dye (EB, 20 mg kg-1) was injected through a jugular catheter 1 min before SP (14.8 nmol kg-1). Airways were dissected out, weighed and placed in formamide for EB extraction and determination by spectrophotometry. 3. EB extravasation induced by SP was significantly reduced in distal intraparenchymal bronchi by inhaled MTX at doses of 50 micrograms kg-1 (58 +/- 9 vs 96 +/- 9 ng EB mg-1 tissue after vehicle, P < 0.001) and 100 micrograms kg-1 (69 +/- 11 vs 137 +/- 26 ng EB mg-1 tissue after vehicle, P < 0.01). Inhaled MTX by itself (100 micrograms kg-1) increased blood pressure: 172 +/- 6 vs 132 +/- 10 mmHg baseline (P < 0.02), but neither induced extravasation nor increased airway resistance. 4. In another set of experiments without SP, MTX was administered intravenously 1 min after EB. At 100 micrograms kg-1, i.v. MTX increased blood pressure to a similar extent as inhaled MTX (180 vs 147 mmHg baseline, P < 0.01), increased airway resistance and caused leakage of plasma proteins in distal intraparenchymal bronchi (79 +/- 7 vs 47 +/- 1 ng EB mg-1 tissue, P < 0.02). 5 Similarly, after sequential i.v. injections of doubling doses of MTX (50-800 microg kg-1), a marked EB extravasation was found in the airways. This was abrogated by pretreatment with prazosin (100 microg kg-1)but not with propranolol (2 mg kg-1).6 These results suggest that microvascular leakage and airway oedema induced by i.v. MTX may be linked to an increase in pressure in the pulmonary circulation, resulting from vasoconstriction of the pulmonary vasculature and acute cardiac dysfunction due to systemic hypertension.7 Our results with inhaled MTX show that direct deposition of MTX at the bronchial vasculature induces a reduction in SP-induced microvascular leakage in rat airways and that inhaled MTX does not share the untoward effect of i.v. MTX inducing airway oedema.
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PMID:Inhibition of substance P-induced microvascular leakage by inhaled methoxamine in rat airways. 753 May 77

The rational design of a non-peptide tachykinin NK1 receptor antagonist, [(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3)P h (28, PD 154075) is described. Compound 28 has a Ki = 9 and 0.35 nM for the NK1 receptor binding site in guinea-pig cerebral cortex membranes and human IM9, cells respectively (using [125I] Bolton-Hunter-SP as the radioligand). It is a potent antagonist in vitro where it antagonises the contractions mediated by SPOMe in the guinea-pig ileum (KB = 0.3 nM). Compound 28 is active in vivo in the guinea-pig plasma extravasation model, where it is able to block the SPOMe-induced protein plasma extravasation (monitored by Evans Blue) in the bladder with an ID50 of 0.02 mg kg-1 iv.
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PMID:Rational design of high affinity tachykinin NK1 receptor antagonists. 792 47

1. The inbred genetically hypertensive strain (GH) of the Otago Wistar rat possesses more sensory neurons containing the neuropeptide substance P (SP) than does its genetically related control normotensive strain. 2. As SP contributes to airway inflammation by increasing microvascular permeability, we assessed the extravasation of Evans Blue dye in trachea and main bronchus of anaesthetized GH and control rats, in the presence of endogenous (capsaicin-liberated) or exogenous SP. 3. Following intravenous administration of either capsaicin (75 microg kg(-1)) or SP (3.3 nmol kg(-1)), extravasation of Evans Blue in airways from GH rats was only about 60% of that in airways of control rats. This difference was not gender-specific and responses to capsaicin were abolished by pretreatment with a selective NK1 receptor antagonist SR 140333 (360 nmol kg(-1)). 4. By contrast, the extravasation of dye caused by intravenous 5-hydroxytryptamine (0.5 micromol kg(-1)) was similar in magnitude in both GH and control strains. 5. Falls in systemic arterial blood pressure in response to exogenous SP (0.1-3 nmol kg(-1)) or acetylcholine (0.2-2 nmol kg(-1)) were also very similar between strains, but those in response to capsaicin (75 microg kg(-1)) in the GH rats were about double those in control rats. The hypotensive response to SP was abolished by SR 140333, but that to capsaicin was unaffected. 6. Our results indicate that the increased peripheral innervation density by SP-nerves in GH rats is accompanied by reduced inflammatory responses to SP. This does not involve decreased vasodilator potency of SP and is therefore probably related to altered endothelial responsiveness.
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PMID:Decreased vascular permeability response to substance P in airways of genetically hypertensive rats. 1019 73

At the time of parturition (fetal delivery) the uterine cervix must "ripen," becoming soft, pliable, and dilated to accommodate the fetus' delivery. The fundamental processes underlying cervical ripening remain poorly understood. Knowledge that abundant autonomic and sensory nerves supply the uterine cervix, that transection of afferent nerves supplying the cervix blocks parturition, and that some of the changes in the cervix resemble those seen in inflammatory reactions suggests nerves may have a role in the cervical ripening changes. The present study utilized immunohistochemistry, plasma extravasation, and solution hybridization-nuclease protection assay to elucidate the complement of primary afferent nerves and some receptors in the rat cervix during pregnancy, and to determine if they may have roles in the ripening process at term. This study revealed an abundance of nerves associated with the cervical vasculature and myometrial smooth muscle containing immunoreactivity for substance P, calcitonin gene-related peptide, secretoneurin, and nitric oxide synthase throughout pregnancy. Many of these are small unmyelinated capsaicin-sensitive C-fibers. Substance P- (NK1-) and calcitonin gene-related peptide receptors were apparent on uterine cervix vasculature from pregnant, parturient, and postpartum rats. NK1 receptor mRNA was maximal at 20 days of pregnancy. Plasma extravasation of i.v. administered Evans Blue or Monastral Blue was most pronounced at parturition (shortly after NK1 mRNA is maximal); this was similar to plasma extravasation evoked by i.v. administration of substance P or capsaicin-treatment. This study revealed new data about the nervous system of the rat uterine cervix and that these nerves and their transmitters could very well be part of a neurogenic inflammatory process involved in cervical ripening.
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PMID:Sensory nerves and neuropeptides in uterine cervical ripening. 1181 32

Substance P (SP) and calcitonin gene-related peptide (CGRP), released from capsaicin-sensitive sensory nerves induce local neurogenic inflammation, while somatostatin exerts systemic anti-inflammatory actions. The aim of the present study was to investigate the release of pituitary adenylate cyclase activating polypeptide-38 (PACAP-38) and its effects on sensory neuropeptide release in vitro and acute neurogenic ear swelling in vivo. Capsaicin (10(-6) M) or electrical field stimulation (EFS; 40 V, 0.1 ms, 10 Hz, 120 s; 1200 impulses)-induced release of PACAP-38, SP, CGRP and somatostatin from isolated rat tracheae was measured with radioimmunoassay. Mustard oil-induced neurogenic inflammation in the mouse ear was determined with a micrometer and in the rat hind paw skin by the Evans Blue leakage technique. Capsaicin and EFS evoked 27% and more than twofold elevation of PACAP-38 release respectively, compared with the prestimulated basal values from isolated trachea preparation. Exogenously administered PACAP-38 (20-2000 nM) diminished both capsaicin- and EFS-evoked sensory neuropeptide release in a concentration-dependent manner. The maximal inhibitory effects of PACAP on capsaicin-induced substance P, CGRP and somatostatin release amounted to 75.4%, 73.3% and 90.0%, while EFS-evoked release of these peptides was 80.03%, 87.7% and 67.7%. In case of capsaicin stimulation the EC50 values for substance P, CGRP and somatostatin were 82.9 nM, 60.1 nM and 66.9 nM, respectively. When EFS was performed, these corresponding EC50 data were 92.1 nM, 67.8 nM and 20.9 nM. PACAP-38 (10, 100 and 1000 microg/kg i.p. in 200 microl volume) inhibited neurogenic ear swelling in the mouse. Furthermore, 100 microg/kg i.p. PACAP also significantly diminished mustard oil-evoked plasma protein extravasation in the rat skin. These results suggest that PACAP-38 is released from the stimulated peripheral terminals of capsaicin-sensitive afferents and it is able to inhibit the outflow of sensory neuropeptides. Based on this mechanism of action PACAP is also able to effectively diminish/abolish neurogenic inflammatory response in vivo after systemic administration.
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PMID:Effect of pituitary adenylate cyclase activating polypeptide-38 on sensory neuropeptide release and neurogenic inflammation in rats and mice. 1693 9

Neuropathic pain consequent to peripheral nerve injury has been associated with local inflammation. Following noxious stimulation afferent fibres release substance P (SP) and calcitonin-gene related peptide (CGRP), which are closely related to oedema formation and plasma leakage. The effect of the anandamide transport blocker AM404 has been studied on plasma extravasation after chronic constriction injury (CCI) which consists in a unilateral loose ligation of the rat sciatic nerve (Bennett and Xie, 1988). AM404 (1-3-10 mg kg(-1)) reduced plasma extravasation in the legated paw, measured as mug of Evans Blue per gram of fresh tissue. A strong effect on vascular permeability was also produced by the synthetic cannabinoid agonist WIN 55,212-2 (0.1-0.3-1 mg kg(-1)). Using specific antagonists or enzyme inhibitors, we demonstrate that cannabinoids act at several levels: data on the 3rd day suggest a strong involvement of substance P (SP) and calcitonin gene-related peptide (CGRP) in the control of vascular tone, whereas at the 7th and 14th days the major role seems to be played by prostaglandins (PGs) and nitric oxide (NO). Capsaicin injection in ligated paws of AM404- or WIN 55,212-2-treated rats resulted in an increase of Evans Blue extravasation, suggesting the involvement of the cannabinergic system in the protective effect of C fibres of ligated paws. Taken together, these data demonstrate the efficacy of cannabinoids in controlling pain behaviour through the modulation of several pain mediators and markers of vascular reactivity, such as SP, CGRP, PGs and NO.
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PMID:AM404, an anandamide transport inhibitor, reduces plasma extravasation in a model of neuropathic pain in rat: role for cannabinoid receptors. 1809 21

Substance P (SP) and calcitonin gene-related peptide (CGRP) released from capsaicin-sensitive sensory nerves induce local neurogenic inflammation in the innervated area. The aim of the present study was to investigate the effects of an endogenous opioid peptide, endomorphin-1, on sensory neuropeptide release in vitro and acute neurogenic and non-neurogenic inflammatory reactions in vivo. Electrical field stimulation (EFS; 40 V, 0.1 ms, 10 Hz, 120 s; 1200 impulses) was performed to evoke SP and CGRP release from peptidergic afferents of the isolated rat tracheae which was determined from the incubation medium with radioimmunoassay. Neurogenic inflammation in the skin of the acutely denervated rat hind paw was induced by topical application of 1% mustard oil and detected by Evans Blue leakage. Mustard oil-induced ear swelling of the mouse was determined with a micrometer during 3 h and myeloperoxidase activity as an indicator of granulocyte accumulation was measured with spectrophotometry at 6 h. EFS evoked about a twofold elevation in the release of both pro-inflammatory sensory neuropeptides. Endomorphin-1 (5 nM-2 microM) diminished the release of SP and CGRP in a concentration-dependent manner, the EC50 values were 39.45 nM and 10.84 nM, respectively. The maximal inhibitory action was about 80% in both cases. Administration of endomorphin-1 (1-100 microg/kg i.p.) dose-dependently inhibited mustard oil-evoked neurogenic plasma protein extravasation in the rat skin as determined by microg Evans Blue per g wet tissue. Repeated i.p. injections of the 10 microg/kg dose three times per day for 10 days did not induce desensitization in this model. Neurogenic swelling of the mouse ear was also dose-dependently diminished by 1-100 microg/kg i.p. endomorphin-1, but non-neurogenic neutrophil accumulation was not influenced. These results suggest that endomorphin-1 is able to inhibit the outflow of pro-inflammatory sensory neuropeptides. Based on this mechanism of action it is also able to effectively diminish neurogenic inflammatory responses in vivo.
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PMID:Inhibitory action of endomorphin-1 on sensory neuropeptide release and neurogenic inflammation in rats and mice. 1824 5

We have recently reported on the efficacy of an NK1 tachykinin receptor antagonist in improving outcome following stroke, including reduced blood-brain barrier (BBB) disruption, reduced cerebral edema and improved functional outcome. The clinically approved stroke treatment, tissue plasminogen activator (tPA), has been associated with an increased risk of hemorrhage and death, if given at later time points. Accordingly, adjunctive therapies have been investigated to reduce the adverse effects of tPA and improve outcome. The aim of the present study was to characterize the effects of a combination of an NK1 tachykinin receptor antagonist with tPA, on BBB permeability and functional outcome following transient ischemic stroke in rats. Stroke was induced in male Sprague-Dawley rats using a reversible thread model of middle cerebral artery occlusion where occlusion was maintained for 2h, followed by reperfusion. Animals received either 25mg/kg of N-acetyl-l-tryptophan or 1mg/kg of tPA, either alone or in combination, or equal volume saline vehicle, intravenously at the time of reperfusion. Functional outcome was assessed by the rotarod, bilateral asymmetry test, modified neuroscore and open field tests. BBB permeability was assessed by Evans Blue extravasation. Combination therapy of an NK1 tachykinin receptor antagonist with tPA significantly reduced BBB permeability, functional deficits and the incidence of intracerebral hemorrhage and death. As such, combined tPA-NK1 tachykinin receptor antagonist treatment may represent a novel therapeutic intervention for the treatment of reperfusion injury in acute ischemic stroke.
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PMID:Combined tissue plasminogen activator and an NK1 tachykinin receptor antagonist: an effective treatment for reperfusion injury following acute ischemic stroke in rats. 2275 Feb 40

The blood spinal cord barrier (BSCB) is disrupted following spinal cord injury (SCI) resulting in vasogenic edema and increased intrathecal pressure (ITP). The neuropeptide substance P (SP) has been implicated in the development of blood-brain barrier (BBB) disruption, edema, and increased intracranial pressure following brain injury, although it has not been investigated in SCI. The balloon compression model of experimental SCI has many advantages in that it replicates the "closed" environment observed clinically. Accordingly, this study characterized whether this model produces an increase in BSCB permeability and edema, and whether a SP, NK1 tachykinin receptor antagonist, N-acetyl-L-tryptophan (NAT) reduces such BSCB disruption and edema formation. At 30 min post-injury, animals were administered 2.5 mg/kg NAT or saline. Subgroups of animals were assessed for BSCB permeability (Evan's Blue) and spinal cord edema (wet weight/dry weight). BSCB permeability and edema were significantly increased in injured groups compared with sham (p < 0.001). There was no significant difference between vehicle and NAT treatment. We conclude that the balloon compression model of SCI produces significant BSCB disruption although NAT treatment did not attenuate BSCB permeability or edema. Further studies are required to fully elucidate the role of SP following SCI.
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PMID:The effect of an NK1 receptor antagonist on blood spinal cord barrier permeability following balloon compression-induced spinal cord injury. 2356 54

The neuropeptide substance P (SP) has been implicated in the disruption of the blood-brain barrier (BBB) and development of cerebral edema in acute brain injury. Cerebral edema accumulates rapidly around brain tumors and has been linked to several tumor-associated deficits. Currently, the standard treatment for peritumoral edema is the corticosteroid dexamethasone, prolonged use of which is associated with a number of deleterious side effects. As SP is reported to increase in many cancer types, this study examined whether SP plays a role in the genesis of brain peritumoral edema. A-375 human melanoma cells were injected into the right striatum of male Balb/c nude mice to induce brain tumor growth, with culture medium injected in animals serving as controls. At 2, 3 or 4 weeks following tumor cell inoculation, non-treated animals were perfusion fixed for immunohistochemical detection of Albumin, SP and NK1 receptor. A further subgroup of animals was treated with a daily injection of the NK1 antagonist Emend (3 mg/kg), dexamethasone (8 mg/kg) or saline vehicle at 3 weeks post-inoculation. Animals were sacrificed a week later to determine BBB permeability using Evan's Blue and brain water content. Non-treated animals demonstrated a significant increase in albumin, SP and NK1 receptor immunoreactivity in the peritumoral area as well as increased perivascular staining in the surrounding brain tissue. Brain water content and BBB permeability was significantly increased in tumor-inoculated animals when compared to controls (p<0.05). Treatment with Emend and dexamethasone reduced BBB permeability and brain water content when compared to vehicle-treated tumor-inoculated mice. The increase in peritumoral staining for both SP and the NK1 receptor, coupled with the reduction in brain water content and BBB permeability seen following treatment with the NK1 antagonist Emend, suggests that SP plays a role in the genesis of peritumoral edema, and thus warrants further investigation as a potential anti-edematous treatment.
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PMID:Treatment with the NK1 antagonist emend reduces blood brain barrier dysfunction and edema formation in an experimental model of brain tumors. 2481 61


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