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 century-old histological technique of silver nitrate staining has proven to be extremely useful for visualizing endothelial cell borders and localizing endothelial gaps, but the significance of the staining is still not fully understood. To gain some insight into what silver nitrate stains, we developed a method that enabled us to use scanning electron microscopy with backscattered and secondary electron imaging to examine silver staining at endothelial cell borders of venules of the rat tracheal mucosa. We found that in normal venules, silver lines followed the smooth contour of cell borders. However, 1 min after endothelial permeability was increased by substance P, cell borders were irregular and displaced from the silver lines by as much as 4.3 microns, and the lines were accompanied by three types of silver deposits. Most common (46% of total) were annulus-shaped silver deposits that surrounded endothelial gaps. These deposits averaged 1.5 microns in width, were positioned symmetrically across cell borders, and were located at a depth of 0.3 micron beneath the luminal surface. Many endothelial gaps were partitioned into multiple pores (mean, 2.4) by fingerlike processes of endothelial cells. Surprisingly, the gaps occupied only 5.4% of the total area of the silver deposits and constituted 0.15% of the luminal surface of the leaky postcapillary venules. A second type of silver deposit (19% of total) was positioned asymmetrically with respect to the cell border and marked sites where endothelial cell margins still overlapped but appeared to be vertically separated by obliquely oriented gaps. A third type marked gaps at three-cell junctions; these were no more abundant than deposits elsewhere around the cell perimeter, suggesting that three-cell junctions were not unusually leaky sites. We conclude that silver nitrate marks endothelial cell borders and outlines endothelial cell gaps by staining an element of intercellular junctions. The annular shape of many silver deposits around gaps suggests that junctional elements in the apposing cells are separated during gap formation but are still present at the gap perimeter.
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PMID:Location of focal silver staining at endothelial gaps in inflamed venules examined by scanning electron microscopy. 757 75

Nitric oxide is a potent mediator of endothelium-dependent vasodilation, the synthesis of which is catalyzed by the constitutively expressed enzyme endothelial nitric oxide synthase. In this study we have investigated whether human dermal microvascular endothelial cells express endothelial oxide synthase and whether the vasodilator neuropeptides, calcitonin gene-related peptide and substance P, stimulate the release of nitric oxide from these cells. Endothelial nitric oxide synthase was identified by immunohistochemistry in the blood vessels in both the papillary and deep dermis of normal skin, and also in monolayers of human dermal microvascular extracts prepared from both the dermis of normal human skin and human dermal microvascular endothelial cells, a 135-kDa band corresponding to endothelial nitric oxide synthase was identified. Nitric oxide was released from unstimulated human dermal microvascular endothelial cells as assessed by inhibition of platelet aggregation and nitrate formation. Endothelial cell-mediated inhibition of platelet aggregation was blocked by hemoglobin. Calcitonin gene-related peptide, (100 pM to 100 nM) directly inhibited platelet aggregation, and this direct effect was not modulated by microvascular endothelial cells. Substance P (10 nM to 1 muM) and calcitonin gene-related peptide (100 pM to 10 nM) significantly (p<0.05) increased nitrite formation, and this increase was blocked by the competitive nitric oxide synthase antagonist, NG-monomethyl-L-arginine. These results demonstrate that endothelial nitric oxide synthase is expressed in the microvascular endothelium of normal human skin and that human dermal microvascular endothelial cells release nitric oxide constitutively and in response to vasodilator neuropeptides.
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PMID:Neuropeptides induce release of nitric oxide from human dermal microvascular endothelial cells. 861

This study is aimed to investigate the relationship between plasma concentrations of nitrite and nitrate as a measure of ongoing nitric oxide (NO) production, the vasodilatory neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP), endotoxemia and hemodynamic changes in human septic shock. Thirteen patients with septic shock were studied within 6 h after the development of hypotension. Hemodynamic measurements and blood samples were recorded simultaneously at 2-h intervals from study admission. Eighteen normotensive patients with sepsis were included as control group of patients. On study entry, circulating levels of endotoxin did not relate to either CGRP or nitrite and nitrate plasma values. Septic shock patients had significantly higher plasma CGRP, and nitrite and nitrate concentrations, at each of the four time points, than patients with sepsis, as well as both groups of patients compared to normal subjects. No differences were found in plasma SP levels between the two groups of patients. For pooled data from all septic shock patients and measurements (n = 52), both plasma concentrations of CGRP and nitrite and nitrate were inversely correlated, independently from each other, to systemic vascular resistance. On study admission and at 2-h intervals, plasma CGRP concentrations correlated directly with nitrite and nitrate values. Our observations, thus, point to CGRP acting in concert with NO as important mediators responsible for hypotension in human septic shock.
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PMID:Relationship between circulating levels of calcitonin gene-related peptide, nitric oxide metabolites and hemodynamic changes in human septic shock. 888 78

1. Changes in the release of nitric oxide (NO) in vivo were studied in rats following the administration of endothelium-dependent and -independent vasodilators as well as the NO synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). NO production was assessed by measuring variations of nitrate in plasma by capillary ion analysis. 2. Intravenous administration of the endothelium-dependent vasodilators, bradykinin (2 and 10 micrograms kg-1 min-1) or substance P (0.3-3 micrograms kg-1 min-1) caused a transient dose-dependent hypotension followed by an increase in plasma nitrate concentration (maximal increments: 33 +/- 5% and 38 +/- 6%, for bradykinin and substance P, respectively). Prior administration of L-NAME (10 mg kg-1 min-1) inhibited the hypotension and increase in plasma nitrate caused by these substances. Intravenous administration of sodium nitrate (200 micrograms kg-1) also produced a transitory elevation in plasma nitrate which was similar in magnitude as that caused by the vasodilators. A rapid and transitory increment in plasma nitrate was observed after i.v. administration of authentic NO (400 micrograms kg-1). 3. Rats receiving the endothelium-dependent vasodilators, prostacyclin (0.6 micrograms kg-1 min-1) or adenosine (3 mg kg-1 min-1) intravenously showed a drop in blood pressure paralleled by a decrease in plasma nitrate (maximal decreases: 34 +/- 5% and 24 +/- 4%, for prostacyclin and adenosine, respectively). A similar effect on the plasmatic concentration of nitrate was observed when L-NAME (10 mg kg-1 min-1, i.v.) was administered to the animals. 4. This study demonstrates that (i) changes in plasma nitrate can be detected in vivo after stimulation or inhibition of NO synthase, (ii) an increased production of NO, measured as plasma nitrate, is related to the hypotension caused by bradykinin and substance P and (iii) a diminished concentration of plasmatic nitrate is associated to the hypotension induced by adenosine or prostacyclin (endothelium-independent vasodilators), suggesting that the L-arginine: NO pathway is capable of rapid down-regulation in response to a fall in blood pressure.
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PMID:Changes in nitric oxide release in vivo in response to vasoactive substances. 893 25

In the rat trachea, substance P causes rapid but transient plasma leakage. We sought to determine how closely the number, morphology, and size of endothelial gaps correspond to the time course of this leakage. Endothelial gaps were examined by scanning electron microscopy (EM), by transmission EM, or by light microscopy after silver nitrate staining. Substance P-induced leakage of the particulate tracer Monastral blue peaked at 1 min but decreased with a half-life of 0.3 min. The number of silver-stained gaps also peaked at 1 min then decreased significantly more slowly (half-life 1.9 min) than the leakage. Scanning EM revealed two types of endothelial gaps, designated vertical gaps and oblique slits. Vertical gaps predominated at peak leakage, whereas oblique slits became more common as the leakage diminished. Measurements of the mean diameter of vertical gaps made by light microscopy, scanning EM, and transmission EM were all in the range of 0.36-0.47 micron. Fingerlike endothelial cell processes that appeared during gap formation became shorter as the leakage diminished (mean length: 1.44 microns at 1 min compared with 1.06 microns at 3 min after substance P), suggesting a role in gap closure. We conclude that the plasma leakage occurring immediately after an inflammatory stimulus results from the rapid formation of endothelial gaps. Multiple factors, including alterations in gap morphology, gap closure, and changes in driving force, are likely to participate in the rapid decrease in the leakage.
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PMID:Endothelial gaps: time course of formation and closure in inflamed venules of rats. 903 15

This study was conducted to test the hypothesis that L-glutamine has differential effects on nitric oxide (NO) synthesis from L-arginine in bovine venular endothelial cells (EC) stimulated by A23187 (a Ca++ ionophore) and receptor-mediated vasodilators (bradykinin and substance P). EC were cultured at 37 degrees C for 24 h in the presence of 0.4 mM L-arginine and 0.0 to 2.0 mM L-glutamine with or without 1 microM A23187, 1 microM bradykinin or 10 microM substance P. The release of nitrite and nitrate by EC was used as an indicator of NO synthesis. A23187, bradykinin or substance P increased NO synthesis from L-arginine by EC in the presence or absence of L-glutamine. The addition of L-glutamine (0.5 and 2 mM) markedly increased intracellular concentrations of L-glutamine, L-glutamate and L-aspartate and decreased NO synthesis by EC in a concentration-dependent manner in the presence or absence of A23187, bradykinin or substance P. L-Glutamine had no effect on L-arginine uptake by EC or on intracellular L-arginine concentration. Neither L-glutamine nor its glutaminase metabolites (ammonia, L-glutamate and L-aspartate) had any effect on endothelial NO synthase activity. Taken together, these results suggest that the inhibition by L-glutamine of NO synthesis from L-arginine is unlikely to result from an effect of L-glutamine on L-arginine transport or NO synthase activity. Although the mechanism involved remains unknown, regulation of the arginine-NO pathway by L-glutamine may have pharmacologic and therapeutic implications in such conditions as inflammation and septic shock by inhibiting NO generation from L-arginine in endothelial cells.
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PMID:L-glutamine inhibits nitric oxide synthesis in bovine venular endothelial cells. 910 29

The aim of the present study was to investigate some putative neurotransmitters involved in nociception and pain in parturients during active labour experiencing intense visceral pain. The concentration of the excitatory amino acid aspartate was significantly increased, and there was a tendency for an increase in glutamate, in lumbar cerebrospinal fluid (CSF) of parturients in active vaginal labour compared with control patients without pain subjected to elective caesarean section. The CSF concentration of the nitric oxide breakdown product nitrate was significantly decreased in parturients compared with control patients and healthy volunteers. No significant differences in the concentrations of substance P, substance P-endopeptidase or met-enkephalin were detected between parturients and controls. Our data suggest a paradoxical negative relationship between CSF concentrations of excitatory amino acids and nitric oxide in labour pain. The mechanisms behind this finding is unclear at present.
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PMID:Increased cerebrospinal fluid concentration of aspartate but decreased concentration of nitric oxide breakdown products in women experiencing visceral pain during active labour. 914 Oct 79

Mystixins are synthetic peptides that inhibit plasma leakage after tissue injury. We sought to determine the mechanism of the antileakage effect of mystixins, with particular reference to the formation of endothelial gaps in postcapillary venules. Intravenous administration of mystixin-7, a prototype heptapeptide (p-anisoyl-Arg-Lys-Leu-Leu-D-Thi-Ile-D-Leu-NH2), decreased Evans blue leakage induced by substance P (5 microg/kg i.v.) with an ED50 (95% confidence limits) of 130 (76-211) microg/kg in trachea and 52 (27-100) microg/kg in skin of anesthetized F344 rats. Leakage was decreased without a reduction in the number or size of endothelial gaps, visualized by silver deposits after silver nitrate staining. The number of silver deposits per tracheal endothelial cell was 11.4 +/- 0.2 (mean +/- S.E.) after vehicle pretreatment vs. 13.0 +/- 0.8 after mystixin-7 pretreatment (100 microg/kg i.v.). Silver deposit diameter was unchanged at 1.4 +/- 0.1 micron. Mean arterial blood pressure dropped by a maximum of 38% from baseline for approximately 10 min after mystixin-7 (100 microg/kg i.v.), then recovered to a plateau at about 13% below baseline. The antileakage effect of mystixin-7 pretreatment in vivo was also demonstrated in aldehyde-fixed vessels perfused in situ with Evans blue at constant flow (skin, 79% reduction; trachea, 49% reduction), which suggests that mystixin can reduce leakage independent of its hypotensive effect. We conclude that the antileakage effect of mystixin does not depend on reducing the number or size of endothelial gaps, but instead could be caused by residual hypotension, which reduces the negative interstitial fluid pressure toward zero, or clogging of endothelial gaps.
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PMID:Anti-inflammatory mystixin peptides inhibit plasma leakage without blocking endothelial gap formation. 945 16

Neurogenic inflammation, in its original definition, the plasma leakage induced by stimulation of peripheral sensory nerves, occurs in the postcapillary venules of the skin and airways. Plasma leakage is accompanied by increased blood flow, which results from dilatation of arterioles. In skin, these phenomena are manifested as wheal and flare, respectively. Both phenomena are mediated by neuropeptides released from capsaicin-sensitive unmyelinated sensory nerve fibers. Substance P is the primary mediator responsible for plasma leakage, acting via tachykinin NK-1 receptors, whereas both calcitonin gene-related peptide and substance P induce vasodilatation. Sensory nerve transmitters also cause release of histamine from mast cells, which contributes substantially to plasma leakage in the skin, but less so in the airways. Substance P causes an increase in vascular permeability as a result of the focal, transient, and fully reversible formation of gaps, approximately 0.5 to 1.5 microns in diameter, located in the intercellular junctions of endothelial cells. The gaps can be visualized by silver nitrate staining of the endothelial cell borders, by lectin staining, or by scanning and transmission electron microscopy. Neurogenic inflammation can be inhibited by preventing the stimulation of sensory nerves, by presynaptic inhibition of neuropeptide release from sensory nerves, or by blocking neuropeptide receptors. The formation of endothelial gaps can also be inhibited by anti-inflammatory drugs that stabilize endothelial cells, such as beta-adrenergic agonists and steroids.
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PMID:Neurogenic inflammation in skin and airways. 948 20

A method for measuring endothelial damage caused by decompression was developed for vessels with a large radius. Segments of the pulmonary artery from pigs (8-12 wk old) were tested for endothelium damage using a system for recording changes in the tension in the vessel wall. Substance P (SP) was used as an endothelial-dependent dilation agonist. A significant decrease was found in the total response (Tmax) for SP as a result of endothelium damage, and the reduction in response was related to the number of bubbles. Furthermore, the sensitivity of the vessels to the agonist was significantly reduced after exposure to bubbles. Staining the endothelium with silver nitrate and light microscopy confirmed mechanical endothelium damage.
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PMID:Endothelial damage by bubbles in the pulmonary artery of the pig. 1035 78


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