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)

Footpad injection of endotoxin causes exclusive ocular inflammation in the rat. In order to clarify its physiopathologic mechanism, we studied the effect of different treatments on endotoxin-induced uveitis (EIU). Salmonella endotoxin was injected into the footpads of Lewis rats. 18 hr later, inflammation was assessed by evaluating proteins and cells in the anterior chamber; arachidonic acid (AA) metabolites, prostaglandin E2 and leukotriene B4, as well as substance P were measured by radioimmunoassay, and Ia-(MHC class II)-antigen expression in ciliary body was assessed by immunohistochemistry. The effect of inhibitors of phospholipase A2 (EPC), of lipoxygenase (azelastine) and of cyclo-oxygenase (diclofenac), as well as dexamethasone, cyclosporine (CsA) and anti-Ia antibody, were evaluated on these parameters. Phospholipase A2 inhibitor EPC and dexamethasone were most effective on inflammation: they also reduced AA metabolites very effectively and prevented Ia-expression. Lipoxygenase and cyclo-oxygenase inhibitors were partially effective on inflammation and on AA metabolites but failed to prevent Ia-expression. Immunosuppressive treatments (CsA and anti-Ia-antibody) also reduced inflammation. Our findings suggest that inflammation mediators initiate inflammation in EIU. Ia-Ag-expression is secondarily produced by mediators leading to additional inflammation due to immune mediated mechanisms.
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PMID:Immunopharmacological analysis of endotoxin-induced uveitis in the rat. 254 43

In the anterior segment of the eye, phosphoinositides of the iris-ciliary body are the major source of AA for PG biosynthesis. In the past several years, we have demonstrated that these phospholipids are highly enriched in AA and have an extremely high metabolic turnover. We have also discovered that their metabolism by phospholipase C, which leads to the formation of IP3 and DG and the liberation of AA, is controlled by the following Ca2+-mobilizing receptors: alpha 1-adrenergic, M3- or M4-muscarinic cholinergic, substance P, and PGs. The release of IP3, DG, and AA in the iris was also demonstrated under in vivo conditions. Furthermore, it was demonstrated that this release is associated with denervation supersensitivity and subsensitivity of the iris. Two pathways have been demonstrated in the iris through which AA can be released directly from phosphoinositides: (a) Phosphoinositides can be hydrolyzed by phospholipase C, followed by hydrolysis of DG via lipases to liberate AA, and (b) AA can be released directly from phosphoinositides via phospholipase A2. Although the evidence for a link between Ca2+-mobilizing receptors and phospholipase C, via G proteins, has been well established, the precise link between these receptors and phospholipase A2 is still unclear. Our studies indicated that PGs may be involved in regulation of contraction and relaxation of the smooth muscles of the iris by increasing IP3 accumulation and consequently Ca2+ mobilization and by elevating the level of cAMP which in turn facilitates muscle relaxation. In addition, evidence of a link between the two pathways through the Ca2+ signaling system has been suggested. In the iris, PAF was found to liberate AA from phosphoinositides through the phospholipase A2, but not the phospholipase C pathway, thus emphasizing the role of this pathway in PG synthesis in the eye. These findings demonstrate that AA release and, consequently, PG synthesis in the iris of the eye are exquisitely regulated. In some species, such as bovine, cat and dog, PGs were found to act as full Ca2+ mobilizing agonists. It is possible that PGs function to maintain muscle tone in the resting iris smooth muscle cells, in addition to their involvement in various Ca2+-dependent processes. Our studies indicate that PGs may be involved in regulation of contraction and relaxation of the smooth muscles of the iris by increasing IP3 accumulation and consequently Ca2+ mobilization and by elevating the level of cAMP which in turn facilitates muscle relaxation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of arachidonate release, prostaglandin synthesis, and sphincter constriction in the mammalian iris-ciliary body. 255 69

We studied the effect of bradykinin on ciliary activity and its modulation by peptidases in cultured rabbit tracheal epithelium in vitro. Bradykinin (10(-7) M) elicited a rapid, transient increase in ciliary beat frequency (CBF) from the baseline values of 1,031 +/- 25 to 1,388 +/- 38 beats/min (mean +/- SE, p less than 0.001), followed by a decline to a steady-state value of 1,180 +/- 30 beats/min, which was still greater than the baseline CBF. This ciliostimulation was dose-dependently inhibited by the B2-receptor antagonist (D-Arg,Hyp3,Thi5.8,D-Phe7)-bradykinin but not by the B1-receptor antagonist (Des-Arg9,Leu8)-bradykinin. Nifedipine, Ca2+-free medium, indomethacin, the phospholipase A2 inhibitor mepacrine, and the methyltransferase inhibitor 3-deazaadenosine reduced the change in CBF. Involvement of tachykinins, leukotrienes, prostaglandin D2, or thromboxane A2 was ruled out because bradykinin's action was not affected by (D-Pro2,D-Trp7.9)-substance P, nordihydroguaiaretic acid, or SQ29548, an antagonist for prostaglandin D2 and thromboxane A2. Bradykinin also increased prostaglandin E2 release (p less than 0.01), an effect that was abolished by indomethacin and Ca2+ deficiency. The CBF dose-response curve for bradykinin was shifted to lower concentrations by 1 log U by the neutral endopeptidase inhibitor phosphoramidon (p less than 0.01), whereas the angiotensin-converting enzyme inhibitor captopril was without effect. These results suggest that bradykinin interacts with B2-type receptors and stimulates ciliary activity through Ca2+-dependent prostaglandin E2 release, and that neutral endopeptidase may play a role in modulating the effect of bradykinin on airway mucociliary transport.
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PMID:Effect of bradykinin on airway ciliary motility and its modulation by neutral endopeptidase. 276 79

Classical techniques for studying modulations of microvascular permeability have a time resolution of minutes. A newly developed method allows continuous measurement of the electrical resistance of the microvascular membrane in vivo (Olesen & Crone 1983). The technique exploits microelectrodes impaled into the vascular lumen and is based on cable analysis of the vessel. It was applied to venules on the surface of the frog brain to test the effect on microvascular permeability of a wide variety of substances. The following agents increased ionic permeability reversibly within seconds: 5-hydroxytryptamine, bradykinin, ATP, ADP, AMP, phospholipase A2, arachidonic acid, leukotriene C4, oxygen-derived free radicals, ionophore A23187, and unbound Evans blue dye. An irreversible permeability increase was induced by protamine sulphate, neuraminidase, trypsin, melittin, and snake venoms from Crotalus durissus terrificus and Bothrops atrox. The following substances were without effect within an administration period of 5 min: histamine, epinephrine, putrescine, angiotensin II, vasoactive intestinal polypeptide (VIP), substance P, neurotensin, vasopressin, adenosine, PGE2, PGF2 alpha, prostacyclin (PGI2), leukotriene B4, albumin, heparin, plant cytokinins, hyaluronidase, thrombin, wasp venom. Variations in pH between 5.1 and 8.6 did not change permeability. Three conclusions are drawn from the observations: (1) the permeability of cerebral microvessels can be modulated by specific agents, (2) the agents induced changes in the endothelium within a few seconds, and (3) the rapid permeability increase induced by inflammatory mediators was less than two-fold and reversible within minutes.
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PMID:Substances that rapidly augment ionic conductance of endothelium in cerebral venules. 348 16

1. Binding of 125I-Tyr8-substance P (SP) to synaptic vesicles shows an uneven distribution within the brain and the spinal cord. The regional distribution has a positive correlation with the SP-content, except in the hypothalamus. 2. Ca2+ and MG2+-ions (1 and 10 mM) decrease the number of binding sites without alteration of affinity. EDTA and EGTA enhance SP-binding which is interpreted as being due to removal of the inhibitory influence of endogenous Ca2+ and Mg2+ through chelation with these agents. No significant inhibition of SP binding was observed by Na+ or K+ in concentrations below 100 mM. 3. Pretreatment of synaptic vesicles with trypsin or with phospholipase A2, C and D leads to a total loss of SP binding showing a proteolipid or a joint protein-phospholipid nature of these binding sites. SH groups do not contribute to SP binding since no effect of N-ethylmaleimide and monoidoacetic acid on SP binding was found.
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PMID:Regional distribution and biochemical properties of 125I-Tyr8-substance P binding sites in synaptic vesicles. 615 17

1. The present experiments were designed to further characterize the specific [3H]substance P (SP) binding to membrane fractions from rabbit brain. 2. The specific binding was resistant to treatment with proteolytic enzymes whereas phospholipase A(0.7 unit/ml), C(0.025 unit/ml) and D(6.2 unit/ml) reduced the specific binding without decreasing total binding. Neuraminidase (0.01 unit/ml) decreased total binding as well as the specific binding. 3. High concentration of Triton X-100 reduced the specific binding whereas deoxycholate, at 0.05%, reduced both total and the specific binding. 4. Na+ (50--200 mM) reduced the specific binding, depending on the concentrations employed, whereas K+ decreased the specific binding at 10 and 100 mM. The binding was reduced considerably by 100 mmol/l of CaCl2. 5. From these results it is suggested that the specific [3H]SP binding sites in membrane fractions from rabbit brain could be phospholipids.
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PMID:Further characterization of the binding of substance P to a fraction from rabbit brain enriched in synaptic membranes. 616 33

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

Neuronal plasticity associated with altered sensations arising from tissue damage involves both established (e.g. substance P and excitatory amino acids) and novel (e.g. nitric oxide and metabolites of arachidonic acid) mediators released from terminals of primary afferent neurons or synthesised in the spinal cord. These and other mediators lead to activity-dependent synaptic plasticity and enhanced sensitivity to noxious stimuli (hyperalgesia). Activation of the N-methyl-D-aspartate (NMDA) receptor results in a calcium-dependent production of nitric oxide, while activation of alpha-amino-3-hydroxy-5-methylisoxazole-5-propionate (AMPA)-and 1,3- trans-1-amino-cyclopentyl-1,3-dicarboxylate (trans-ACPD)-sensitive glutamate receptors results in a phospholipase A2 (PLA2)-mediated production of different intracellular mediators, including arachidonic acid. Thermal hyperalgesia requires NMDA receptor activation and is primarily mediated by production of nitric oxide. Mechanical hyperalgesia requires AMPA and metabotropic glutamate receptor coactivation, and is primarily mediated by cyclo-oxygenase products of arachidonic acid metabolism.
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PMID:Spinal mediators of hyperalgesia. 752 81

Somatostatin enhances an inward rectifier K conductance in cultured locus coeruleus neurons, while substance P reduces an inward rectifier K conductance in cultured nucleus basalis and locus coeruleus neurons. The role of arachidonic acid metabolites in these responses was studied. The somatostatin-induced response was reduced by phospholipase A2 inhibitors, non-specific lipoxygenase inhibitors and specific 5-lipoxygenase inhibitors. A cyclooxygenase inhibitor and a 12-lipoxygenase inhibitor had no effect. 5(S)-HPETE occasionally increased the K conductance, but failed to occlude the somatostatin response. The substance P response was suppressed by a 5-lipoxygenase inhibitor but not by a 12-lipoxygenase inhibitor. These results suggest that the 5-lipoxygenase pathway is not a specific messenger of either one of these responses, but that it plays a more general role in maintaining or enhancing the effectiveness of both somatostatin and substance P responses.
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PMID:The role of arachidonic acid metabolism in somatostatin and substance P effects on inward rectifier K conductance in rat brain neurons. 753 42

The tachykinins, substance P (SP) and neurokinins A (NKA) and B (NKB), have been identified in the respiratory tract and implicated in mediating neurogenic inflammation of the airways. To the extent that these neuropeptides may be involved in the pathogenesis of asthma, a condition associated with hyperplasia of airway smooth muscle (ASM), we examined the mitogenic effects and mechanisms of action of tachykinins in cultured rabbit ASM cells. SP was found to elicit dose-dependent (10(-14) to 10(-4) M) stimulation of ASM cell proliferation, with a mean (+/- SE) maximal increase in cell number of 169 +/- 6.1% of control. In contrast, NKA and NKB had little and no effect on ASM cell growth, respectively. Because SP is nonselective in its binding to the tachykinin receptors, to identify the specific NK receptor subtype(s) mediating the promitogenic action of SP, in separate studies we found that 1) the NK1-receptor-specific agonist, [beta-Ala4, Sar9, Met(O2)11]SP-(4-11) induced stimulation of ASM cell growth similar in magnitude to that elicited by SP; 2) in contrast, neither the NK1- nor NK2-receptor-specific agonists, [beta-Ala8]NKA-(4-10) and [MePhe7]NKB, respectively, had any effect on ASM cell growth; and 3) the promitogenic action of SP was inhibited by the NK1-receptor antagonist, GR-82,334. Moreover, in extended experiments, we found that the phospholipase C and phospholipase A2 inhibitors, neomycin and quinacrine, respectively, each inhibited SP-induced ASM cell proliferation by approximately 45%. Collectively, these observations provide new evidence that the tachykinin SP induces ASM cell proliferation, and that this action is mediated by transmembrane signaling coupled to selective activation of the NK1 receptor.
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PMID:Tachykinin regulation of airway smooth muscle cell proliferation. 757 67


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