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)

Previous work has suggested that vasa nervorum are 'tonically' vasodilated by substance P (SP) and calcitonin gene-related peptide (CGRP) arising from perivascular afferent nerve fibers. Local application of specific receptor antagonists of SP or CGRP results in constriction of vasa nervorum. In this work, we examined the responsiveness of vasa nervorum to epineurial spantide and spantide II (SP antagonists) and hCGRP (8-37) (CGRP antagonist) using serial hydrogen clearance curves in the rat sciatic nerve. Vasoconstriction from spantide and hCGRP (8-37) was dose-dependent, and was slightly greater with spantide than hCGRP (8-37). Spantide II induced vasoconstriction comparable to that of spantide. The vasoconstrictive effects of both spantide and hCGRP (8-37) were eliminated by concurrent systemic treatment with with either phentolamine or nimodipine. The findings support the hypothesis that SP or CGRP blockade interrupts 'tonic' peptide vasodilatation and permits vasoconstriction, perhaps by unopposed adrenergic action mediated through calcium channels. The findings however do not exclude a unique direct vasoconstrictive action of the peptide antagonists.
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PMID:Vasa nervorum constriction from substance P and calcitonin gene-related peptide antagonists: sensitivity to phentolamine and nimodipine. 769 27

The role of calcitonin gene-related peptide (CGRP) in the vagal cholinergic-mediated increase in gastric mucosal blood flow (GMBF) induced by the stable thyrotropin-releasing hormone (TRH) analogue RX-77368 injected intracisternally (ic, 30 ng) was investigated in urethan-anesthetized rats using the hydrogen gas clearance technique. alpha-CGRP (14 micrograms.kg-1.h-1) or bethanechol (150 micrograms.kg-1.h-1) infused close intra-arterially to the stomach or RX-77368 injected intracisternally increased GMBF by 76, 102, and 131%, respectively, 30 min after administration. The CGRP antagonist, human CGRP-(8-37) [hCGRP-(8-37)], injected intravenously (15 micrograms/kg bolus and 3 micrograms.kg-1.h-1) inhibited by 100, 97, and 73% the gastric hyperemic response to alpha-CGRP, TRH analogue, and bethanechol, respectively, whereas the substance P antagonist CP-96,345 (3 mg/kg iv) had no effect. In capsaicin-pretreated rats, hCGRP-(8-37) no longer blocked the increase in GMBF induced by intracisternal RX-77368. These results suggest that the gastric hyperemic response to central vagal activation induced by intracisternal TRH analogue at 30 ng is mediated by local effector function of capsaicin-sensitive afferent fibers releasing CGRP.
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PMID:Central vagal activation by TRH induces gastric hyperemia: role of CGRP in capsaicin-sensitive afferents in rats. 781 Jun 51

This study investigated the relationship between oxygen radicals and exsanguination-induced bronchoconstriction using antioxidant in guinea pigs. To accomplish this, two phases of studies were carried out. In phase 1, 34 guinea pigs weighing 342 +/- 11 g were divided into five groups: control (n = 7); acute dimethylthiourea (DMTU, n = 7); chronic DMTU (n = 8); superoxide dismutase (SOD, n = 6); and catalase (n = 6). Animals in the control group were not treated. DMTU, SOD, and catalase were employed for the scavenging of hydroxyl radical, superoxide anion, and hydrogen peroxide, respectively. Ten additional guinea pigs weighing 293 +/- 6 g were divided into two groups in phase 2: sham (n = 6) and chronic apocynin (n = 4). Animals in the sham group received injections of the vehicle, whereas apocynin was used to suppress the production of superoxide anion. All animals were anesthetized, sternotomized, and artificially ventilated. Before (baseline) as well as at fixed intervals 5-30 minutes following the exsanguination, the maximal expiratory flow maneuver was performed and the dynamic compliance (Cdyn) was obtained. Decreases in the maximal expiratory flow at 50% baseline vital capacity and Cdyn were used as indicators of bronchoconstriction. Exsanguination in the control and sham groups caused a gradual increase in airway constriction with time that was significantly ameliorated by chronic DMTU and chronic apocynin pretreatments but was not affected by other acute treatments. These results indicate that chronic treatment with antioxidants ameliorates exsanguination-induced, tachykinin-mediated airway constriction.
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PMID:Oxygen radicals in exsanguination-induced bronchoconstriction of guinea pigs. 793 52

Coronary artery contractility is well known to be modulated by oxygen partial pressure. Both smooth muscle and the endothelium contribute to coronary artery oxygen sensitivity. Mechanisms underlying endothelium-dependent effects of oxygen include the sensitivity of the nitric oxide/endothelium-derived relaxing factor (EDRF), hydrogen peroxide, and eicosanoid pathways. In the present study, we characterize a novel endothelium-dependent component of porcine coronary artery oxygen sensitivity that is independent of these known pathways. Porcine coronary arteries were stimulated with either KCl or U46619. Hypoxia elicited a transient increase in force that was much greater in endothelium-intact arteries. This effect was abolished by nitric oxide/EDRF pathway inhibitors NG-monomethyl-L-arginine and N-nitro-L-arginine. In the steady state, hypoxia reduced isometric force to a similar degree in both intact and denuded arteries. Reoxygenation elicited a rapid and transient relaxation only in intact arteries. In contrast, this endothelium-dependent relaxation was not inhibited by nitric oxide/EDRF pathway inhibitors nor inhibitors of other potential oxygen-sensitive pathways, such as indomethacin, aminotriazole, superoxide dismutase, catalase, propranolol, or ouabain. The reoxygenation relaxation was, however, sensitive to very low levels of oxygen and was inhibited by cyanide and rotenone, suggesting an involvement of mitochondrial metabolism. Interestingly, the relaxation response to reoxygenation, similar to that for substance P, could be restored in denuded arteries by coupling with an endothelium-intact donor artery. This "sandwich" experiment suggests that the endothelium dependence is mediated by a transmissible factor. Our results indicate that a novel class of endothelium-dependent factors may contribute to coronary artery responses to changes in oxygen partial pressure.
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PMID:Reoxygenation-induced relaxation of coronary arteries. A novel endothelium-dependent mechanism. 815 34

In the airways and lungs, activated afferent C-fibers release tachykinins, which induce noncholinergic bronchoconstriction. We have, for several years, focused our research on the role of axon reflex and oxygen radicals in noncholinergic airway constriction in guinea pigs. In this species, the noncholinergic bronchial constriction is not affected by administration of a ganglionic blocking agent, chlorisondamine, indicating that only the afferent C-fiber, not a complete reflex arc, is required for this constriction. Accordingly, we investigated the role of axon reflex by using tetrodotoxin (TTX) and bupivacaine to block impulse conduction in the axon. For the role of oxygen radicals, superoxide dismutase (SOD), catalase (CAT), and dimethylthiourea (DMTU) were employed to scavenge superoxide anion, hydrogen peroxide, and hydroxyl radical, respectively. We used capsaicin, resiniferatoxin (RTX), or hyperventilation to activate afferent C-fibers which, in turn, release tachykinins and lead to noncholinergic airway constriction. The constriction was quantified by measuring the maximal expiratory flow rate (Vmax) and dynamic compliance (Crs). Both capsaicin and RTX caused an immediate decrease in Vmax and Crs, indicating severe bronchoconstriction. This constriction decreased gradually with time. Tachykinin depletion abolished neurotoxin-induced airway constriction, suggesting that tachykinins mediate the constriction. Both TTX and bupivacaine significantly attenuated the constriction at 15-20 min after neurotoxin administration. Therefore, these data suggest that the axon reflex plays an important role in noncholinergic bronchial constriction. In other studies, capsaicin- or hyperventilation-induced bronchoconstriction was abolished by tachykinin depletion, as well as significantly ameliorated by the administration of antioxidants. These data indicate that oxygen radicals modulate the tachykinin-mediated noncholinergic airway constriction.
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PMID:Noncholinergic airway constriction: role of axon reflex and oxygen radicals. 819 89

Substance P binds to and activates the neurokinin-1 receptor with high affinity, thereby modulating several neuronal pathways including pain transmission and neurogenic inflammation. Several high affinity non-peptide antagonists have recently been described. To elucidate the molecular interactions specific for binding to the neurokinin-1 receptor, site-directed mutagenesis has been utilized to identify amino acid residues that interact directly with antagonists. Glutamine 165 in the fourth transmembrane segment was shown to be critical for the binding of CP-96,345 but not SR140333. Analysis of quinuclidine analogs suggests that glutamine 165 interacts with the C-3 heteroatom in this class of antagonists, probably through a hydrogen bond. Glutamine 165 also plays a minor role in the binding of peptides and RP67580. In contrast, serine 169 was determined to be critical for the binding of RP67580. These data indicate that residues 165 and 169 in the fourth transmembrane segment, along with residues in the fifth, sixth, and seventh transmembrane segments as demonstrated previously, form the non-peptide antagonist binding site in the neurokinin-1 receptor. Furthermore, the antagonist binding site overlaps with the binding site for peptide agonists in the fourth and seventh transmembrane segments.
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PMID:Interaction of glutamine 165 in the fourth transmembrane segment of the human neurokinin-1 receptor with quinuclidine antagonists. 819 29

The binding characteristics of histogranin (HN), an endogenous peptide first recognized for its antagonism of N-methyl-D-aspartate (NMDA) responses, were determined in membrane preparations of rat brain. [125I][Ser1]HN, a stable bioactive analog of HN, bound specifically and reversibly to a homogenous population of high-affinity sites with a Kd of 25 nM and a Bmax of 410 fmol/mg protein. The binding of [125I][Ser1]HN increased linearly with membrane protein concentration and was destroyed upon membrane pretreatment with trypsin. The binding displayed rapid association and dissociation kinetics and was blocked by peptides possessing close homology with HN in the following order: [Ser1]HN-(1-15) > HN > [Ser1]HN-(1-14) > HN-(2-15) > [Ser1]-HN-(1-10) > HN-(6-10). Unrelated peptides such as substance P, beta-endorphin, neuropeptide Y, [Met5]enkephalin, [Leu5]enkephalin, dynorphin A(1-13) and neuromedin C were inactive in competition binding assays against [125I]Ser1]HN. Ligands of the binding domains of the NMDA receptor, such as (+)3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, (+) 5-methyl-10,11-dihydro 5H-dibenzo[a, d]cyclohepten-5,10-imine hydrogen maleate, 1-N-(2-thienyl)cyclohexylpiperidine, glycine and glutamate were also ineffective in competing for [125I][Ser1]HN binding sites. Interestingly, specific ligands for the polyamine site on the NMDA receptor, as well as the cations Mg++ and Zn++ inhibited [125I][Ser1]HN binding. The polyamine antagonist diethylenetriamine produced a noncompetitive inhibition with an IC50 (175 nM) comparable to that of HN (75 nM). The cations Zn++ and Mg++ displaced [125I][Ser1]HN binding with IC50 values of 18 and 240 microM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of [125I][Ser1]histogranin binding sites in rat brain. 822 61

Previous studies suggested that the antagonist binding site in the neurokinin-1 receptor is composed of phylogenetically conserved residues, while phylogenetically divergent residues affect the conformation of the binding site. To test this hypothesis, we investigated the role of conserved residues in antagonist binding. Histidine 197 in the human receptor was found to interact with CP-96,345 but not RP67580. In addition, a nearby residue, histidine 265 of the human receptor, is required for the binding of RP67580 but not CP-96,345 or substance P. The interaction between residue 265 and RP67580 is consistent with a hydrogen bonding interaction. Analysis of several analogs of CP-96,345 revealed that histidine 265 of the human receptor is in proximity to the substituted benzyl moiety of CP-96,345, and can interact with other analogs of CP-96,345. In contrast to the human neurokinin-1 receptor, both histidine 197 and histidine 265 in the rat neurokinin-1 receptor appear to interact with both CP-96,345 and RP67580. These results support a conformational difference between the antagonist binding sites of the rat and human neurokinin-1 receptors and provide a model for examining specific interactions between antagonists and the receptor.
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PMID:The role of histidine 265 in antagonist binding to the neurokinin-1 receptor. 830 Jun 4

1H NMR chemical shift assignments for neuropeptide K (NPK) and neurokinin A (NKA) have been determined at 600 MHz in 28% trifluoroethanol/water solution. Two-dimensional NMR techniques were used to assign proton resonances, and interproton distances were estimated from the observed nuclear Overhauser effects (NOEs). These distances were used as constraints in a simulated annealing protocol within the program XPLOR to generate structures consistent with experimental data. NPK forms a regular amphipathic alpha-helical structure from Asp 3, terminating at Gly 18. Slowly exchanging amide protons identified in this region are likely to be involved in hydrogen bonds to stabilize the helix. The remainder of the molecule displays many sequential NOEs, with some i-(i + 2) contacts, but little further evidence of defined secondary conformation. NKA displays strong sequential connectivities between amide protons from Thr 3 to Met 10, and some i-(i + 2) connectivities suggestive of a series of dynamic turns in equilibrium. A comparison of the tail region of NPK with the related peptide homologue, neurokinin A, in the same solvent system, indicates that both show increasing order when trifluoroethanol is titrated into water solution, with the appearance of sequential NOEs between backbone amide protons. Differences between the corresponding spans of primary sequence appear to be minimal. The clear finding that NPK adopts a well-defined helix in its N-terminal half and is relatively disordered in the C-terminal half, which includes the entire NKA sequence, may have important implications for understanding the increased selectivity of NPK over NKA for one class of neurokinin receptor.
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PMID:Determination of the solution structure of neuropeptide K by high-resolution nuclear magnetic resonance spectroscopy. 839 41

1. Cigarette smoke induces plasma exudation in the airways of rodents by activation of capsaicin-sensitive 'sensory-efferent' nerves. The response is mediated predominantly by substance P (SP) and the magnitude of exudation is regulated by neutral endopeptidase (NEP). The component(s) of the smoke responsible for the activation of the nerves may be reactive oxygen radicals. We investigated the effect of the hydroxyl radical scavenger dimethylthiourea (DMTU), a regulator of superoxide anion, superoxide dismutase (SOD), and a regulator of hydrogen peroxide, catalase, on plasma exudation (measured using Evans blue dye) induced by cigarette smoke in guinea-pig main bronchi in vivo. The effect of DMTU on plasma exudation and non-cholinergic bronchoconstriction (measured as pulmonary insufflation pressure, PIP) induced by electrical stimulation of the vagus nerves was also assessed. Interaction between hydroxyl radicals and NEP was assessed with the NEP inhibitor phosphoramidon. 2. In each of the experiments, cigarette smoke increased plasma exudation by approximately 200% above air-exposed controls. Acute administration of DMTU (1.5 g kg-1, i.v. for 20 min) significantly reduced cigarette smoke-induced plasma exudation by 69%. In contrast, neither SOD (240,000 u kg-1, i.v.) nor catalase (400,000 u kg-1, i.v.) significantly affected the exudative response. 3. Chronic pretreatment with DMTU (1.25 g kg-1 over 4 days) significantly reduced bronchial plasma exudation induced by cigarette smoke by 72%. Phosphoramidon (1.5 mg kg-1, i.v.) completely reversed the inhibition by DMTU of cigarette smoke-induced plasma exudation. 4. Vagal stimulation increased plasma exudation by approximately 200% and PIP by approximately 250%. Acute treatment with DMTU had no significant inhibitory effect on these responses, whereas chronic pretreatment inhibited them by approximately 80%. Phosphoramidon reversed the inhibition by chronic DMTU. 5. SP (1 nmol kg-1) increased plasma exudation by approximately 250%, a response which was not inhibited by either acute or chronic DMTU. 6. We conclude that hydroxyl radicals, rather than superoxide anion or hydrogen peroxide, are involved in the induction of neurogenic plasma exudation and bronchoconstriction induced by cigarette smoke or by electrical stimulation of the vagus nerves. These radicals also affect the activity of NEP. Acute DMTU may affect directly the neural actions of hydroxyl radicals contained in the cigarette smoke. Chronic pretreatment with DMTU may inhibit the neurogenic airway responses by effects on tachykinin biosynthesis and/or axonal transport.
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PMID:Involvement of hydroxyl radicals in neurogenic airway plasma exudation and bronchoconstriction in guinea-pigs in vivo. 882 33


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