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)

Angiotensin-converting enzyme, although most prominent in vascular endothelium, has been identified in numerous tissues. Recent studies have indicated that several hormones, including glucocorticoids and thyroid hormone, may affect the activity of this enzyme. In the present study, angiotensin-converting enzyme was examined in homogenates of cultured human skin fibroblasts. Angiotensin-converting enzyme activity was measured by a radiometric assay using [Glycine-1-14C] Hippuryl-L-histidyl-L-leucine (1.1 mmol/L) as substrate, and was expressed as nmol hippuric acid formed per minute/mg protein. Angiotensin-converting enzyme was identified in all five cell strains tested, and the activity observed was 0.97 +/- 0.18 nmol/min/mg protein (mean +/- SE). The optimum pH was between 6.9 and 7.6, and optimum temperature was 37 degrees C, with loss of activity of 55 degrees C and higher. Buffer strength was optimized at Tris 0.025 mol/L, and 1.0 mol/L NaCl. Activity increased linearly with protein concentration and with time, and the Km = 1.14 mmol/L. The most potent inhibitor of fibroblast ACE was captopril (SQ 14,225) with an IC50 = 10(-10) mol/L; other inhibitors included SQ 20,881, EDTA, and phenanthroline. Competitive substrates included angiotensin-I, substance P, and bradykinin. Four hormones, T3 (10(-9)-10(-7) mol/L), 1,25 (OH)2D3 (10(-8)-10(-7) mol/L), dexamethasone (10(-7)-10(-6) mol/L), and a synthetic androgen, R1881 (10(-8)-10(-7) mol/L) were incubated with cells for 72 hours. In all incubations, there was no significant effect on cellular ACE activity induced by any agent. Angiotensin-converting enzyme activity in serum free media was less than 1% of cell activity and was unaltered by hormone treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Angiotensin-converting enzyme: characteristics in human skin fibroblasts. 302 Mar 42

Vasoactive peptides contain a high proportion of proline residues which make them resistant to hydrolysis by many peptidases. However, post proline cleaving enzyme (PPCE; EC 3.4.21.26), a proline specific endopeptidase which specifically hydrolyzes internal peptide bonds on the carboxyl side of proline residues, has been shown to inactivate numerous vasoactive peptides including angiotensins, kinins, substance P, vasopressin and oxytocin. In order to determine whether PPCE could be involved in vascular metabolism of vasoactive peptides, we carried out localization and characterization studies of PPCE-like activity in hog aorta and mesenteric artery. PPCE was assayed fluorometrically at pH 7.0 using the specific PPCE substrate CBZ-Gly-Pro-4-methyl-coumarinylamide. The subcellular distribution of vascular PPCE was essentially the same as that of the cytosolic marker enzyme lactic dehydrogenase (LDH). PPCE was enriched six-fold in the cytosolic fraction (11.4 +/- 2.7 units/mg) and unlike the plasma membrane-bound proline specific exopeptidase dipeptidyl-(amino)peptidase IV (DAP IV; EC 3.4.14.5), little or no activity could be detected in the microsomal or plasma membrane fractions. Similar to PPCE characterized from other sites, vascular PPCE was stabilized and activated by dithiothreitol and EDTA, and inhibited by DFP, p-chloromercuriphenyl sulfonic acid, L-1-tosylamido-2-phenylethylchloromethyl ketone, Cu++, Ca++, and Zn++. Vascular PPCE was unaffected by inhibitors of trypsin and kallikrein (Aprotinin, ABTI), aminopeptidase M (bestatin, amastatin), neutral endopeptidase (phosphoramidon), angiotensin I converting enzyme (captopril) or carboxypeptidase N (MERGETPA). These data demonstrate that PPCE is present in vascular endothelium and/or smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vascular, post proline cleaving enzyme: metabolism of vasoactive peptides. 354 18

Among the metabolic functions of the lungs are the formation, release, activation and inactivation of biologically active peptides. The following peptides may be present or formed in normal lung: vasoactive intestinal peptide or a peptide closely related to it, a spasmogenic peptide not yet fully identified, bradykinin, substance P, a bombesin-like peptide (especially in fetal and neonatal lung), and eosinophil-chemotactic peptides. These peptides are found in special neuroendocrine cells, in neurons, or in mast cells. Normal lung also inactivates bradykinin and activates angiotensin; both processes are catalysed by the same enzyme (kininase II or angiotensin-converting enzyme), located in pulmonary vascular endothelium. Pulmonary tumours and certain non-tumorous lesions can produce and release a variety of peptide hormones that are not normally generated by the lung in substantial amounts. This 'ectopic' secretion of hormones may be detectable only by sensitive assays or may result in specific clinical syndromes.
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PMID:The lung in relation to vasoactive polypeptides. 616 26

We have characterized the receptor(s) mediating contraction and relaxation produced by tachykinins in the rabbit isolated jugular vein. The tachykinin NK1 receptor-selective agonists septide and [Pro9]substance P produced concentration-dependent contractions which were potentiated by either the removal of the vascular endothelium (Emax = +106% and +72%, respectively) or by pretreatment with L-nitroarginine (100 microM; 60 min before) (Emax = +123% and +71%, respectively). The tachykinin NK1 receptor-selective antagonist, (+/-)-CP-96,345 ([2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1- azabicyclo[2,2,2]octan-3-amine]) (10-300 nM) competitively antagonized septide (pKB = 9.0) with 10-fold greater potency than [Pro9]substance P (pKB = 8.0). In preparations with intact endothelium both septide and [Pro9]substance P (from 0.1 to 100 nM) relaxed the noradrenaline-(10 microM) induced tone, and their effects were markedly reduced by (+/-)-CP-96,345 (100 nM). In noradrenaline-precontracted veins L-nitroarginine (100 microM) reversed the tachykinin-induced vasodilation into a contraction, providing evidence for the involvement of nitric oxide in this response. The tachykinin NK3 and NK2 receptor-selective agonists senktide and [beta Ala8]neurokinin A-(4-10) were either ineffective, or produced small effects antagonized by (+/-)-CP-96,345 (100 nM), respectively. In conclusion, tachykinin NK1 receptors mediate both tachykinin-induced contraction and relaxation in the rabbit jugular vein. This preparation, deprived of the endothelium or pretreated with L-nitroarginine, is suitable for evaluating tachykinin agonists or antagonists.
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PMID:Tachykinin NK1 receptors mediate both vasoconstrictor and vasodilator responses in the rabbit isolated jugular vein. 749 15

Substance P (SP) immunocytochemistry and receptor autoradiography were used to define the innervation of the equine synovial membrane of joints equivalent to the wrist and knuckle of man. SP-immunoreactive fibers were mainly concentrated around blood vessels in the subsynovial layer, although not exclusively, while in the more distal joint, SP fibers were more frequently seen in the synovial surface layer. Iodinated SP receptor autoradiography studies revealed silver grain concentrations in the advential layer of blood vessels associated with the vasa vasorum, on the vascular endothelium and in the synovial surface. These findings suggest that SP has various sites of action within the synovial membrane, each of which may contribute both a sensory function and a different component of the inflammatory process to the joint.
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PMID:Substance P innervation of equine synovial membranes: joint differences and neural and nonneural receptor localizations. 751 50

Substance P (SP) and adrenocorticotropic hormone (ACTH) are peptides that have been shown to have both neurological and immunological effects. Because of the demonstrated effects upon immune function, we examined the effects of these peptides on T-lymphocyte adhesion to vascular endothelium and surface adhesion receptor expression. Neither the adhesion assays nor the expression assays showed any statistically significant effect of SP (10 microM) or ACTH (1 microM) for any incubation period used. We conclude that, while SP and ACTH have a variety of immunomodulatory effects, direct modulation of T-lymphocyte adhesion to vascular endothelium is probably not one of them.
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PMID:Substance P and adrenocorticotropic hormone do not affect T-lymphocyte adhesion to vascular endothelium or surface expression of adhesion receptors. 751 58

We examined the activities of bradykinin, substance P, and vasopressin in isolated human cerebral arteries to better understand humoral control of cerebrovascular tone. Basilar and middle cerebral arteries were isolated from human cadavers during autopsy, and isometric tension was measured in helical strips of the arteries. Both bradykinin and substance P relaxed strips of both arteries precontracted with prostaglandin F2 alpha to similar extents. The relaxations induced by both peptides were abolished by removal of the vascular endothelium and were markedly reduced by pretreatment with NG-nitro-L-arginine, an inhibitor of endothelium-derived relaxing factor. Treatment with indomethacin, a cyclooxygenase inhibitor, did not attenuate the relaxations. These results indicate that the responses of human cerebral arteries to bradykinin and substance P are mediated by endothelium-derived relaxing factor. In contrast, vasopressin primarily produced endothelium-independent contractions in human cerebral arteries. Contractions of basilar arteries induced by vasopressin were much less than those of middle cerebral arteries. Two of eighteen basilar arteries, but none of the middle cerebral arteries, responded to vasopressin with endothelium-dependent relaxation. This suggests that the function of vasopressin receptors differs in basilar and middle cerebral arteries.
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PMID:Human basilar and middle cerebral arteries exhibit endothelium-dependent responses to peptides. 752 7

Many inflammatory mediators trigger the adhesion of leukocytes to the vascular endothelium. We sought to determine whether the beta 2-adrenergic receptor agonist formoterol can inhibit the adhesion of neutrophils and eosinophils to the endothelium of venules in the rat airway mucosa. We also tested whether this action is mediated by beta 2-adrenergic receptors. Inflammation was induced in the airways of anesthetized pathogen-free F344 rats by injecting substance P (5 micrograms/kg) or bradykinin (10 mg/kg) intravenously. The rats were perfused with fixative 5 min later, and the tracheas were removed. Adherent intravascular neutrophils and eosinophils, stained by a histochemical reaction for myeloperoxidase, were counted in tracheal whole mounts. We found that, after the injection of substance P, formoterol (0.1, 1.0, or 10.0 micrograms/kg i.v.) reduced the number of adherent neutrophils by 8, 59, or 56% and reduced the number of eosinophils by 59, 90, or 86%, respectively. The three doses of formoterol reduced the amount of substance P-induced extravasation of Monastral blue by 21, 66, or 80%, respectively. Both effects of formoterol were blocked by the beta 2-adrenergic receptor antagonist ICI-118,551, which by itself produced neither leukocyte adhesion nor plasma extravasation. After the injection of bradykinin, the three doses of formoterol reduced the number of adherent neutrophils by 28, 67, or 62% and reduced the number of eosinophils by 17, 38, or 57%, respectively. We conclude that formoterol, acting via beta 2-adrenergic receptors, not only can reduce the amount of plasma leakage but also can reduce the number of neutrophils and eosinophils that adhere to the vascular endothelium at sites of inflammation.
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PMID:Inhibition of neutrophil and eosinophil adhesion to venules of rat trachea by beta 2-adrenergic agonist formoterol. 752 29

Human polymorphonuclear cells (PMN) were found to adhere to a novel model of blood vessel wall-associated IgG. The internal surfaces of cellulose acetate hollow fibres, of comparable internal diameter to small blood vessels, were coated with normal serum human IgG, heat-aggregated IgG (HAIgG), laminin or fibrinogen. Under conditions of flow mimicking those in a small vessel, PMN were found to adhere markedly only to immunoglobulin-coated fibres. Arrest on HAIgG was inhibited by excess soluble IgG but not by bovine serum albumin (BSA), demonstrating that the adhesion was IgG-specific and presumably mediated by Fc gamma R on the PMN surface. Pre-adsorption of serum components onto HAIgG-coated fibres enhanced PMN arrest, due most probably to fixation of complement components by immobilized HAIgG, resulting in additional potential to entrap PMN via complement receptors such as CR3. Treatment of PMN with the regulatory neuropeptide substance P also enhanced adhesion to HAIgG-coated fibres and caused increased surface expression of Fc gamma RI, Fc gamma RII and Fc gamma RIII. A mouse cell line derived from L cells, hR4C6, stably transfected with human Fc gamma RII, was found to adhere under flow to HAIgG-coated fibres, whilst untransfected parent L cells did not. This adhesion was similarly inhibited by excess soluble IgG, confirming the capability of Fc gamma R to mediate cell arrest. The study strongly suggests that Fc gamma R may play an important role in intravascular PMN arrest and we speculate that in inflammatory diseases PMN may adhere via Fc gamma R to immobilized immunoglobulin on the vascular endothelium, with subsequent degranulation and tissue damage.
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PMID:Human neutrophil Fc receptor-mediated adhesion under flow: a hollow fibre model of intravascular arrest. 753 10

Neutral endopeptidase 24.11, a membrane-bound metallopeptidase, cleaves, and degrades vasoactive peptides such as atrial natriuretic peptide, endothelin, angiotensin I, substance P, and bradykinin. Therefore, the presence of this metallopeptidase may contribute to the regulation of vascular tone and local inflammatory responses in the vascular endothelium and elsewhere. We determined neutral endopeptidase in cultured human endothelial cells from different vascular beds and studied its regulation by protein kinase C. Neutral endopeptidase was detected in all cultured endothelial cell types. Lowest concentrations were measured in human endothelial cells from umbilical veins (360 +/- 14 pg/mg protein), followed by pulmonary and coronary arteries; higher concentrations were found in endothelial cells from the cardiac microcirculation (1099 +/- 73 pg/mg protein). Neutral endopeptidase content increased during cell growth but was not affected by endothelial cell growth factor or modifications of the growth medium. Stimulation of protein kinase C with 1-oleoyl-2-acetyl-rac-glycerol (0.1 to 1 mumol/L) and phorbol 12-myristate 13-acetate (0.01 to 0.1 mumol/L) induced a time- and concentration-dependent increase of endothelial cells that was inhibited by cycloheximide (5 mumol/L), an inhibitor of protein synthesis. Incubation with phospholipase C (1 mumol/L) and thrombin (10 IU/mL) induced upregulation of neutral endopeptidase, resulting in 158 +/- 26% and 150 +/- 22% increases, respectively, compared with controls. The thrombin effect was inhibited by calphostin C (1 mumol/L), an inhibitor of protein kinase C. Endothelial neutral endopeptidase is constitutively expressed in endothelial cells from different origins and is inducible by thrombin via activation of the protein kinase C pathway.
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PMID:Regulation and differential expression of neutral endopeptidase 24.11 in human endothelial cells. 763 30


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