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)

Since 1984 25 cases of enalapril induced angioedema have been reported to the Netherlands Center for Monitoring of Adverse Reactions to Drugs. Two patients with enalapril induced angioedema are described. The pathophysiological mechanism of this potentially life-threatening adverse effect is probably not a direct allergic response to the drug itself. Enalapril inhibits angiotensin converting enzyme, which not only metabolizes angiotensin I but also bradykinin and 'substance P'. Bradykinin and 'substance PH may then accumulate and cause angioedema in a direct or indirect way. It is of great importance that instances of oropharyngeal swelling are considered a possible result of an adverse reaction to ACE-inhibitors.
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PMID:[Angioedema caused by enalapril]. 200 23

1. Effects of inhibition of angiotensin converting enzyme (ACE, EC 3.4.15.1) in brain on psychomotor, exploratory, stereotyped and cognitive behaviour in rats were investigated. To inhibit brain ACE captopril (D-3-mercaptopropanoyl-L-proline) was given orally (p.o., 50 mg/kg) or intracerebroventricularly (i.c.v., 5 micrograms/rat). 3. Captopril given p.o. but not i.c.v. significantly enhanced stereotypy, overall number of conditioned avoidance responses, and decreased blood pressure. 4. No statistically significant influence of captopril given by either route on the number of crossings, rearings and bar approaches in the open field, performance of passive avoidance and number of correct choices as well as the speed of running for food in the T-maze was observed. 5. In conclusion, a small decrease of the activity of nigrostriatal dopaminergic system caused by the decrease of AII and/or increase of bradykinin, substance P, enkephalins and neurotensin in brain resulting from ACE inhibition is postulated.
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PMID:Some behavioural effects of captopril in rats. 227 85

Peptidyl-dipeptidase A (angiotensin converting enzyme; ACE, EC 3.4.15.1), has been purified from pig kidney and striatum by affinity chromatography employing the selective inhibitor lisinopril as ligand. The inclusion of a 2.8 nm spacer arm improved the yield of the enzyme compared with the 1.4 nm spacer arm described in previous work. Two forms of striatal ACE (Mr 180,000 and 170,000), but only a single form of kidney ACE (Mr 180,000), were isolated by this procedure. Both forms of striatal ACE were recognized by a polyclonal antibody to kidney ACE. No significant differences in substrate specificity or inhibitor sensitivity between kidney and striatal ACE could be detected. In particular, the amidated neuropeptide, substance P, was hydrolysed identically by both preparations and no significant hydrolysis of the related tachykinin peptides neurokinin A and neurokinin B could be detected. After chemical or enzymic deglycosylation, kidney and both forms of striatal ACE migrated identically on sodium dodecyl sulphate/polyacrylamide-gel electrophoresis with an apparent Mr of 150,000. We suggest that the two detectable forms of ACE in pig brain are not isoenzymes but are the result of differential glycosylation in different cell types in the brain. It appears that ACE, unlike endopeptidase-24.11, does not have the general capacity to hydrolyse and inactivate the tachykinin peptides at a significant rate in brain.
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PMID:Isolation of two differentially glycosylated forms of peptidyl-dipeptidase A (angiotensin converting enzyme) from pig brain: a re-evaluation of their role in neuropeptide metabolism. 243 65

Angiotensin I converting enzyme (kininase II; ACE) has been described as a peptidyldipeptidase or dipeptidyl carboxypeptidase (EC 3.4.15.1) of the pulmonary endothelial cells, which liberates angiotensin II or inactivates kinins. However, ACE has a much wider distribution and substrate specifity; it is concentrated in human epithelial cells (e.g. brush border of the kidney, placenta, intestine and choroid plexus), neuroepithelial cells (subfornical organ, pallidonigral dendrites, median eminence) and male genital tract (testes, prostate, epididymides, seminal plasma). Its substrates include enkaphalins, the C-terminal extended proenkephalins and a protected chemotactic tripeptide. Recent, mostly in vitro studies with purified ACE, indicate that ACE also cleaves peptides by other than peptidyldipeptidase action. Homogeneous human ACE inactivated substance P in spite of its blocked C-terminus (Met11-NH2) primarily by releasing the C-terminal tripeptide. A blocked C-terminal tripeptide, Arg-Pro-Gly-NH2 was also released from the luteinizing hormone releasing hormone (LHRH). Although ACE shares many properties with carboxypeptidases, it surprisingly cleaves the N-terminal tripeptide greater than Glu1-His2-Trp3 from LHRH. Because human ACE hydrolyzes a variety of peptide hormones, actions of its inhibitors may go well beyond blocking the conversion of angiotensin I.
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PMID:The broad substrate specificity of human angiotensin I converting enzyme. 244 Jun 24

The aim of this study was to investigate whether ACE-inhibitors could influence bronchial reactivity and interfere with inflammatory skin responses. Ten hypertensive subjects, who had reacted with coughs during ACE-inhibitor therapy, were treated in a double-blind crossover fashion for two weeks with enalapril and with placebo. Enalapril reduced the PC20 value for histamine and augmented the dermal response. Circulating eosinophilic leukocyte level in venous blood dropped markedly after the histamine bronchoprovocation performed during enalapril treatment. Plasma substance P was reduced after histamine provocation performed during placebo treatment, whereas this reduction was abolished by enalapril. In this study, we have demonstrated ACE-inhibitor-induction of moderately increased bronchial reactivity in subjects with suspected ACE-inhibitor-elicited coughs. It is suggested that coughing during ACE-inhibitor therapy is due to an increased inflammatory state in the airways.
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PMID:Increased bronchial reactivity and potentiated skin responses in hypertensive subjects suffering from coughs during ACE-inhibitor therapy. 254 75

In the brain angiotensin converting enzyme is highly localized to a striatonigral pathway, which contains no endogenous angiotensin. Substance P, also localized to a striatonigral pathway, is degraded by ACE via two different pathways. The lung and striatal isozymes of angiotensin converting enzyme exhibit differential cleavage of substance P, with lung preferring an initial tripeptide cleavage, and striatum an initial dipeptide cleavage. Substance K is degraded by the striatal isozyme but is not cleaved by the lung isozyme. Substance P 5-11 is not cleaved by either form of angiotensin converting enzyme.
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PMID:Substance K and substance P as possible endogenous substrates of angiotensin converting enzyme in the brain. 258 May 30

We have purified angiotensin-converting enzyme (ACE, EC 3.4.15.1) from rat brain corpus striatum and rat lung. The brain enzyme has Mr 165,000 by sodium dodecyl sulfate gel electrophoresis, whereas the lung enzyme is 175,000. This difference is not an artifact of preparation since mixture of the two tissues prior to purification results in isolation of two proteins with Mr 165,000 and 175,000. Separation of tryptic fragments of 125I-labeled lung and brain ACE by reverse-phase chromatography yields distinct but similar patterns. No differences between the native enzymes are detected in dansyl-tripeptide cleavage specificity, inhibitor profile, immunological properties, sucrose gradient sedimentation, or gel filtration of ACE from the two tissues. However, lung and brain ACE can be differentiated in their ability to cleave amidated peptides. Both lung and brain ACE cleave Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (substance P) via two pathways. In one pathway, ACE first releases Gly-Leu-Met-NH2 and then dipeptides sequentially from the carboxyl terminus. The other first produces Leu-Met-NH2, and then releases dipeptides to leave substance P 1-5. Lung ACE favors initial tripeptide release 3:1, while the striatal enzyme acts via the two pathways to a similar extent. Lung and striatal ACE also differ in their ability to degrade other amidated peptides. His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH2 (substance K) and bombesin are degraded by striatal but not lung ACE. Physalaemin and luteinizing hormone-releasing hormone are cleaved by both enzymes, while eledoisin, kassinin, thyrotropin-releasing hormone, and substance P 5-11 are not cleaved by either enzyme. Physalaemin is degraded more rapidly by the lung enzyme. The coincidence of an ACE isozyme with substance P and substance K in the descending striatonigral pathway and the unique ability of this isozyme to cleave substance P and substance K suggest that one or both of these peptides is a physiological substrate for striatonigral ACE.
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PMID:A rat brain isozyme of angiotensin-converting enzyme. Unique specificity for amidated peptide substrates. 299 Dec 65

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

1. A thiol proteinase from human pituitaries was purified approximately 400 fold and shown to have different chromatographic properties from that of calf brain. Among substrates cleaved were myelin basic protein, histones, beta-lipotropin, neurophysin, and Substance P. 2. The enzyme showed properties associated with a cathepsin-B like enzyme: dependence on -SH groups, pH optimum of 6.5, inhibition by leupeptin and a synthetic analog, Boc-D-Phe-Pro-arginal, and cleavage of dipeptidyl arylamides with basic residues adjacent to or penultimate to the chromatographic grouping. 3. Membranes present in the P2 fraction of rat brain contained three or more enkephalinases when submitted to DEAE-cellulose chromatography. Further purification on an IgG-Sepharose affinity column prepared with antibody to lung angiotensin converting enzyme indicated the presence of dipeptidyl carboxypeptidase(s) with properties distinct from those of ACE. In addition, the DEAE-cellulose fractions contained various aminopeptidase activities when tested with Leu-Gly-Gly, Leu-Nap, and Ala-Ala-Nap as substrates.
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PMID:Peptide processing in the central nervous system. 625 8

We studied the role of neutral endopeptidase (NEP) and kininase II (angiotensin-converting enzyme; ACE) in the modulation of exogenous substance P (SP)-induced nasal response in normal subjects and in patients with allergic rhinitis. We measured the nasal conductance in response to increasing doses of SP 2 h after oral administration of either placebo or the ACE inhibitor, cilazapril (5 mg), or the NEP inhibitor, acetorphan (300 mg), given in a randomized, double-blind, cross-over manner. We performed three separate studies: acetorphan versus placebo and cilazapril versus placebo, in normal subjects (n = 6 and n = 8, respectively), and acetorphan versus cilazapril versus placebo in patients with allergic rhinitis (n = 6). In normal as well as in rhinitic subjects, SP decreased nasal conductance in a dose-dependent fashion (p < 0.001). With placebo, the decrease in nasal conductance in normal subjects was similar to that in patients with allergic rhinitis (p > 0.5). In normal subjects, acetorphan potentiated the decrease in nasal conductance (p < 0.001), whereas cilazapril did not (p = 0.12). In patients with allergic rhinitis, the decrease in nasal conductance was potentiated by acetorphan (p < 0.001) and by cilazapril (p < 0.001). With acetorphan, the decrease in nasal conductance was not different in patients with allergic rhinitis and in normal subjects (p > 0.9). Conversely, with cilazapril, the nasal response to SP was greater in patients with allergic rhinitis than in normal subjects (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of neutral endopeptidase and kininase II on substance P-induced increase in nasal obstruction in patients with allergic rhinitis. 750 44


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