Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Kinins and substance P have been implicated in the pathogenesis of inflammatory arthritis by virtue of their abilities to induce vasodilation, edema, and pain. The relative biological potencies of these peptides in vivo would depend at least in part upon their rates of catabolism in the joint. We hypothesized that human synovial lining cells may regulate intraarticular levels of kinins and neuropeptides via degradation by cell surface-associated peptidases. We exposed intact human synovial fibroblasts to kinins and substance P, in the presence or absence of specific peptidase inhibitors, and measured the amount of intact substrate remaining and degradation product(s) generated over time. Aminopeptidase M (AmM; EC 3.4.11.2), neutral endopeptidase-24.11 (NEP-24.11; EC 3.4.24.11), and dipeptidyl(amino)peptidase IV (DAP IV; EC 3.4.14.5) were identified on the cell surface of synovial cells. Bradykinin degradation was due entirely to NEP-24.11 (1.39 +/- 0.29 nmol/min per well). Lysylbradykinin was also degraded by NEP-24.11 (0.80 +/- 0.19 nmol/min per well); however, in the presence of phosphoramidon, AmM-mediated conversion to bradykinin (3.74 +/- 0.46 nmol/min per well) could be demonstrated. The combined actions of NEP-24.11 (0.93 +/- 0.15 nmol/min per well) and DAP IV (0.84 +/- 0.18 nmol/min per well) were responsible for the degradation of substance P. AmM (2.44 +/- 0.33 nmol/min per well) and NEP-24.11 (1.30 +/- 0.45 nmol/min per well) were responsible for the degradation of the opioid peptide, [Leu5]enkephalin. The identity of each of the three peptidases was confirmed via synthetic substrate hydrolysis, inhibition profile, and immunological identification. The profiles of peptidase enzymes identified in cells derived from rheumatoid and osteoarthritic joints were identical. These data demonstrate the human synovial fibroblast to be a rich source of three specific peptidases and suggest that it may play a prominent role in regulating peptide levels in the joint.
 ...
PMID:Cultured human synovial fibroblasts rapidly metabolize kinins and neuropeptides. 138 26

The enzyme neutral metalloendopeptidase (E.C. 3.4.24.11), also known as the common acute lymphocytic leukemia antigen, neutral endopeptidase, or enkephalinase, functions as an inactivator of a wide variety of signaling oligopeptides such as substance P, neurokinin A, enkephalins, endothelin, atrial natriuretic factor, and formyl chemotactic peptides. A cDNA clone isolated from a human lung library encodes a fragment of neutral metalloendopeptidase containing an internal 81 base pair deletion when compared with the human placental cDNA for this enzyme. Comparison of the deleted cDNA sequence with the intron-exon structure recently determined as the common acute lymphocytic leukemia antigen reveals that the 81 base pairs corresponds precisely with exon 16. RNA analysis using splice junction oligonucleotides indicates that the 16 del form constitutes a minor but significant fraction of the RNA species present in human lung. Expression of constructs containing "wild type" and "exon 16 del" neutral endopeptidases in COS-7 cells reveals that deletion of this 27 amino acid segment reduces enzymatic activity toward the synthetic substrate glutaryl-alanyl-alanyl-phenyl-alanyl-4-methoxy-2-naphthylamide to barely detectable levels.
 ...
PMID:Exon 16 del: a novel form of human neutral endopeptidase (CALLA). 153 84

Aminopeptidase M (AmM; EC 3.4.11.2) is a membrane-bound peptidase present on renal brush border and vascular plasma membrane. In the present study, AmM, purified from rabbit kidney cortex, produced a single immunoprecipitin line against AmM antisera, hydrolyzed alanyl-, leucyl- and arginyl-beta-naphthylamides at rates of 5.1 +/- 0.5, 3.9 +/- 0.5 and 2.6 +/- 0.3 mumol/min/mg, respectively, exhibited little or no alpha-glutamyl-, aspartyl- or glycyl-prolyl-naphthylamidase activities (less than or equal to 0.14 mumol/min/mg), and was inhibited by o-phenanthroline, amastatin (IC50 = 400 nM) and bestatin (IC50 = 6 microM). The alanyl-naphthylamidase activity of unfractionated rabbit plasma was found to be identical to purified AmM regarding relative rates of hydrolysis of alanyl-, leucyl- and arginyl-naphthylamides (100:79:42), pH optimum, and inhibition profile. In comparative studies with the purified enzyme, immunoreactive AmM accounted for essentially all of the alanyl-2-naphthylamidase activity of rabbit plasma. N-Terminal metabolism of (Met5)enkephalin by purified renal AmM was 3.92 +/- 0.69 mumol/min/mg, followed by somatostatin (1.25 mumol/min/mg), hepta(5-11)substance P (1.14 +/- 0.13 mumol/min/mg), (Asn1)angiotensin II (1.11 +/- 0.06 mumol/min/mg), angiotensin III (0.45 +/- 0.04 mumol/min/mg) and des(Asp1)-angiotensin I (0.36 +/- 0.04 mumol/min/mg). In contrast, substance P, bradykinin, (Sar1,Ala8)angiotensin II and neurokinin analogs containing modified N-termini (e.g. Ac-Arg) were resistant to hydrolysis by AmM. Peptide degradation was optimal at neutral pH and was inhibited by amastatin (IC50 = 200 nM) and bestatin (IC50 = 5 microM). Apparent Km values ranged from 15.7 +/- 0.4 microM for angiotensin III to 102 +/- 2 microM for (Met5)enkephalin. These data support a significant role for vascular and plasma AmM in the metabolism of circulating vasoactive peptides.
 ...
PMID:Metabolism of vasoactive peptides by plasma and purified renal aminopeptidase M. 197 75

Aminopeptidase M (EC 3.4.11.2), an enzyme present on the cell surface of vascular endothelium and/or smooth muscle, rapidly hydrolyzes leucyl- and arginyl-2-naphthylamides and a number of vasoactive peptides at physiologic pH. Utilizing both thin-layer chromatography and high pressure liquid chromatography, it was found that vascular aminopeptidase M converted kallidin to bradykinin and inactivated des(Asp1)angiotensin I, angiotensin III, hepta(5-11)substance P and hexa(6-11)substance P. Aminopeptidase M did not, however, hydrolyze bradykinin, angiotensin I, angiotensin II, saralasin, vasopressin, oxytocin or any form of substance P containing a component of the Arg-Pro-Lys-Pro sequence. Both the naphthylamidase and peptidase activities were inhibited similarly by known amino-peptidase M inhibitors including o-phenanthroline, amastatin, bestatin and puromycin. However, inhibitors of angiotensin I converting enzyme (captopril), carboxypeptidase N (MERGETPA), neutral endopeptidase (phosphoramidon), post proline cleaving enzyme and dipeptidyl(amino)peptidase IV (diisopropylphosphofluoridate, DFP) were without effect. These results demonstrate that vascular, cell surface aminopeptidase M can selectively metabolize vasoactive peptides and may play a role in modulating their levels in the circulation and/or within the vessel wall.
 ...
PMID:Vascular, plasma membrane aminopeptidase M. Metabolism of vasoactive peptides. 240 81

Aminopeptidase M (EC 3.4.11.2), which can degrade low molecular weight opioid peptides, has been reported in both peripheral vasculature and in the CNS. Thus, we have studied the metabolism of opioid peptides by membrane-bound aminopeptidase M derived from cerebral microvessels of hog and rabbit. Both hog and rabbit microvessels were found to contain membrane-bound aminopeptidase M. At neutral pH, microvessels preferentially degraded low molecular weight opioid peptides by hydrolysis of the N-terminal Tyr1-Gly2 bond. Degradation was inhibited by amastatin (I50 = 0.2 microM) and bestatin (10 microM), but not by a number of other peptidase inhibitors including captopril and phosphoramidon. Rates of degradation were highest for the shorter peptides (Met5- and Leu5-enkephalin) whereas beta-endorphin was nearly completely resistant to N-terminal hydrolysis. Km values for the microvascular aminopeptidase also decreased significantly with increasing peptide length (Km = 91.3 +/- 4.9 and 28.9 +/- 3.5 microM for Met5-enkephalin and Met5-enkephalin-Arg6-Phe7, respectively). Peptides known to be present within or in close proximity to cerebral vessels (e.g., neurotensin and substance P) competitively inhibited enkephalin degradation (Ki = 20.4 +/- 2.5 and 7.9 +/- 1.6 microM, respectively). These data suggest that cerebral microvascular aminopeptidase M may play a role in vivo in modulating peptide-mediated local cerebral blood flow, and in preventing circulating enkephalins from crossing the blood-brain barrier.
 ...
PMID:Metabolism of opioid peptides by cerebral microvascular aminopeptidase M. 287 69

A recent study determined that cultured human skeletal muscle adult myoblasts, myotubes, and fibroblasts degraded angiotensins and kinins via neutral endopeptidase-24.11 (NEP-24.11: EC 3.4.24.11) and aminopeptidase N (APN: EC 3.4.11.2). Due to the possible importance of other peptides to skeletal muscle blood flow and function, the present study looked specifically at the metabolism of the neurokinins substance P (SP) and neurokinin A (NKA) by skeletal muscle peptidases. The results show that SP is degraded not only by NEP-24.11, but also sequentially by dipeptidyl(amino)peptidase IV (DAP IV: EC 3.4.14.5)/APN. NKA is unaffected by DAP IV but is metabolized by NEP-24.11 and APN. NEP-24.11 was inhibited by phosphoramidon (IC50 = 80 nM), thiorphan and ZINCOV, DAP IV by diprotin A (IC50 = 8 microM), and APN by amastatin (IC50 = 50 nM) and bestatin (IC50 = 100 microM). Skeletal muscle myocyte and fibroblast metabolism of SP and NKA may regulate local skeletal muscle vascular and extravascular functions including SP- and NKA-mediated nerve-induced vasodilation. Inhibition of both NEP-24.11 and DAP IV/APN may increase skeletal muscle blood flow and decrease peripheral vascular resistance via potentiation of local neurokinin levels.
 ...
PMID:Substance P and neurokinin A metabolism by cultured human skeletal muscle myocytes and fibroblasts. 897 37

The uterotonic potencies of the naturally occurring mammalian tachykinins and the synthetic subtype-selective agonist analogues of these agents [Lys5,MeLeu9,Nlel0]neurokinin A-(4-10) and [Nle10]neurokinin A-(4-10) (tachykinin NK2 receptor-selective), [Sar9,Met(O2)11]substance P (tachykinin NK1 receptor-selective) and senktide (tachykinin NK3 receptor-selective) were determined using preparations from oestradiol-treated rats. The endopeptidase 24.11 inhibitor, N-[N-[1-(S)-carboxyl-3-phenylpropyl]-(S)-phenyl-alanyl-(S)-isoserine+ ++ (SCH 39370), potentiated responses to neurokinin A, neurokinin B and substance P, but not to [Lys5,MeLeu9,Nle10)]neurokinin A-(4-10) or senktide. [Nle10]neurokinin A-(4-10) effects were potentiated by SCH 39370 with amastatin and those to [Sar9,Met(O2)11]substance P were potentiated by SCH 39370 and captopril in combination. In the presence of optimal concentrations of peptidase inhibitors the relative order of agonist potency was: neurokinin A > substance P > neurokinin B for the naturally occurring mammalian tachykinins and [Lys5,MeLeu9,Nle10]neurokinin A-(4-10) > [Nle10]neurokinin A-(4-10) > [Sar9,Met(O2)11]substance P > senktide for the synthetic tachykinin analogues. Thus, while a tachykinin NK2 receptor predominates in the oestrogen-primed uterus, a tachykinin NK1 receptor may also be present. The non-peptide tachykinin NK3 receptor antagonist, SR 142801, did not antagonise the effects of senktide suggesting that tachykinin NK3 receptors do not mediate its relatively minor effect on the uterus of the oestrogen-primed rat.
 ...
PMID:Potencies of agonists acting at tachykinin receptors in the oestrogen-primed rat uterus: effects of peptidase inhibitors. 936 77

1. The in vitro and in vivo pharmacology of SDZ NKT 343 (2-nitrophenyl-carbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N- methylamide), a novel tachykinin NK1 receptor antagonist was investigated. 2. SDZ NKT 343 inhibited [3H]-substance P binding to the human NK1 receptor in transfected Cos-7 cell membranes (IC50 = 0.62+/-0.11 nM). In comparison, in the same assay Ki values for FK888, CP 99,994, SR 140,333 and RPR 100,893 were 2.13+/-0.04 nM, 0.96+/-0.20 nM, 0.15+/-0.06 nM and 1.77+/-0.41 nM, respectively. SDZ NKT 343 showed a markedly lower affinity at rat NK1 receptors in whole forebrain membranes (IC50 = 451+/-139 nM). 3. SDZ NKT 343 caused an increase in EC50 as well as reduction in the number of binding sites (Bmax) determined for [3H]-substance P, suggesting a non-competitive interaction at the human NK1 receptor. SDZ NKT 343 also caused a reduction in the maximum elevation of [Ca2+]i evoked by substance P (SP) in human U373MG cells and depressed the maximum [Sar9]SP sulphone-induced contraction of the guinea-pig isolated ileum. The antagonism of SP effects on U373MG cells by SDZ NKT 343 was reversible. 4. SDZ NKT 343 showed weak affinity to human NK2 and NK3 receptors in transfected Cos-7 cells (Ki of 0.52+/-0.04 microM and 3.4+/-1.2 microM, respectively). SDZ NKT 343 was inactive in a broad array of binding assays including the bradykinin B2 receptor the histamine H1 receptor, opiate receptors and adrenoceptors. SDZ NKT 343 only weakly inhibited the voltage-activated Ca2+ and Na+ currents in guinea-pig dorsal root ganglion neurones. The enantiomer of SDZ NKT 343, (R,R)-SDZ NKT 343 was about 1000 times less active at human NK1 receptors expressed in Cos-7 cell membranes. 5. Contractions of the guinea-pig ileum by [Sar9]SP sulphone were inhibited by SDZ NKT 343 in a concentration-dependent manner, with an IC50 = 1.60+/-0.94 nM, while the enantiomer (R,R)-SDZ NKT 343 was 100 times less active (IC50 = 162+/-26 nM). In comparison, in the same assay IC50 values for other NK1 receptor antagonists CP 99,994, SR 140,333, RPR 100,893 and FK 888 were 2.90+/-07 nM, 0.14+/-0.02 nM, 11.4+/-2.9 nM and 2.4+/-0.83 nM, respectively. 6. In anaesthetized guinea-pigs i.v. administered SDZ NKT 343 antagonized [Sar9]SP sulphone-evoked bronchoconstriction (70% reduction at 0.4 mg kg(-1), i.v.). Basal airway resistance, mean arterial blood pressure and heart rate were not affected. 7. In conclusion, SDZ NKT 343 is a highly selective NK1 receptor antagonist with high potency at the human and guinea-pig receptors. SDZ NKT 343 may be used as a potential novel therapeutic agent in human diseases where NK1 receptor hyperfunction is involved.
 ...
PMID:Comparative, general pharmacology of SDZ NKT 343, a novel, selective NK1 receptor antagonist. 963 Mar 47

1. We investigated the effect of MEN 11467 ((1R,2S)-2-N[1(H)indol-3-yl-carbonyl]-1-N-[N(alpha)(p-tolylacetyl)-N(alpha)(methyl)-D-3-(2-naphthyl)alanyl]diaminocyclohexane) on tachykinin-induced mucus secretion in ferret trachea in vitro and determined its effect on secretion by tracheae from allergic ferrets in response to allergen challenge. 2. Repeated administration of [Sar(9),Met(O(2))(11)]-substance P ([Sar(9)]SP, 1 microM) maintained mucus output above control values for at least 1.75 h. MEN 11467 inhibited secretion in a concentration-dependent manner with maximal inhibition at 10 microM and an approximate IC(50) of 0.3 microM. Inhibition by MEN 11467 (0.1--10 microM) was maintained, to varying degree, for at least 1.75 h after washout in the continued presence of [Sar(9)]SP. 3. In electrically stimulated tracheae, tachykininergic neural secretion was virtually abolished by 1 microM MEN 11467. 4. In tracheae from ovalbumin-sensitised animals, repeated administration of ovalbumin maintained mucus output above controls for 1.5 h. MEN 11467 inhibited ovalbumin-induced secretion in a concentration-dependent manner, with complete inhibition at 1 microM. Inhibition by MEN 11467 (1 and 10 microM) was maintained, to varying degree, after drug washout for the 1.5 h of ovalbumin stimulation. 5. MEN 11467 1 microM did not affect secretion induced by either acetylcholine or histamine, whereas 10 microM MEN 11467 did inhibit agonist-induced secretion. 6. We conclude that, in ferret trachea in vitro, MEN 11467 at concentrations of 0.1--1 microM is a long acting and selective inhibitor of tachykininergic-induced mucus secretion, and may have therapeutic potential for bronchial hypersecretion associated with allergic conditions, for example in asthma.
 ...
PMID:Effect of the long-acting tachykinin NK(1) receptor antagonist MEN 11467 on tracheal mucus secretion in allergic ferrets. 1115 77

We have studied the effect of selective tachykinin NK(1) and NK(2) receptor antagonists on airway hyperreactivity to acetylcholine and increase of inflammatory cells on bronchoalveolar lavage fluid induced by sephadex beads (20 mg/kg, i.v.) in guinea pigs. Airway hyperreactivity was assessed by measuring the increase of bronchial insufflation pressure to acetylcholine (0.01-30 micromol/kg, i.v.) at 3 h (early phase) and 24 h (late phase) after sephadex administration. An increase in inflammatory cells in bronchoalveolar lavage fluid (eosinophils and macrophages) was detected at 24 h (from 11.6 x 10(6) to 49.3 x 10(6) cells) but not at 3 h from sephadex administration. Neurokinin A and substance P levels in bronchoalveolar lavage fluid showed a significant increase at 24 h (from 31.7+/-11.6 to 561+/-231 pg/ml and from 5.9+/-2.6 to 29.3+/-4.1 pg/ml for neurokinin A and substance P, respectively). At this time point, the tachykinin in bronchoalveolar lavage cellular content was depleted from 232+/-43 to 21+/-20 pg/sample and from 56.6+/-6.7 to 2+/-2 pg/sample for neurokinin A and substance P, respectively. Capsaicin pretreatment abolished the early but not the late phase of airway hyperreactivity induced by sephadex without modifying bronchoalveolar lavage total cells number and bronchoalveolar lavage levels of neurokinin A and substance P. Administration of the tachykinin NK(2) (nepadutant) and/or the NK(1) receptor antagonist (MEN 11467 or (1R,2S)-2-N[1(H)indol-3-yl-carbonyl]-1-N[N-(p-tolylacetyl)-N-(methyl)-D-3(2-naphthyl)alanyl)diaminocyclohexane)), 5 min before sephadex, prevented the early phase of airway hyperreactivity to acetylcholine but only nepadutant prevented the late phase. Nepadutant was able to abolish the early phase of airway hyperreactivity if given after sephadex administration and reduced by about 50% the increase of cell number in bronchoalveolar lavage fluid during the late phase, without affecting the levels of neurokinin A and substance P. These findings indicate an involvement of endogenous tachykinins in the genesis of airway hyperreactivity in a guinea-pig model of non-allergic asthma. Early airway hyperreactivity apparently involves release of tachykinins from capsaicin-sensitive afferent nerves acting via tachykinin NK(1)/NK(2) receptors. Late airway hyperreactivity involves tachykinins acting via tachykinin NK(2) receptors: inflammatory cells activated/recruited in response to sephadex challenge appear a likely source of tachykinins involved in the late phase of the response.
 ...
PMID:Role of tachykinins in sephadex-induced airway hyperreactivity and inflammation in guinea pigs. 1193 5


1 2 Next >>