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)

Angiotensin I-converting enzyme (ACE, E.C.3.4.15.1) has been recently shown to contain two very similar domains, each of which bears a functional active site hydrolyzing Hip-His-Leu or angiotensin I (AI). The substrate specificity of the two active sites of ACE was compared using wild-type recombinant ACE and mutants, where one active site is suppressed by deletion or inactivated by mutations of 2 histidines coordinating an essential zinc atom. Both active sites converted bradykinin (BK) to BK1-7 and BK1-5 with similar kinetics and with Kappm at least 30 times lower and kcat/kappm 10 times higher than for AI. The carboxyl-terminal active site, but not the amino-terminal site, was activated by chloride; however, chloride activation was minimal compared with AI. Both domains also hydrolyzed substance P and cleaved a carboxyl-terminal protected dipeptide and tripeptide. The carboxyl-terminal active site was more readily activated by chloride and hydrolyzed substance P faster. Luteinizing-hormone releasing hormone was hydrolyzed by both active sites, but hydrolysis by the amino-terminal active site was faster. It performed the endoproteolytic amino-terminal cleavage of this peptide at least 30 times faster than the carboxyl-terminal active site. Both active sites cleaved a carboxyl-terminal tripeptide from luteinizing hormone-releasing hormone. Thus, both active sites of ACE possess dipeptidyl carboxypeptidase and endopeptidase activities. However, only the carboxyl-terminal active site can undergo a chloride-induced alteration that greatly enhances the hydrolysis of AI or substance P, and the amino-terminal active site possesses an unusual amino-terminal endoproteolytic specificity for a natural peptide. This suggests physiologically important differences between the subsites of the two active centers, and different substrate specificity, despite the high degree of sequence homology.
 ...
PMID:Differences in the properties and enzymatic specificities of the two active sites of angiotensin I-converting enzyme (kininase II). Studies with bradykinin and other natural peptides. 768 54

We studied the effect of neurogenic inflammation on airway blood flow in anesthetized F-344 rats. Three successive determinations of blood flow were made by injecting radionuclide-labeled microspheres suspended in 70% dextrose into the left ventricle. A selective agonist of the tachykinin receptor neurokinin 1 (NK1) increased airway blood flow, but NK2- and NK3-selective agonists were without effect. The natural agonist of NK1 receptors, substance P (1 micrograms/kg), increased airway blood flow, an effect that was abolished by the selective NK1 receptor antagonist CP-99,994 [(+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine] but not by the (2R,3R)-enantiomer CP-100,263. Capsaicin (25 micrograms/kg), a drug that releases tachykinins and calcitonin gene-related peptide from sensory nerves, increased airway blood flow, and again this effect was abolished by CP-99,994. We also studied the effect of a selective inhibitor (captopril, 2.5 mg/kg) of the tachykinin-degrading enzyme kininase II [or angiotensin-converting enzyme (ACE)] on substance P-induced airway vasodilation. Captopril potentiated and prolonged the vasodilator effect of substance P. We conclude that neurogenic vasodilation in rat airways is due to the release of substance P, acts via NK1 receptors, and may be modulated by ACE.
 ...
PMID:NK1 receptors mediate neurogenic inflammatory increase in blood flow in rat airways. 768 98

In order to examine the role of peptidases in modulating bronchoconstrictor responses to i.v. administered capsaicin, a potent C-fiber stimulant, we measured changes in pulmonary conductance (GL) and dynamic compliance (Cdyn) in anesthetized mechanically ventilated guinea-pigs. Control guinea-pigs, and guinea-pigs treated with the neutral endopeptidase (NEP) inhibitors thiorphan (1.7 mg/kg) or SCH32615 (1 mg/kg), the angiotensin converting enzyme (ACE) inhibitor captopril (5.7 mg/kg), or combinations of NEP and ACE inhibitors, were given increasing doses of capsaicin by rapid i.v. injection. The doses of capsaicin required to cause a 50% decrease in GL and Cdyn (ED50GL and ED50Cdyn respectively) were computed for each animal. None of the peptidase inhibitors, when given alone, had any effect on the changes in pulmonary mechanics induced by capsaicin. However, combined administration of thiorphan and captopril, or SCH32615 and captopril, caused a decrease in ED50Cdyn for capsaicin, and prolonged the time during which the peak changes in GL induced by capsaicin persisted. These data support the hypothesis that substances whose degradation is inhibited by combined NEP and ACE inhibitors contribute to the bronchoconstriction induced by iv administered capsaicin. This profile of enzymatic degradation is consistent with the tachykinin, substance P.
 ...
PMID:Pulmonary mechanical responses to intravenously administered capsaicin in guinea-pigs: effect of peptidase inhibitors. 769 75

Neutral endopeptidase (NEP, EC 3.4.24.11), angiotensin-converting enzyme (ACE, EC 3.4.15.1) and carboxypeptidase N (CPN, EC 3.4.17.3) are potentially important enzymes which regulate the degradation of neuropeptides, such as bradykinin (BK) and substance P (SP), in the respiratory mucosa. Some neuropeptides are also degraded by these enzymes in vitro and in vivo. We investigated the localization of these enzymes in the human nasal mucosa by an indirect immunohistochemical technique (immunogold silver staining). NEP-immunoreactive areas were present in the epithelium, the serous cells of the submucosal glands, and the endothelial cells of small vessels. The epithelium and the serous cells were the predominant areas of NEP immunoreactivity in the nasal mucosa. ACE-immunoreactive areas were seen in the outer layer of the epithelium, the endothelial cells of vessels, and widely distributed in the superficial lamina propria. The endothelial cells of the vessels showed maximum positive intensity to ACE. CPN-immunoreactive areas were observed in the epithelium, the endothelium of vessels and the superficial lamina propria, except for the gland cells. The superficial lamina propria exhibited maximum immunoreactivity for CPN. We observed that the enzymes were widely distributed in the nasal mucosa. The epithelium, including the epithelial cells and glycocalyx, contains all three enzymes. These enzymes play an important role in the mucosal immunity of the respiratory mucosa by degrading active neuropeptides. These results show that NEP secretion is regulated by a glandular, cholinergic control. On the other hand, ACE and CPN secretion are regulated by vascular permeability.
 ...
PMID:Immunological localization of neuropeptide-degrading enzymes in the nasal mucosa. 783 83

Several neuropeptides, including neurotensin, somatostatin, bradykinin, angiotensin II, substance P, and luteinizing hormone-releasing hormone but not vasopressin and oxytocin, were actively metabolized through proteolytic degradation by cultivated astrocytes obtained from rat cerebral cortex. Because phenanthroline was an effective degradation inhibitor, metalloproteases were responsible for neuropeptide fragmentation. Neurotensin was cleaved by astrocytes at the Pro10-Tyr11 and Arg8-Arg9 bonds, whereas somatostatin was cleaved at the Phe6-Phe7 and Thr10-Phe11 bonds. These cleavage sites have been found previously with endopeptidases 24.16 and 24.15 purified from rat brain. Addition of specific inhibitors of these proteases, the dipeptide Pro-Ile and N-[1-(RS)-carboxy-3-phenylpropyl]-Ala-Ala-Phe-4-aminobenzoate, significantly reduced the generation of the above neuropeptide fragments by astrocytes. The presence of endopeptidases 24.16 and 24.15 in homogenates of astrocytes could also be demonstrated by chromatographic separations of supernatant solubilized cell preparations. Proteolytic activity for neurotensin eluted after both gel and hydroxyapatite chromatography at the same positions as found for purified endopeptidase 24.16 or 24.15. In incubation experiments or in chromatographic separations no phosphoramidon-sensitive endopeptidase 24.11 (enkephalinase) or captopril-sensitive peptidyl dipeptidase A (angiotensin-converting enzyme) could be detected in cultivated astrocytes. Because astrocytes embrace the neuronal synapses where neuropeptides are released, we presume that the endopeptidases 24.16 and 24.15 on astrocytes are strategically located to contribute significantly to the inactivation of neurotensin, somatostatin, and other neuropeptides in the brain.
 ...
PMID:Endopeptidases 24.16 and 24.15 are responsible for the degradation of somatostatin, neurotensin, and other neuropeptides by cultivated rat cortical astrocytes. 790 52

The effects of inhibition of angiotensin converting enzyme (ACE) and glycopyrrolate on cough caused by inhaled capsaicin were investigated in a double-blind, randomised cross-over study in twelve normal volunteers. The capsaicin challenge was performed before and 2 h after dosing with 75 mg captopril or matched placebo given orally, and 20, 40 and 60 min after giving 1 mg glycopyrrolate i.v. to each subject. Captopril and placebo did not alter the cough response when compared to baseline. Glycopyrrolate, however, caused a significant increase in the threshold sensitivity (D2) from baseline, and a significant decrease in the total cough response at 40 and 60 min both after captopril and placebo. The D2-baseline and D2-40 min after glycopyrrolate (mean SD), respectively, were 3.2 (1.0); 17.9 (4.2) after placebo and 2.5 (8.5); 23.6 (6.9) after captopril. Elimination of vagal influences implies attenuation of the effects of tachykinins but not those prostaglandins. We postulate that tachykinins, such as substance P, play a more important role than prostaglandins in capsaicin-induced cough. We conclude that the vagus is important in the capsaicin-induced cough reflex, but, as suppression of this reflex by glycopyrrolate was delayed, the relevant receptors are either poorly accessible peripheral receptors or they are located in the central nervous system.
 ...
PMID:Effects of glycopyrrolate on capsaicin-induced cough in normal volunteers treated with captopril. 795 39

We have investigated the contractile effect of bradykinin (BK) in guinea pig lung in vitro. BK induces a dose-related contraction of lung parenchymal strips which is increased significantly in the presence of 10(-5) M captopril (an angiotensin converting enzyme inhibitor) or 10(-5) M DL-thiorphan (a neutral endopeptidase inhibitor). The kininase I inhibitor, DL-2-mercaptomethyl-3-guanidino-ethylthiopropionic acid (MGTPA), has no effect on the BK-induced contraction. BK is more potent in contracting parenchymal lung strips than other contractile agents (histamine, carbachol and substance P), however the BK-induced maximal contraction is lower than those obtained with histamine and carbachol. The B1 agonist, des-Arg9-BK, does not contract lung parenchymal strips. The new BK B2 receptor antagonists (Hoe 140, NPC 17731 and NPC 17761), which possess binding affinities in the nanomolar range, inhibit the BK-induced contractile response in a dose-dependent manner. The BK-induced contraction was unaffected by propranolol, atropine, tetrodotoxin, capsaicin pre-treatment, triprolidine, methysergide, Ro 19-3704 and N omega-nitro-L-arginine-methyl-ester (L-NAME), excluding the involvement of nervous pathways, preformed mast cell mediators, platelet-activating factor and nitric oxide. However, indomethacin, a cyclooxygenase inhibitor, AA-861, a 5-lipoxygenase inhibitor, and furegrelate, a thromboxane A2 synthase inhibitor, decreased the contractile response to BK, suggesting that both cyclooxygenase and 5-lipoxygenase products are involved in this contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Bradykinin-induced contraction of guinea pig lung in vitro. 799 Sep 78

A new metallo-endopeptidase which hydrolyzes atrium natriuretic factor (ANF) has been isolated from human neuroblastoma NB-OK-1 cells. In the present study we show that this metallo-endopeptidase is also present in several other human neuroblastoma cell lines, which include CHP 100, SH-SY5Y, SK-N-BE(2), BE(2)-C and BE(2)M-17. Additionally, we show that this endopeptidase activity is reduced to about 20% of the control during retinoic acid (RA)-induced neuronal differentiation in the RA-sensitive SK-N-BE(2) cells, but not in the RA-resistant BE(2)-M17 cells. This suggests that the inhibition is related to neuronal differentiation and not to a direct effect of 5 microM RA on the enzyme activity. This new enzyme is clearly distinct from neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-converting enzyme (ACE,EC 3.4.15.1), since specific inhibitors for these endopeptidases (10 microM phosphoramidon and 1 mM captopril, respectively) had no effect on their activity. However, this enzyme was inhibited 100% by 10 mM o-phenanthroline showing an inhibitory spectrum similar to that of another novel metallo-endopeptidase recently isolated in our laboratory from Xenopus laevis skin secretion. Although the physiological function of this new enzyme in human neuroblastoma cells is not known at the present time, we suggest that it may participate in inactivation of neuropeptides such as atrium natriuretic factor (ANF), substance P, somatostatin-14 and bradykinin in vivo.
 ...
PMID:Human neuroblastoma cells express a novel metallo-endopeptidase activity able to inactivate atrial natriuretic factor: inhibition during retinoic acid-induced differentiation. 813 18

We used Evans blue dye to assess the effects of bradykinin on vascular extravasation in nasal mucosa of pathogen-free F344 rats. There was a dose-dependent increase in Evans blue extravasation when bradykinin was delivered by topical instillation in the nose (doses, 25-100 nmol). Only the highest intravenous doses (2 and 5 mumol/kg) of bradykinin caused increased extravasation. When bradykinin was delivered by either route, its effect on extravasation was exaggerated by pharmacological inhibition of the enzymes neutral endopeptidase (NEP) and kininase II [angiotensin-converting enzyme (ACE)]. When bradykinin was instilled locally, the effect of NEP inhibition was predominant; when bradykinin was injected intravenously, the effect of ACE inhibition was predominant. The mechanism of extravasation also varied with the mode of bradykinin delivery: when bradykinin was instilled locally in the nose, the selective neurokinin 1 (NK1) receptor antagonist CP-96,345 markedly inhibited the response, whereas it had no effect on Evans blue extravasation when bradykinin was injected intravenously. We conclude that bradykinin causes dose-related increases in Evans blue dye extravasation in the nose and that these effects are exaggerated when NEP and ACE are inhibited. Topically instilled bradykinin causes vascular extravasation to a large extent via NK1 receptor stimulation, thus suggesting a major role for tachykinins released from sensory nerve endings.
 ...
PMID:Role of peptidases and NK1 receptors in vascular extravasation induced by bradykinin in rat nasal mucosa. 839 2

The increase in vascular permeability associated with neurogenic inflammation in the nasal mucosa is mediated by neuropeptides such as substance P released from sensory nerves. Substance P is degraded by the peptidases neutral endopeptidase-24.11 (NEP-24.11) and angiotensin converting enzyme (ACE). In the present study, we used capsaicin to produce neurogenic inflammation in the nasal mucosa of rats, and we examined the effect of inhibition of NEP-24.11 by phosphoramidon, inhibition of ACE by captopril or inhibition of both enzymes by giving both inhibitors. Using as tracers intravenous Evans blue dye to quantify the extravasation and Monastral blue pigment to localize the sites of leakage, we examined the magnitude and distribution of capsaicin-induced plasma extravasation in the nasoturbinates, maxilloturbinates, ethmoidal turbinates and septum. Capsaicin caused a dose-dependent increase in Evans blue extravasation in the naso- and maxilloturbinates but had only a slight effect in the septum. The leaky blood vessels responsible for this plasma extravasation, as manifested by Monastral blue labeling, were most numerous in the naso- and maxilloturbinates, particularly near the front and free borders. After phosphoramidon, the leakage of Monastral blue was more widespread and extended in a more caudal direction. The response to capsaicin was augmented by phosphoramidon alone but not by captopril alone. However, in the presence of phosphoramidon, captopril further augmented the capsaicin-induced extravasation. We conclude that neurogenic inflammation in the rat nasal mucosa is greatest in the naso- and maxilloturbinates and can be modulated by NEP-24.11 and, to a lesser extent, by ACE.
 ...
PMID:Neurogenic plasma extravasation in the rat nasal mucosa is potentiated by peptidase inhibitors. 842 49


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>