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)

To determine the roles of endogenous enkephalinase (EC.3.4.24.11) in regulating tachykinin-induced contraction of airway smooth muscle, the authors studied the effects of the enkephalinase inhibitor leucine-thiorphan on the contractile responses to substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) in isolated ferret tracheal smooth muscle segments. Leucine-thiorphan shifted, in concentration-dependent fashions, the dose-response curves to all tachykinins to lower concentrations. Leucine-thiorphan changed the rank order of tachykinin potency from NKA greater than SP greater than NKB to NKA = NKB greater than SP. Removal of the epithelium slightly enhanced the contractile responses to SP and NKA but not to NKB. Atropine shifted the dose-response curves of all tachykinins to higher concentrations. Each tachykinin increased the contractile response to electrical field stimulation (5 Hz, 20 sec of duration, 20 V) in a dose-dependent fashion. This effect was not altered by hexamethonium, indomethacin, BW755C or naloxone but was potentiated by leucine-thiorphan and inhibited by the tachykinin receptor antagonist (D-Pro2, D-Trp7,9)-SP and by atropine. Because tachykinins did not affect contractile responses to acetylcholine significantly, their effects were probably on presynaptic postganglionic nerves. Captopril, bestatin and leupeptin did not alter contractile responses, suggesting that angiotensin converting enzyme, aminopeptidases and serine proteinases did not modulate tachykinin-induced effects. Enkephalinase immunofluorescence was found in the smooth muscle and epithelium and confirmed the authors' finding of enkephalinase-like activity in the muscle. The results suggest that tracheal enkephalinase is an important modulator of tachykinin-induced effects.
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PMID:Enkephalinase inhibitor potentiates mammalian tachykinin-induced contraction in ferret trachea. 244 68

The hydrolysis of substance P by membrane peptidases prepared from the rat substantia nigra was studied in the presence of selective inhibitors. Substance P degradation by synaptic and mitochondrial membranes was completely inhibited by 1,10-phenanthroline (1 mM), a non-specific metallopeptidase inhibitor. Captopril and bestatine, selective inhibitors of angiotensin converting enzyme and aminopeptidases respectively, were without effects. However, phosphoramidon (1 microM), a putative 'enkephalinase' inhibitor, selectively inhibited substance P degradation by synaptic membranes. These results suggest that a phosphoramidon-sensitive endopeptidase may be the principal enzyme responsible for substance P degradation in substantia nigra.
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PMID:Degradation of substance P by membrane peptidases in the rat substantia nigra: effect of selective inhibitors. 245 Mar 19

To determine whether neutral endopeptidase regulates the binding of substance P to the receptors, and if so, what the mechanism is, we determined the effect of neutral endopeptidase inhibitors, thiorphan and phosphoramidon, on specific binding of 3H-substance P to homogenates of rat ileum. Specific binding was of high affinity and was saturable (dissociation constant, KD = 2.4 +/- 0.17 nM and number of maximal binding sites, Bmax = 101.1 +/- 5.5 fmol/mg protein), and the receptor subtype was substance P-P type. Neutral endopeptidase inhibitors increased the specific binding to up to 160% of control (P less than 0.005). Neutral endopeptidase inhibitors prevented the degradation of 3H-substance P during the binding assay and increased the amount of 3H-substance P remaining in the assay system to up to 4.5-fold of control (P less than 0.005), but did not significantly change the KD or Bmax values of specific binding. Protease inhibitors of kininase II, serine proteinases, or thiol proteinases did not significantly change either specific binding or the amount of 3H-substance P remaining in the assay system. We conclude that neutral endopeptidase regulates the binding of substance P to the receptors and that it does so by decreasing the amount of substance P available to the receptors, without significantly changing the affinity or the number of receptors.
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PMID:Effect of neutral endopeptidase inhibitors on 3H-substance P binding in rat ileum. 245 38

To determine the role of endogenous neutral endopeptidase (NEP), also called enkephalinase (EC 3.4.24.11), in regulating tachykinin-induced contraction of gut smooth muscle, we studied the effects of NEP inhibitors on the contractile responses to substance P (SP) in isolated longitudinal strips of ileum or duodenum in rats and ferrets. Leucine-thiorphan and phosphoramidon shifted the concentration-response curves of SP to lower concentrations in all tissues studied, but the sensitivity to SP was greater and the effect of leucine-thiorphan was less in the ferret, a finding that correlated with the observation that the ferret ileum contained substantially less NEP activity than rat ileum. Captopril, bestatin, MGTA, leupeptin, and physostigmine did not alter contractile responses to SP, suggesting that kininase II, aminopeptidases, carboxypeptidase N, serine proteinases, and acetylcholinesterase do not modulate the SP-induced effects. These studies suggest that, in the ileum and duodenum, NEP modulates the actions of SP and, furthermore, that the sensitivity of tissues may be determined, at least in part, by the amount of enzymatically active NEP present.
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PMID:Neutral endopeptidase inhibitors potentiate substance P-induced contraction in gut smooth muscle. 246 69

The first inhibitor of angiotensin converting enzyme (ACE) was found in and isolated from the venom of the South American pit viper Bothrops jararaca. This was done after it was discovered that bites of the pit viper inhibit the breakdown of a proinflammatory peptide, bradykinin, in prey. Treatment with newly developed orally active ACE-inhibitors has been reported to cause symptoms such as adverse skin reactions, angioneurotic oedema, coughs and, in asthmatics, rapidly decreasing lung function. In this thesis the ACE-inhibitor MK 422 (active parent diacid of enalapril) was demonstrated to potentiate wheal and flare reactions induced by allergens, bradykinin or capsaicin, and to increase infiltration of "inflammatory cells", like eosinophils and neutrophils, into inflammatory dermal test sites in sensitized guinea pigs. MK 422 also augmented spontaneous and allergen-triggered histamine release in vitro from guinea pig skin and lung tissue. Capsaicin "desensitization" of guinea pig skin markedly reduced the wheal and flare reactions to allergens and attenuated the proinflammatory effect of the ACE-inhibitor. The histamine release in vitro from capsaicin-pretreated skin was also decreased, and no clear potentiating effect of MK 422 was demonstrated. In man, enalapril augmented anti-IgE-induced wheal and flare responses and increased bronchial reactivity to histamine. The drop of circulating eosinophils in venous blood was more pronounced after the provocations performed during enalapril treatment, and plasma substance P tended to increase. The alpha 2-adrenoceptor agonist clonidine, known to attenuate "neurogenic inflammation", reduced the wheal and flare reactions in guinea pig skin and decreased infiltration of neutrophils and eosinophils into inflammatory test sites. Furthermore, clonidine abolished the proinflammatory effect of MK 422 on the allergen- evoked wheal and flare reactions in guinea pig skin without counteracting the blood pressure lowering effect of the ACE-inhibitor. Contrarily, an additive hypotensive effect was demonstrated when clonidine was combined with MK 422. It is suggested that the proinflammatory properties demonstrated by ACE-inhibitors is due to augmentation of "neurogenic inflammation".
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PMID:New aspects on inflammatory reactions and cough following inhibiton of angiotensin converting enzyme. 246 91

To determine the regulatory role of neutral endopeptidase (NEP) in the tachykinin-induced increase in vascular permeability, we examined the effects of NEP inhibitors and of other protease inhibitors on plasma extravasation induced by intradermal injection of substance P, neurokinin A, and neurokinin B in guinea pig skin. The three tachykinins induced plasma extravasation in concentration-dependent fashions. A significant NEP activity was found to be present in the guinea pig skin. The tachykinin-induced responses were increased by the NEP inhibitors phosphoramidon and thiorphan. However, other protease inhibitors, including a kininase II inhibitor, did not affect the response. We conclude that NEP modulates the tachykinin-induced increase in vascular permeability in the skin.
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PMID:Neutral endopeptidase modulates tachykinin-induced increase in vascular permeability in guinea pig skin. 247 Jun 80

Substance P is a neuropeptide released in vivo from the substantia nigra, the principal substance P nerve terminal region in the rat brain. Its inactivation was investigated in a purified nigral synaptic membrane preparation. The membrane-bound enzyme shares many features with the endopeptidase 24-11 (EC 3.4.24.11): 1) hydrolysis of peptide bonds Gln6-Phe7, Phe7-Phe8 and Gly9-Leu10, 2) sensitivity to the inhibition by phosphoramidon and 3) relative affinity for substance P. Bestatine and captopril inhibit only the hydrolysis of the metabolites. These results suggest that substance P is inactivated in substantia nigra by endopeptidase 24-11 and that a bestatin-sensitive aminopeptidase and angiotensin converting enzyme may play a role in subsequent degradation of the substance P metabolites.
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PMID:Metalloendopeptidase (EC 3.4.24.11) but not angiotensin converting enzyme is involved in the inactivation of substance P by synaptic membranes of the rat substantia nigra. 247 Oct 29

The therapeutic inhibition of angiotensin converting enzyme (ACE) is associated with the production of a dry cough, which occurs more commonly in women than men and appears to be unrelated to concurrent illness. At present the exact incidence of ACE inhibitor cough and the substrate of ACE responsible for this effect is unknown. Cough challenge by inhalation of aerosols of tussive agents such as citric acid and capsaicin may be used to study the effect of drug administration on the cough reflex. In normal subjects, an oral dose of captopril (25 mg) causes a significant shift in the dose-response curve to capsaicin inhalation, but not that to distilled water or citric acid. The exacerbation of artificially induced cough by ACE inhibition may be the result of a local increase in perineuronal substance P or bradykinin concentrations within the lung.
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PMID:Cough associated with angiotensin converting enzyme inhibition. 247 6

A range of N-terminal fragments of substance P (SP) were evaluated for inhibitory activity against angiotensin converting enzyme (ACE) from rat lung and brain (striatum). SP inhibited the enzyme from both sources in a concentration dependent manner (IC50 30 microM). The N-terminal fragments SP[1-7], SP[1-6], SP[1-4] and SP[3-4] were equipotent with SP for both sources of the enzyme. However, SP[1-3] showed a difference in its activity, being more active than SP (IC50 10 microM) in inhibiting the brain enzyme, but inactive against lung ACE. These results suggest that the inhibitory action of SP on ACE resides in the N-terminus of the peptide. The difference in reactivity towards SP[1-3] lends support to the idea that lung and brain ACE are different isozymes.
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PMID:Inhibition of angiotensin converting enzyme by N-terminal fragments of substance P. 248 49

Airway responses to rapid intravenous infusions of substance P (SP), selected carboxy terminal fragments (SP3-11, SP5-11, SP7-11, and SP9-11), and an amino terminal fragment (SP1-9) were measured in anesthetized, mechanically ventilated guinea pigs. The dose of each peptide required to decrease pulmonary conductance (GL) to 50% of baseline value was calculated in each animal. The order of ED50GL was: SP5-11 less than SP3-11 less than SP less than SP7-11. SP9-11 and SP1-9 were inactive at doses up to 1000 nmol/kg i.v. The effects of the neutral metalloendopeptidase (NEP) inhibitor, thiorphan, and the angiotensin converting enzyme (ACE) inhibitor, captopril, on airway responses to SP5-11 were examined in order to test the hypothesis that differences in degradation of SP and SP5-11 contribute to the difference in airway responsiveness to the two peptides. Thiorphan (0.5 mg/animal, i.v.) caused a significant decrease in ED50GL for SP5-11, as has been previously noted for SP. In contrast, captopril (1.7 mg/animal i.v.) had no effect on ED50GL for SP5-11, although it has a substantial effect on SP responses. These results indicate that while the carboxy terminal of SP is essential for peptide bronchoactivity, loss of amino terminal peptides (up to four residues) actually enhances bronchoconstrictor responses to the peptide. Part of this enhancement appears to result from differences in the degradation of SP and SP5-11 by ACE. The data suggest that cleavage of SP by dipeptidyl aminopeptidases could enhance its bioactivity.
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PMID:Airway responses to substance P and substance P fragments in the guinea pig. 248 79


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