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)

The effects of various peptidase inhibitors were examined upon the K+-evoked overflow of substance-like immunoreactive material (SPLI) from slices of rat substantia nigra in order to assess the possible involvement of "enkephalinase," angiotensin-converting enzyme (ACE) and calpain in the enzymatic inactivation of endogenous substance P in brain tissues. The calpain inhibitor leupeptin and the enkephalinase inhibitors thiorphan and phosphoramidon increased markedly SPLI overflow, whereas the two ACE inhibitors, captopril and enalaprilat (up to 10 microM in the superfusing medium), were inactive. Surprisingly kelatorphan, which inhibits not only enkephalinase but also aminopeptidase and dipeptidylaminopeptidase activities, was less potent than thiorphan or phosphoramidon to enhance SPLI overflow. However, in the presence of ICI-154129 or naloxone to block opiate receptors, kelatorphan was as potent as thiorphan, therefore suggesting some negative influence of endogenous opioids on SPLI release with kelatorphan but not thiorphan. In agreement with this interpretation, the direct stimulation of delta opiate receptors by deltakephalin was found to significantly reduce SPLI overflow. Furthermore, an increased outflow of [Met]enkephalin-like material was observed from substantia nigra slices superfused with kelatorphan but not thiorphan. These results indicate that endogenous substance P released within the substantia nigra is very probably inactivated by enkephalinase and calpain, but not ACE. They also demonstrate that endogenous opioids can exert a negative control upon substance P release in this brain region.
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PMID:Enkephalinase is involved in the degradation of endogenous substance P released from slices of rat substantia nigra. 244 57

To determine the role of endogenous enkephalinase (EC 3.4.24.11) in regulating peptide-induced contraction of airway smooth muscle, we studied the effect of the enkephalinase inhibitor, leucine-thiorphan (Leu-thiorphan), on responses of isolated ferret tracheal smooth muscle segments to substance P (SP) and to electrical field stimulation (EFS). Leu-thiorphan shifted the dose-response curve to SP to lower concentrations. Atropine or the SP antagonist [D-Pro2,D-Trp7,9]SP significantly inhibited SP-induced contractions in the presence of Leu-thiorphan. Leu-thiorphan increased the contractile responses to EFS dose dependently, an effect that was significantly inhibited by the SP antagonist [D-Pro2,D-Trp7,9]SP. SP, in a concentration that did not cause contraction, increased the contractile responses to EFS. This effect was augmented by Leu-thiorphan dose dependently and was not inhibited by hexamethonium or by phentolamine but was inhibited by atropine. Because contractile responses to acetylcholine were not significantly affected by SP or by Leu-thiorphan, the potentiating effects of SP were probably on presynaptic-postganglionic cholinergic neurotransmission. Captopril, bestatin, or leupeptin did not augment contractions, suggesting that enkephalinase was responsible for the effects. These results suggest that endogenous tachykinins modulate smooth muscle contraction and endogenous enkephalinase modulates contractions produced by endogenous or exogenous tachykinins and tachykinin-induced facilitation of cholinergic neurotransmission.
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PMID:Enkephalinase inhibitor potentiates substance P- and electrically induced contraction in ferret trachea. 244 55

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

This study was designed to evaluate the role of endogenous enkephalinase in regulating bronchoconstrictor responses in guinea pigs. We evaluated the effects of phosphoramidon, an enkephalinase inhibitor, on the increases in lung resistance (RL) caused by exogenous substance P and inhaled capsaicin (an agent thought to provoke bronchoconstriction in guinea pigs by stimulating the release of tachykinins from afferent nerve endings). In 6 of 6 animals, phosphoramidon potentiated the substance P-induced increase in RL (RL increased 380 +/- 100% [mean +/- SEM] before phosphoramidon and 1,300 +/- 400% afterward, p less than 0.025). In 4 of 4 animals, the repeated administration of a single dose of substance P after saline did not result in potentiation of the increase in RL caused by substance P. Similarly, in 6 animals exposed to inhaled capsaicin, phosphoramidon significantly increased capsaicin responsiveness when compared to 6 capsaicin-exposed animals not treated with phosphoramidon. Phosphoramidon-induced augmentation of the airway responsiveness to substance P and to capsaicin was not simply the result of a nonspecific increase in airway smooth muscle responsiveness because phosphoramidon failed to potentiate the bronchoconstrictor response to inhaled acetylcholine. These results suggest the enkephalinase plays an important role in modulating in vivo bronchoconstrictor responses to substance P in guinea pigs. Therefore, alterations in enkephalinase activity could contribute to in vivo alterations in bronchoconstrictor responsiveness.
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PMID:Phosphoramidon potentiates the increase in lung resistance mediated by tachykinins in guinea pigs. 244 5

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

1. The influence of epithelium removal and/or thiorphan on the effects of neurokinins (substance P (SP), neurokinin A (NKA), neurokinin B (NKB)) and related peptides on airway contractility was investigated on the guinea-pig isolated trachea. 2. Removing the tracheal epithelium significantly enhanced the sensitivity but not the maximum contractile responses to the peptides. 3. After removal of the epithelial layer, the shifts to the left of the log concentration response curves were greater for SP and SP-OMe (1.62 and 1.94 log units, respectively) than for two SP analogues substituted in position 9 namely [Pro9]SP sulfone and [beta-Ala4, Sar9]SP(4-11) sulfone (0.66 and 0.68 log units, respectively). The leftward shifts for compounds related to NKA or NKB lay between 0.58 and 0.73 log units. 4. The leftward shifts of the log concentration-response curves for SP, SP-OMe, [Pro9]SP sulfone, [beta-Ala4, Sar9]SP(4-11) sulfone and NKA were of similar magnitude after removal of the epithelium or after pretreatment with thiorphan (10(-5) M), an enkephalinase inhibitor, in the presence of epithelium. No significant additional shift of the curves to the left was observed with thiorphan plus epithelium removal. 5. The results obtained with the selective agonists for each of the three classes of neurokinin receptor (i.e NK1, NK2, NK3) suggest that the guinea-pig trachea contains receptors for SP and NKA but few if any for NKB. 6. It was concluded that neurokinins and related peptides (especially SP and analogues not substituted in position 9) are degraded by enkephalinase mainly located in the tracheal epithelium and that the addition of thiorphan or epithelium removal results in an inhibition or loss of enkephalinase activity, thereby increasing similarly the potencies of these peptides. It was, therefore, suggested that the supersensitivity to neurokinins produced by epithelium removal was due neither to the elimination of a permeability barrier nor to reduced production of a relaxant factor, but mainly to reduced peptide degradation.
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PMID:Comparison of the effects of epithelium removal and of an enkephalinase inhibitor on the neurokinin-induced contractions of guinea-pig isolated trachea. 246 Jan 77

To study the roles of substance P and endogenous neutral endopeptidase in mediating cough, we measured cough responses in awake guinea pigs in response to exogenous substance P and capsaicin aerosols in the presence and absence of the neutral endopeptidase inhibitors leucine-thiorphan and phosphoramidon. Substance P stimulated cough in very low concentrations (10(-17)-10(-16) M). In a second study where the investigator did not know whether substance P or diluent alone was aerosolized, substance P (10(-16) M) caused cough. Leucine-thiorphan (10(-5) M) and phosphoramidon (10(-5) M) potentiated substance P-induced cough; NEP inhibitors also potentiated capsaicin-induced cough significantly. These findings suggest that substance P is a potent stimulator of cough responses, that capsaicin-induced cough is mediated by substance P or another similar neuropeptide, and that cough responses are modulated by endogenous neutral endopeptidase.
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PMID:Neutral endopeptidase inhibitors potentiate substance P- and capsaicin-induced cough in awake guinea pigs. 246 67

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

To determine whether neutral endopeptidase (NEP), also called enkephalinase (EC 3.4.24.11), modulates the effects of exogenous and endogenous tachykinins in vivo, we studied the effects of aerosolized phosphoramidon, a specific NEP inhibitor, on the responses to aerosolized substance P (SP) and on the atropine-resistant response to vagus nerve stimulation (10 V, 5 ms for 20 s) in guinea pigs. SP alone (10(-7) to 10(-4) M; each concentration, 7 breaths) caused no change in total pulmonary resistance (RL, P greater than 0.5). Phosphoramidon (10(-4) M, 90 breaths) caused no change either in base-line RL (P greater than 0.5) or in the response to aerosolized acetylcholine (P greater than 0.5). However, in the presence of phosphoramidon, SP (7 breaths) produced a concentration-dependent increase in RL at concentrations greater than or equal to 10(-5) M (P less than 0.001). Phosphoramidon (10(-7) to 10(-4) M; each concentration, 90 breaths) induced a concentration-dependent potentiation of SP-induced bronchoconstriction (10(-4) M, 7 breaths; P less than 0.01). Vagus nerve stimulation (0.5-3 Hz), in the presence of atropine, induced a frequency-dependent increase in RL (P less than 0.001). Phosphoramidon potentiated the atropine-resistant responses to vagus nerve stimulation (P less than 0.001) at frequencies greater than 0.5 Hz. The tachykinin antagonist [D-Arg1,D-Pro2,D-Trp7,9,Leu11]-substance P abolished the effects of phosphoramidon on the atropine-resistant response to vagus nerve stimulation (2 Hz, P less than 0.005). NEP-like activity in tracheal homogenates of guinea pig was inhibited by phosphoramidon with a concentration producing 50% inhibition of 5.3 +/- 0.8 nM.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Airway neutral endopeptidase-like enzyme modulates tachykinin-induced bronchoconstriction in vivo. 246 81


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