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 effect of peptidase inhibitors on neuropeptide release from peripheral endings of capsaicin-sensitive sensory neurons was studied in cerebral superior sagittal and transverse sinuses of guinea-pig. Capsaicin (1 microM)-evoked release of substance P-like immunoreactivity (SP-LI) was increased in a concentration-dependent manner by thiorphan (0.1-10 microM). Captopril (10 microM) or a mixture of bestatin (10 microM), leupeptin (10 microM) and bacitracin (10 microM) did not affect the capsaicin-evoked SP-LI release. Thiorphan (10 microM) increased also the capsaicin-evoked release of neurokinin A-like immunoreactivity (TK-LI) and calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) by 228% and 172%, respectively, while captopril (10 microM) was without effect. Thiorphan (10 microM), but not captopril (10 microM), enhanced by 239% CGRP-LI release induced by bradykinin (10 microM). In the cerebral venous vessels neutral endopeptidase (EC 3.4.24.11, NEP)-like activity was 58.8 +/- 6.1 pmol/mg protein/min, while angiotensin converting enzyme-like activity was below the detection limit of the assay. A thiorphan-sensitive mechanism, putatively attributable to NEP, plays a major role in the inactivation of peptides released from or acting on capsaicin-sensitive sensory fibres of cerebral venous sinuses of guinea-pig.
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PMID:The effect of thiorphan on release of sensory neuropeptides from guinea-pig cerebral venous sinuses. 206 52

Thiorphan, a well known inhibitor of 'enkephalinase' (endopeptidase 24.11) potentiated and prolonged the contractile response to substance P (SP) and neurokinin A (NKA) on strips of the guinea-pig isolated urinary bladder and this effect was evident both in presence and absence of the mucosal layer. Thiorphan also enhanced and prolonged the capsaicin-induced contraction in strips from the bladder dome which is thought to be mediated by release of endogenous tachykinins. Exposure to capsaicin produced simultaneous release of SP- and tachykinin-like immunoreactivity both in presence and absence of mucosa. This effect of capsaicin was potentiated by thiorphan. Endopeptidase 24.11 activity was detected in the guinea-pig urinary bladder, being more concentrated in the mucosal than the muscular layer. These findings indicate that endopeptidase 24.11 terminates the activity of tachykinins in the guinea-pig urinary bladder and modulates the intensity of the biological response produced after their release from peripheral endings of sensory nerves.
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PMID:Effect of thiorphan on the response of guinea-pig isolated urinary bladder to exogenous and endogenous tachykinins. 223 60

Nonadrenergic, noncholinergic contractile responses of guinea pig hilar bronchi to transmural electrical stimulation (TES) have been suggested to be due to release of endogenous tachykinins from capsaicin-sensitive neurons (C-fibers). Thiorphan and phosphoramidon, inhibitors of neutral endopeptidase (NEP, the major enzyme responsible for degrading tachykinins), were found to potentiate contractile responses of this isolated airway segment to TES and exogenously applied capsaicin, substance P and neurokinin A. However, the magnitude of potentiation by either inhibitor was smaller for TES and capsaicin (less than 10-fold leftward shift) than for the substrate agonists (about 100-fold leftward shift). This quantitative difference in potentiation by NEP inhibitors does not appear to be due to an influence of vasoactive intestinal peptide or calcitonin gene-related peptide, two endogenous peptides that might be released concomitantly by TES. Neither peptide caused marked effects on contractile responses to TES or tachykinins when applied to the isolated tissues. Addition of inhibitors of serine proteases, aminopeptidases, acetylcholinesterase and angiotensin-converting enzyme failed to further potentiate responses to TES in the presence of thiorphan. Therefore, the contractile response does not appear to be further modified by the activity of these peptidases. Neuropeptide gamma, but not neuropeptide K, was potentiated by thiorphan. The data suggest that peptides that are not substrates for NEP (for example, neuropeptide K) may also be released by TES from capsaicin-sensitive neurons to cause contraction. This may, at least in part, explain the quantitative difference in potentiation by NEP inhibitors of contractile responses to TES and to exogenously applied NEP-sensitive tachykinins in the guinea pig hilar bronchus.
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PMID:Pharmacologic studies on the differential influence of inhibitors of neutral endopeptidase on nonadrenergic, noncholinergic contractile responses of the guinea pig isolated hilar bronchus to transmural electrical stimulation and exogenously applied tachykinins. 239 13

To study the roles of substance P (SP) and endogenous peptidases in regulating mucus secretion from ferret trachea, we measured the SP-induced release of 35SO4-labeled macromolecules after incubating segments of trachea in Ussing chambers in the presence and absence of selected inhibitors of proteolytic enzymes. Our strategy was based on the idea that if endogenous peptidases degrade SP, then inhibitors of these enzymes should potentiate SP-induced secretion. We found that tracheas of ferrets contained SP-like immunoreactivity, and that SP stimulated the release of bound 35SO4 with rapid onset and offset. Eighty-five percent of the total macromolecular radioactivity released was contained in fractions of molecular weights greater than 10(6). The response to SP was concentration-dependent and reproducible. Thiorphan potentiated the secretory response to SP in a concentration-dependent fashion and phosphoramidon potentiated SP-induced secretion, whereas other inhibitors of proteinases and peptidases were without effects. These results suggest that substance P may regulate mucus secretion in ferrets, and that enkephalinase (dipeptidyl carboxypeptidase II, EC 3.4.24.11) in the airway degrades SP in a physiologically significant fashion, and thereby regulates peptide-induced secretion.
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PMID:Enkephalinase inhibitors potentiate substance P-induced secretion of 35SO4-macromolecules from ferret trachea. 243 22

We tested the effects of the neutral metalloendopeptidase (NEP) inhibitor, thiorphan (0.17, 0.5, and 1.7 mg i.v), and the angiotensin-converting enzyme (ACE) inhibitor, captopril (0.5, 1.7, and 5.0 mg i.v.), on the bronchoconstrictor response to rapid intravenous infusions of substance P (0.1 to 30 nmol/kg) in anesthetized, mechanically ventilated guinea pigs. The decreases in pulmonary conductance and dynamic compliance caused by substance P were greater in animals treated with either thiorphan or captopril than in control animals. Thiorphan (0.5 mg) had no effect on airway responsiveness to intravenously administered methacholine, whereas captopril (1.7 mg) caused a small increase in methacholine responsiveness. Both drugs significantly increased the recovery of immunoreactive substance P in arterial plasma after exogenous administration of the peptide. We conclude that degradation of substance P by both NEP and ACE is important for determining the magnitude of the bronchoconstriction caused by intravenous administration of this neuropeptide. These data suggest that conditions associated with diminished peptidase activity could result in enhanced responses to stimuli which cause the release of endogenous substance P.
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PMID:Substance P-induced bronchoconstriction in the guinea pig. Enhancement by inhibitors of neutral metalloendopeptidase and angiotensin-converting enzyme. 244 4

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

We have assessed the ability of thiorphan, an inhibitor of enkephalinase, to influence the potentiation of the nerve-mediated contractions of the rat isolated vas deferens (pars prostatica) by mammalian tachykinins [substance P, (SP); neurokinin A (NKA); and neurokinin B (NKB)] and selective tachykinin agonists. In the absence of thiorphan, the rank order of potency of mammalian tachykinins was NKA greater than NKB much greater than SP. The maximal response to SP did not exceed 40% of that to NKA or NKB. Thiorphan (10 microM) had no effect on twitches per se, but increased the potency and maximum effect of mammalian tachykinins. [Pro9]-SP sulfone, a selective NK-1 receptor agonist had no effect, either in the absence or presence of thiorphan. [MePhe7]-NKB had some potentiating effect, but only at micromolar concentrations. [Nle10]-NKA (4-10) and [beta-Ala8]-NKA (4-10), two selective NK-2 agonists displayed good activity. [Nle10]-NKA (4-10) was potentiated by thiorphan. On the other hand, the action of [beta Ala8]-NKA (4-10) was completely thiorphan-resistant. These findings indicate that estimate of activity of tachykinins and tachykinin related peptides in this bioassay is influenced markedly by peptide degradation via a thiorphan-sensitive mechanism. NK-2 receptors are the main if not the sole mediators of the response to tachykinins in this bioassay organ.
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PMID:Effect of thiorphan on tachykinin-induced potentiation of nerve-mediated contractions of the rat isolated vas deferens. 254 44

We studied the effects of the neutral endopeptidase (NEP) inhibitor thiorphan (1.7 mg/kg iv) and the angiotensin-converting enzyme (ACE) inhibitor captopril (5.7 mg/kg iv) on airway responses to rapid intravenous infusions of neurokinin A (NKA) and neurokinin B (NKB) in anesthetized, mechanically ventilated guinea pigs. The dose of NKA required to decrease pulmonary conductance to 50% of its base-line value (ED50GL) was fivefold less (P less than 0.0001) in animals treated with thiorphan compared with controls. NKA1-8, a product resulting from cleavage of NKA by NEP, had no bronchoconstrictor activity. Similar results were obtained by using NKB as the bronchoconstricting agent. Captopril had no significant effect on airway responses to NKA or NKB. In contrast, both thiorphan and captopril decrease the ED50GL for substance P (SP). We also compared the relative bronchoconstrictor potency of NKA, NKB, and SP. In control animals, the rank order of ED50GL values was NKA much less than NKB = SP. NKA also caused a more prolonged bronchoconstriction than SP or NKB. Thiorphan had no effect on the rank order of bronchoconstrictor potency, but in animals treated with captopril, the rank order of ED50GL values was altered to NKA less than SP less than NKB. These results suggest that degradation of NKA and NKB by NEP but not by ACE is an important determinant of the bronchoconstriction induced by these peptides. The degradation by ACE of SP but not NKA or NKB influences the observed relative potency of the three tachykinins as bronchoactive agents.
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PMID:Degradative enzymes modulate airway responses to intravenous neurokinins A and B. 255 2

1. The possible involvement of enzymatic degradation in the inactivation of tachykinin neurotransmitters was examined in the spinal cord of the neonatal rat. 2. The magnitude of substance P (SP)- or neurokinin A (NKA)-evoked depolarization of a lumbar ventral root in the isolated spinal cord preparation was increased by a mixture of peptidase inhibitors, consisting of actinonin (6 microM), arphamenine B (6 microM), bestatin (10 microM), captopril (10 microM) and thiorphan (0.3 microM). The mixture augmented the response to NKA more markedly than that to SP. 3. In the isolated spinal cord-cutaneous nerve preparation, the saphenous nerve-evoked slow depolarization of the L3 ventral root was augmented by the mixture of peptidase inhibitors in the presence of naloxone (0.5 microM) but not in the presence of both naloxone and a tachykinin receptor antagonist, GR71251 (5 microM). 4. Application of capsaicin (0.5 microM) for 6 min to the spinal cord evoked an increase in the release of SP from the spinal cord. The amount of SP released was significantly augmented by the mixture of peptidase inhibitors. 5. Synaptic membrane fractions were prepared from neonatal rat spinal cords. These fractions showed degrading activities for SP and NKA and the activities were inhibited by the mixture of peptidase inhibitors. The degrading activity for NKA was higher than that for SP and the inhibitory effect of the mixture for NKA was more marked than that for SP. Although some other fractions obtained from homogenates of spinal cords showed higher degrading activities for SP, these activities were insensitive to the mixture of peptidase inhibitors. 6. Effects of individual peptidase inhibitors on the enzymatic degradation of SP and NKA by synaptic membrane fractions were examined. Thiorphan, actinonin and captopril inhibited SP degradation, while thiorphan and actinonin, but not captopril, inhibited NKA degradation. The potency of the inhibition of each peptidase inhibitor was lower than that of the mixture.7. The present results suggest that enzymatic degradation is involved in the inactivation of tachykinin neurotransmitters in the spinal cord of the neonatal rat.
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PMID:Involvement of enzymatic degradation in the inactivation of tachykinin neurotransmitters in neonatal rat spinal cord. 752 13

Two analogues of the aminopeptidase inhibitor bestatin, Z 4212 (N-[(2S, 3R)-3-Amino-2-hydroxy-4-(4-methylsulphonyl-phenyl)-1-oxobutyl]-1- aminocyclopentanecarboxylic) and Z 1796 ((2S)-N-[(2S,3R)-3-Amino-2-hydroxy-4-(4-methylsulphonyl-phenyl)-1- oxobutyl]-L-leucine) were found to behave as hypoalgesics when intracerebroventricularly (i.c.v.) administered to mice in the hot-plate test. At high doses, Z 4212 was also found to reduce the pain threshold after intraventricular (i.v.) administration. Hypoalgesia induced by bestatin analogues was prevented by prior treatment with the opiate receptor blocker naloxone. Thiorphan, a potent inhibitor of NEP, was found to enhance the hypoalgesic effect of low doses of either Z 4212 or Z 1796. These results indicate that both the major opioid-degrading peptidases, i.e. aminopeptidases and neutral endopeptidase (NEP), are individually implicated in the hypoalgesia induced by peptidase inhibitors. In vitro studies showed that these new bestatin analogues readily inhibit aminopeptidases in membranes from mouse c. striatum whereas more than 1000 times the concentration was required for NEP to be blocked. Ex vivo experiments showed that, at variance with bestatin, the hypoalgesic action of Z 4212 or Z 1796 appeared to implicate central aminopeptidases but not NEP, so partially sparing the metabolism of other NEP substrates that might produce additional alterations (substance P and ANP). On the basis of the antitumour and immunomodulatory actions of bestatin, these new analogues might be potentially useful as mixed antitumour and hypoalgesic agents in malignancy.
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PMID:Hypoalgesic action of bestatin analogues that inhibit central aminopeptidases, but not neutral endopeptidase. 824 55


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