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 the angiotensin converting enzyme (ACE) inhibitor captopril and the neutral endopeptidase (NEP) inhibitors thiorphan and SCH 32615 on the changes in airway opening pressure (PaO) and the recovery of offered peptide were studied after intratracheal administration of substance P (SP) and neurokinin A (NKA) in isolated guinea pig lungs superfused through the trachea. Pao changes and the recovery of offered peptide were significantly greater in NEP inhibitor-treated lungs than in control lungs. Captopril did not cause a significant change in the physiological effects or the recovery of SP and NKA. HPLC analysis of [3H]Pro2,4-SP and 125I-Histidyl1-NKA perfused through the airways showed major cleavage products consistent with NEP action. We conclude that there is significant degradation of both SP and NKA after tracheal infusion of peptides by NEP-like but not by ACE activity; this effect significantly influences the physiological effects of these peptides.
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PMID:Peptidase modulation of the pulmonary effects of tachykinins in tracheal superfused guinea pig lungs. 168 68

Acute intravenous administration of the selective D1 receptor blocker SCH-23390 resulted in an enhanced respiratory motor output as evidenced by the phrenic nerve activity, whereas local perfusion into the region of nucleus tractus solitarii had no effect. The increase in phrenic nerve activity was accompanied by a concomitant increase in the release of substance P in the region of nucleus tractus solitarii as measured by in vivo microdialysis technique. Chronic administration of SCH-23390 via subcutaneously implanted Alzet mini osmotic pumps, significantly decreased the level of preprotachykinin-A mRNA in the region of respiratory relay neurons in nucleus tractus solitarii but was without effect in the ventral medullary surface structure, wherein the central chemoreceptors are thought to be located. A smaller, but significant decrease was also seen in the striatum. The results suggest that chronic treatment with SCH-23390 leads to a disinhibition of an inhibitory dopaminergic input to the neurons in nucleus tractus solitarii from a suprapontine level, which may account for a subsequent inhibition of tachykinin-containing neurons in the nucleus tractus solitarii, the relay station for respiratory reflexes.
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PMID:Chronic treatment with SCH-23390, a selective dopamine D1 receptor blocker decreases preprotachykinin-A mRNA levels in nucleus tractus solitarii of the rabbit: role in respiratory control. 170 40

The effects of sustained blockade of dopamine receptors by selective dopamine antagonists on the tachykinin (substance P and neurokinin A) content in the substantia nigra were examined. The treatment of rats for 14 days with D-1/D-2 dopamine receptor antagonist haloperidol (2 mg/kg) or selective D-2 antagonist sulpiride (100 mg/kg) produced a similar and significant decrease in nigral substance P and neurokinin A-like immunoreactivity content, about 32-36% and 27-28% of control respectively. In contrast, administration of SCH 23390 (1 mg/kg), a selective and potent D-1 dopamine receptor antagonist, failed to affect the levels of substance P and neurokinin A in the substantia nigra and did not change the sulpiride-induced reduction of the nigral tachykinin peptides. These results indicate that the D-1 dopamine receptors are not involved in the modulation of nigral substance P and neurokinin A content and suggest that the blockade of the D-2 dopamine receptor subtype exerts the same regulation of the tachykinin gene expression, in spite of the existence of three mRNAs encoding substance P and neurokinin A.
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PMID:Tachykinins in the rat substantia nigra: effects of selective dopamine receptor antagonists. 171 46

We studied the effects of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) inhibition on the airway responses and the recovery of endogenously released substance P- and neurokinin A-like immunoreactivities (SP-LI and NKA-LI) after tracheal injection of capsaicin in isolated guinea pig lungs superfused through the trachea. Capsaicin in doses from 10(-10) to 10(-7) mol induced a dose-dependent increase in airway opening pressure and release of SP-LI and NKA-LI. Airway opening pressure changes and the recovery of SP-LI and NKA-LI were significantly greater in lungs superfused with the NEP inhibitor SCH 32615 than in control lungs. ACE inhibition with captopril did not increase the mechanical response or the recovery of SP-LI compared with lungs not receiving captopril. In lungs from guinea pigs pretreated with high doses of capsaicin 7-10 days before study, a regimen designed to deplete endogenous tachykinins, there was a significant decrease in the content and release of NKA-LI and SP-LI. There were no detectable airway effects of acute capsaicin infusion even after doses of 10(-5) mol. Because NEP is important in modulating the airway effects of endogenously released tachykinins after tracheal infusion of capsaicin, but ACE is not, it seems likely that tracheal administration of capsaicin releases tachykinins from epithelial rather than endothelial loci.
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PMID:Capsaicin-induced release of tachykinins: effects of enzyme inhibitors. 171 6

The responses of extrapyramidal and limbic neuropeptide and striatal dopamine and serotonin systems were evaluated after treatment with fenfluramine in rats. After multiple administrations of fenfluramine, its active metabolite, norfenfluramine, and methamphetamine (METH), striatal neurotensin (NT) content was similarly increased to approximately 200% of control. In contrast, nigral NT levels were unaltered by fenfluramine, intermediately increased by norfenfluramine (148% of control) and maximally increased by METH (267% of control). Striatal and nigral substance P (SP) and dynorphin A (Dyn) systems were unaltered by fenfluramine, whereas norfenfluramine caused an intermediate increase in striatal Dyn content but did not significantly alter striatal SP or nigral SP and Dyn levels. However, METH significantly elevated striatal and nigral Dyn and SP concentrations to 280 to 425% (Dyn) and 140% (SP) of control. For the most part, the response of the limbic peptides was similar to that seen in the striatum with a couple of notable differences. Further investigation of the striatal NT system showed that the increases induced by fenfluramine were completely blocked by the D1 antagonist, SCH 23390, and the noncompetitive N-methyl-D-aspartate antagonist, MK801. Depletion of 5-hydroxytryptamine with pretreatment by parachloroamphetamine did not alter the response of the striatal NT system to fenfluramine. The present results demonstrate common and unique features in the response of peptide systems to fenfluramine and methamphetamine, which might explain some of the similarities and differences between these two drugs.
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PMID:Response of extrapyramidal and limbic neuropeptides to fenfluramine administration: comparison with methamphetamine. 172 53

In order to better understand the neuroleptic-like effects of neurotensin in vivo, the effects of neurotensin in vitro on dopamine D2 and D1 agonist and antagonist binding sites were characterized in membranes from the neostriatum and the subcortical limbic area. Neurotensin increased the KD but not the Bmax value of S(-)[N-propyl-3H(N)]propylnorapomorphine [( 3H]NPA) binding sites with a maximal increase of 20-40% at 3-10 nM of neurotensin in both areas. The KD increase was preferentially due to an increase in the dissociation rate. The maximal reduction of [3H]NPA binding (35%) was obtained within 5 min from the addition of neurotensin. Neurotensin increased the KH of dopamine vs [3H]raclopride binding and, in the presence of GTP, also KL. Neurotensin did not affect the percentage of binding sites in the high vs low affinity states or the binding characteristics of [3H]spiperone, [3H]SKF 38393, and [3H]SCH 23390. Serotonin (10 nM), neuropeptide Y (10 nM), Substance P (10 nM), dynorphin A (10 nM), morphine (10 nM), nicotine (100 nM), gamma-amino-n-butyric acid (1 microM), or N-methyl-D-aspartate (1 microM) did not affect [3H]NPA binding. These results indicate that neurotensin in vitro selectively reduces D2 agonist affinity by an enhancement of the dissociation rate. This antagonistic intramembrane interaction may underlie the neuroleptic-like effects of neurotensin at low concentrations in vivo on D2 agonist binding, dopamine release, and on D2-mediated behaviours.
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PMID:Biochemical characterization of the intramembrane interaction between neurotensin and dopamine D2 receptors in the rat brain. 183 40

The autoradiographic distribution of D1 dopaminergic binding sites was studied in the human ventral mesencephalon using the D1 antagonist [3H]SCH 23390. [3H]SCH 23390 binding was characterized by a single class of sites with a Kd of 2.5 nM and a Bmax of 31 fmol/mg of tissue. The density of [3H]SCH 23390 binding sites was high in the substantia nigra, moderate in the ventral tegmental area and low in the peri- and retrorubral field (catecholaminergic region A8). Binding densities were similar in pars compacta and pars reticulata of the substantia nigra, except for a peak value of high [3H]SCH 23390 in the pars reticulata, at a level just ventral to a zone of hyperdensity of melanized dopaminergic neurons in the pars compacta. The anatomical organization of the human ventral mesencephalon was analysed on adjacent sections stained for acetylcholinesterase histochemistry and tyrosine hydroxylase, substance P, dynorphin B, somatostatin and methionine-enkephalin immunohistochemistry, respectively. The similarity in distribution of [3H]SCH 23390 binding sites and substance P or dynorphin B immunoreactivity suggests that D1 binding sites are mainly located on the striatonigral projections. In accordance with these results: (1) the density of [3H]SCH 23390 binding sites was reduced in the substantia nigra of a patient with Huntington's chorea, a disease associated with a degeneration of striatonigral neurons; (2) the density of [3H]SCH 23390 binding sites was unaffected in the substantia nigra of a patient with Parkinson's disease, a disorder characterized by a marked loss in nigral tyrosine hydroxylase-positive neurons. [3H]SCH 23390 binding sites showed a characteristic, heterogeneous distribution within the human ventral mesencephalon, confirming data obtained in other species. The preferential localization of D1 dopamine receptors on striatonigral projections in human brain suggests that pharmacological manipulation of these receptors modulates the activity of striatonigral pathways, thereby affecting the various outputs of the nigral complex.
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PMID:Microtopography of D1 dopaminergic binding sites in the human substantia nigra: an autoradiographic study. 198 69

Conditions were established to stimulate human gingival fibroblast explant cultures to synthesize milligram quantities of the metalloproteinase proenzymes, prostromelysin and procollagenase. To stimulate enzyme production, cells were treated with 1 nM recombinant human IL-1 beta for approximately 7 days under serum free conditions. Using a combination of rapid column chromatography steps, approximately 10 milligrams of prostromelysin and 5 milligrams of procollagenase were purified from 1 liter of conditioned media. Prostromelysin electrophoresed as a doublet with molecular weights of 55,57 kD, whereas, procollagenase migrated with slightly lower molecular weights of 52, 54 kD. Both proenzymes were treated with trypsin or aminophenylmercuric acetate to generate active species. The molecular weights of the active enzymes were approximately 10 kD smaller than the proenzymes. Active enzymes were inhibited by metal chelators and the natural metalloproteinase inhibitor, tissue inhibitor of metalloproteinase (TIMP), but not by the serine protease inhibitor, phenylmethylsulfonyl fluoride (PMSF). Activated stromelysin degraded a number of substrates including transferrin, proteoglycan monomer, proteoglycan aggregated with hyaluronic acid, and substance P. By contrast, collagenase degraded interstitial type I collagen and the peptide thioester, Ac-Pro-Leu-Gly-SCH(iBu)Co-Leu-GlyOEt. Identity of both enzymes were confirmed by amino-terminal protein sequence analysis as well as by immunoblot analysis using monoclonal antibodies.
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PMID:Production and purification of prostromelysin and procollagenase from IL-1 beta-stimulated human gingival fibroblasts. 217 90

Peptides derived from prodynorphin, dynorphin A and B, (Leu)-enkephalin and (Leu)enkephalyl-Arg, as well as substance P, were measured in substantia nigra, striatum and globus pallidus, after subacute (5 doses at 6 hr intervals) treatment of rats with a number of dopamine receptor agonists and antagonists. Drugs selective for the dopamine D1 and D2 receptors, respectively, as well as unselective drugs were used. In the substantia nigra, levels of immunoreactive dynorphin A and dynorphin B were increased after treatment with a D2-antagonist (sulpiride) and a D1-agonist (SKF 38393), while a D1-antagonist (SCH 23390) reduced levels. The mixed D1 and D2 antagonist cis-flupenthixol reduced only the level of dynorphin A. A corresponding increase of the levels of (Leu)enkephalin in the nigra was found after treatment with sulpiride. In contrast to dynorphin peptides, the levels of (Leu)enkephalyl-Arg were markedly increased after both D1- and D2 (LY 171555)-stimulation. Substance P tended to be reduced after D1-stimulation and treatment with all the dopamine antagonists; the reduction was significant with sulpiride and cis-flupenthixol. Levels of peptides in striatum and globus pallidus were generally affected in the same direction as levels in the nigra. The results in this study present further evidence that dopamine receptor agents affect dynorphin peptides and substance P, differentially. Effects on (Leu)enkephalin and (Leu)enkephalyl-Arg only partly paralleled the effects on levels of dynorphin. Thus, the D1 and D2 receptors differentially affect levels of different products of prodynorphin, that is, seem to affect certain steps of the processing of prodynorphin selectively.
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PMID:Dopamine receptors mediate alterations in striato-nigral dynorphin and substance P pathways. 244

Repeated administration to rats of SCH 23390, a specific antagonist of the D-1 dopamine receptor, produced an increase in the substance P immunoreactivity in the striatum but not in the substantia nigra, whereas similar treatment with sulpiride, a specific D-2 dopamine receptor antagonist, reduced the nigral but not the striatal content of the peptide. When the two antagonists were given together, the SCH 23390-induced increase in striatal substance P was significantly reduced. The SCH 23390-induced increase in striatal substance P was curtailed by concomitant administration of progabide, a selective gamma-aminobutyric acid (GABA) receptor agonist. These results suggest the existence in the nigro-striatal complex of two different substance P-containing neurons which are differentially regulated by the dopamine receptor subtypes and indicate a role of GABA in the action of SCH 23390.
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PMID:Selective antagonists of dopamine receptor subtypes differentially affect substance P levels in the striatum and substantia nigra. 244 3


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