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)

1. Effects of inhibition of angiotensin converting enzyme (ACE, EC 3.4.15.1) in brain on psychomotor, exploratory, stereotyped and cognitive behaviour in rats were investigated. To inhibit brain ACE captopril (D-3-mercaptopropanoyl-L-proline) was given orally (p.o., 50 mg/kg) or intracerebroventricularly (i.c.v., 5 micrograms/rat). 3. Captopril given p.o. but not i.c.v. significantly enhanced stereotypy, overall number of conditioned avoidance responses, and decreased blood pressure. 4. No statistically significant influence of captopril given by either route on the number of crossings, rearings and bar approaches in the open field, performance of passive avoidance and number of correct choices as well as the speed of running for food in the T-maze was observed. 5. In conclusion, a small decrease of the activity of nigrostriatal dopaminergic system caused by the decrease of AII and/or increase of bradykinin, substance P, enkephalins and neurotensin in brain resulting from ACE inhibition is postulated.
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PMID:Some behavioural effects of captopril in rats. 227 85

Captopril (1-5 mg/kg, i.v.) did not affect the vasodepressor responses to substance P (1-30 micrograms/kg, i.v.) in anaesthetized rats. Substance P (100 micrograms/kg, s.c.) produced significant algesia in mice; this was not potentiated by the smaller doses of captopril (1-2 mg/kg, i.p.), but was instead antagonized by the high dose (5 mg/kg, i.p.). It is concluded that captopril does not have any influence on substance P degradation in vivo since the pharmacological actions of the undecapeptide are not enhanced after captopril treatment.
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PMID:Captopril does not potentiate hypotension and algesia by substance P. 243 36

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

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 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 involvement of neurokinins, especially substance P, in the opiate withdrawal syndrome was studied by treating rats with drugs that have been reported to increase (captopril) or decrease (capsaicin) tissue levels of substance P. Preliminary experiments with captopril (0.1, 0.3, 1 or 3 mg/kg, SC) showed that the 0.3 mg/kg dose enhanced some of the naloxone-precipitated withdrawal signs. Captopril alone had no effect in the morphine-dependent rat. On experimental days, either saline or captopril (0.3 mg/kg) was injected (SC) immediately before naloxone in morphine-dependent rats that were pretreated (4 to 10 days before the morphine pellet implantation) with either capsaicin (125 mg/kg, SC) or the capsaicin vehicle (N = 8 for each of 4 groups). Capsaicin treatment inhibited the following withdrawal signs: rhinorrhea, lacrimation and salivation. Captopril increased the occurrence of these secretory responses in vehicle-treated but not in capsaicin-treated animals. Other withdrawal signs were not altered by either captopril or capsaicin treatment. The results support the conclusion that substance P and related neurokinins may be involved in the expression of some signs of opioid withdrawal.
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PMID:Captopril and capsaicin modify opioid withdrawal in the morphine-dependent rat. 248 12

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

Captopril, enalapril, lisinopril, ramipril, cilazipril, and quinipril have all been documented to induce cough with an estimated frequency of at least 15% of treated patients. Common descriptors include tickling, dry, nonproductive, and persistent. Onset usually occurs during the first week of therapy and lasts as long as the drug is taken, remitting within a few days after the agent is discontinued. Alternative angiotensin-converting enzyme (ACE) inhibitors replicate the cough. The mechanism seems related to stimulation of lung afferent C fibers, perhaps by prostaglandin E2. It may also be related to decreased breakdown of substance P, the neurochemical mediator of the cough reflex released in response to stimulation of C fibers and metabolized by ACE. The possible role of prostaglandins is supported by two anecdotal reports of cough disappearing in patients receiving nonsteroidal antiinflammatory agents. Future trials should recognize cough as a side effect of ACE inhibitor therapy, and prospective determination of its true frequency and cross-occurrence are necessary.
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PMID:The positive association of cough with angiotensin-converting enzyme inhibitors. 265 76

A dipeptidyl carboxypeptidase, which cleaved the Gly3-Phe4 bond of enkephalins, was purified from guinea pig serum 420-fold. The optimum pH of the enzyme was in the neutral range (pH 7.25), and the molecular weight was estimated to be approx. 280,000. The enzyme hydrolyzed Met- and Leu-enkephalin with Km values of 0.30 and 0.50 mM, respectively. The enzyme was inhibited by metal chelators and p-chloro-mercuribenzoate. Captopril showed high inhibitory potency, while phosphoramidon and Phe-Ala showed no effect on the enzyme activity. Therefore, the obtained enzyme can be classified as an angiotensin-converting enzyme (EC 3.4.15.1). Among the bioactive peptides examined, bradykinin and angiotensin I were hydrolyzed by the enzyme. Angiotensin III showed a stronger inhibitory effect than that of angiotensin II. Substance P, gastrin I, and secretin were also inhibitory toward the enzyme activity. On high-performance liquid chromatography analysis, Met-enkephalin-Arg6-Phe7 and Leu-enkephalin-Arg6 were cleaved sequentially at the second peptide bond of the C terminus. Thus, the dipeptidyl carboxypeptidase in guinea pig serum may play a role not only in the angiotensin-bradykinin system but also in the metabolism of circulating enkephalins and other bioactive peptides.
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PMID:Enkephalin-degrading dipeptidyl carboxypeptidase in guinea pig serum: its properties and action on bioactive peptides. 299 Mar 46


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