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. We investigated the effect of the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and the peptidase alpha-chymotrypsin on non-adrenergic, non-cholinergic (NANC neural) bronchoconstriction induced by electrical stimulation of the vagus nerves and by capsaicin in anaesthetized guinea-pigs in vivo using pulmonary insufflation pressure (PIP) as an index of bronchial tone. We also investigated the contribution of soluble guanylyl cyclase (SGC) to NANC neural relaxant mechanisms. 2. In the presence of atropine and propranolol, electrical stimulation of the vagus nerves induced a frequency-dependent increase in PIP above baseline of 67% at 2.5 Hz, of 128% at 5 Hz and of 230% at 10 Hz. L-NAME (1-50 mg kg-1, i.v.), at doses inducing increases in systemic blood pressure, dose-relatedly potentiated NANC bronchoconstriction. At 10 mg kg-1 i.v., L-NAME significantly (P < 0.05) potentiated NANC bronchoconstriction by a further 106% at 2.5 Hz and a further 147% at 5 Hz but did not potentiate the increase in PIP at 10 Hz. L-NAME did not induce bronchoconstriction in sham-stimulated control animals. D-NAME did not potentiate NANC bronchoconstriction. Raising systemic blood pressure with phenylephrine did not potentiate vagally-induced bronchoconstriction (2.5 Hz). 3. The NO precursor L-arginine, but not D-arginine, (100 mg kg-1, i.v.) significantly reversed the potentiation by L-NAME of NANC bronchoconstriction. L-Arginine alone significantly inhibited neurogenic bronchoconstriction at 10 Hz (by 74%); the inhibition of 25% at 2.5 Hz was not significant. 4. L-NAME did not significantly affect the increases in PIP induced by intravenous substance P. neurokinin A (NKA) or capsaicin. 5. The inhibitor of SGC, methylene blue (10 mg kg', i.v.) potentiated (by 110-140%) NANC neural bronchoconstriction induced by lower frequencies of nerve stimulation and reversed the reduction in PIP induced by the SGC activator, sodium nitroprusside (SNP, 1.05 mg kg- 1, i.v.). SNP significantly (P <0.05) reduced by 65% the bronchoconstriction induced by nerve stimulation at 10 Hz. Methylene blue did not effect baseline PIP in sham-stimulated controls. The airway effects of methylene blue and SNP were not associated with their cardiovascular effects. 6. a-Chymotrypsin (2 units kg-', i.v.) significantly potentiated vagally-induced bronchoconstriction by a further 63% at 2.5 Hz, by a further 95.6% at 5 Hz but did not potentiate the increase in PIP at 10 Hz. alpha-Chymotrypsin also potentiated (by 116%) capsaicin-induced bronchoconstriction. Vasoactive intestinal peptide (VIP, 10 ig kg-' i.v. infused over min) significantly reduced by 70% the increase in PIP induced by NKA (0.1 .Lmol kg-' i.v., infused over 30 s). 7. The combination of a-chymotrypsin (2 units kg-', i.v.) and L-NAME (5 mg kg-', i.v.) significantly potentiated NANC bronchoconstriction by a further 304% at 2.5 Hz, an increase in PIP which was greater than that induced by either a-chymotrypsin or L-NAME alone (P <0.05). 8. We conclude that endogenous NO and a bronchodilator peptide, possibly VIP, released in association with nerve stimulation, as well as activation of soluble guanylyl cyclase, regulate the magnitude of NANC neurogenic bronchoconstriction in guinea-pigs in vivo.
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PMID:Regulation of NANC neural bronchoconstriction in vivo in the guinea-pig: involvement of nitric oxide, vasoactive intestinal peptide and soluble guanylyl cyclase. 767 32

1. The mediators of non-adrenergic non-cholinergic (NANC) relaxation of the longitudinal muscle of rat proximal, middle and distal colon were examined in vitro. 2. Electrical transmural stimulation (TMS) of proximal, middle and distal segments of rat colon induced NANC relaxations which were inhibited by tetrodotoxin (1 microM), but not by atropine (1 microM) or guanethidine (4 microM). 3. In the proximal colon, L-nitro-arginine (N5-nitroamidino-L-2,5-diaminopentanoic acid) inhibited the TMS-induced NANC relaxation and L-arginine (1 mM) reversed this inhibition. Nitric oxide (0.3-10 microM) induced relaxation of the proximal segment. 4. NANC relaxation of the proximal segments was still evident after desensitization to vasoactive intestinal peptide (VIP). A VIP antagonist (VIP 10-28, 10 microM) had no effect on the TMS-induced NANC relaxation, which was also resistant to alpha-chymotrypsin (2 units ml-1) and a substance P antagonist ([D-Pro2, D-Trp7,9]substance P, 1 microM). 5. In the middle colon, L-nitro-arginine did not inhibit the TMS-induced NANC relaxation in 6 of 9 preparations tested and partially inhibited the relaxation in the other 3 preparations. L-Arginine did not reverse the partial inhibition. 6. Complete desensitization to VIP was not achieved in the middle colon. The VIP antagonist had no effect on the TMS-induced NANC relaxation. After alpha-chymotrypsin treatment of the segment, desensitization of the segments to substance P, or in the presence of the substance P antagonist, the TMS-induced NANC relaxation was augmented. 7. In the distal colon, L-nitro-arginine did not have any significant effect on the TMS-induced relaxation and nitric oxide did not induce relaxation. The VIP antagonist significantly inhibited TMS-induced NANC relaxation. Alpa-Chymotrypsin-treatment of the distal segments resulted in significant inhibition of NANC relaxation. No desensitization to substance P was achieved. Treatment with the substance P antagonist had no effect. 8. These results suggest that nitric oxide is the mediator of the NANC inhibitory response in the proximal region of rat colon; in the middle colon, substance P acts as an excitatory neurotransmitter, antagonizing the NANC relaxation caused by the mediator of the response, which is still uncertain. Our results suggest that that VIP is the most likely candidate as a NANC transmitter in the distal colon.
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PMID:Mediators of nonadrenergic, noncholinergic inhibition in the proximal, middle and distal regions of rat colon. 768 May 92

We describe a new approach for the production of peptides using a combination of recombinant DNA technology, chemical synthesis, and proteinase-catalyzed processing. An artificial substance P-precursor is produced as a beta-galactosidase (1-459) fusion protein containing nine copies of the decapeptide sequence Arg-Leu-Arg-Arg-Pro-Lys-Pro-Gln-Gln-Phe. The fusion protein accumulates in E. coli as insoluble inclusion bodies which are easily isolated and purified. The decapeptide blocks are selectively cleaved from the insoluble fusion protein by alpha-chymotrypsin. Alternatively, a dodecapeptide ester is produced when a dipeptide ester is included in the chymotrypsin reaction mixture. This peptide ester is converted converted to substance P by papain-catalyzed acyl transfer and subsequent tryptic cleavage. These results demonstrate that peptides can be readily produced by a combination of recombinant DNA technology and proteinase-catalyzed conversion. The approach allows incorporation of groups other than natural amino acids into oligo- and polypeptides.
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PMID:Peptide production by a combination of gene expression, chemical synthesis, and protease-catalyzed conversion. 768 60

Non-adrenergic, non-cholinergic (NANC) nerve stimulation results in excitation (e.j.p., rebound depolarization, contractions) or inhibition (i.j.p., afterhyperpolarization, relaxations) of the gut. NANC neuronal mechanisms participate in the maintenance of the basal tone and spontaneous activity of the gut. There are however species differences, i.e. both NANC excitation and inhibition are present in the guinea pig and only NANC inhibition in the rat intestine. Substance P-like neuropeptide/s are suggested to be mediators released from excitatory NANC and sensory nerves. The latter are activated by histamine and degenerated by capsaicin. There is evidence in favor of a nitric oxide-like substance rather than ATP, dopamine, GABA and neuropeptides (e.g. VIP, PHI/PHM) as the inhibitory NANC mediator in the gut. TTX, high Mg(2+)-low Ca2+ media, 3,4-diaminopyridine, dipyridamol and adenosine deaminase modulate NANC excitation and inhibition. The NANC excitation is more sensitive than the NANC inhibition to the action of catecholamines, reserpine, 6-hydroxydopamine, chymotrypsin, prednisolon, bacitracin, opioids, free oxygen species and low concentration of local anesthetics.
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PMID:NANC transmission in intestines and its pharmacological modulation. 839 Nov 98

Smooth muscle cells distributed in the visceral organs are under the control of the autonomic nervous system, and contraction or relaxation of the muscle cells plays an important physiological role in the control of blood pressure, motility of the digestive, respiratory and urinary tracts and secretion. Recent physiological, pharmacological and histochemical investigations indicate that neurotransmitters other than acetylcholine or noradrenaline are involved in peripheral autonomic neuro-effector transmission, and these neurotransmitters are generally termed non-adrenergic, non-cholinergic (NANC) neurotransmitters. The neurotransmitters responsible for excitatory and inhibitory NANC neurotransmission (e-NANC and i-NANC respectively) have not been conclusively identified, but ATP, nitric oxide (NO) and peptides such as VIP and substance P are candidates for these roles. In this review, we discuss the possible role of ATP and NO as e- or i-NANC neurotransmitter in the digestive, respiratory and urinary tracts. Much of the work on NANC innervation in the digestive tract has been carried out on the circular muscle layers of the ileum. This receives inhibitory NANC innervation with ATP responsible for fast relaxation and VIP, and possibly NO, for the slow response. Early and late excitatory junction potentials can be recorded in the presence of atropine. The second is due to substance P since it is blocked in the presence of spantide and by desensitization of the tissue with high doses of substance P. The transmitter responsible for the early NANC contraction has not been identified. Electrical field stimulation (EFS) applied to the tracheal smooth muscle during contraction induced by 5-HT in the presence of atropine and guanethidine elicited monophasic NANC relaxation. By contrast, NANC relaxation elicited in the smaller airways was biphasic, comprising an initial fast component followed by a second slow one. L-NAME selectively abolished the first component without affecting the second. VIP-antagonists or alpha-chymotrypsin considerably attenuated the amplitude of the L-NAME insensitive relaxation. These results indicate that at least two neurotransmitters, possibly NO or NO-containing compounds and VIP, are involved in i-NANC neurotransmission in the airway. In the urinary bladder a large, transient atropine resistant contraction occurs in response to pelvic nerve stimulation. This is blocked by alpha, beta methylene ATP suggesting that it is due to ATP. There is no evidence of inhibitory innervation. In the urethra contraction is completely blocked by atropine and guanethidine; a rapid NANC relaxation is abolished by drugs that block NO synthesis. Nerves containing peptides supply both urethra and bladder and may also be involved. These results suggest that all visceral smooth muscles may receive inhibitory NANC innervation involving NO. ATP produces contraction of the urinary bladder but relaxation of the digestive tract. The role of peptides is not yet clear but there is evidence that substance P may be an excitatory transmitter and VIP an inhibitory transmitter in many organs.
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PMID:[The control of smooth muscle tissues by nonadrenergic noncholinergic (NANC) nerve fibres in the autonomic nervous system]. 856 58

The effects of capsaicin and neuropeptides were examined in equine tracheal smooth muscle (TSM). Neither capsaicin nor substance P (SP) contracted TSM. Capsaicin (100 microM) elicited relaxation in TSM contracted with methacholine. This relaxation was not mimicked by SP or calcitonin gene-related peptide (CGRP). Relaxation was not attenuated by removal of the epithelium or by pretreatment of tissue with meclofenamate or the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine. Previous exposure of TSM to capsaicin did not eliminate the relaxation responses to subsequent capsaicin. Although vasoactive intestinal peptide (VIP) elicited marked relaxation that was attenuated by alpha-chymotrypsin, alpha-chymotrypsin did not affect the capsaicin-induced relaxation. Capsaicin-induced relaxation was abolished by charybdotoxin, a blocker of large-conductance Ca(2+)-activated K+ channels. These results indicate that capsaicin-induced equine TSM relaxation is not mediated either by neuropeptides such as SP or CGRP released from capsaicin-sensitive sensory nerves or by prostanoids, NO, or VIP. Relaxation is due to the effect of capsaicin on large-conductance Ca(2+)-activated K+ channels. The peptidergic nerves play no important role in the regulation of TSM tone in horse airways.
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PMID:Mechanism of capsaicin-induced relaxation in equine tracheal smooth muscle. 937 26

An enzyme activity capable of hydrolysing the neuroactive undecapeptide substance P (SP) between its Phe7-Phe8 residues was purified from the membrane-bound fraction of human spinal cords. The enzyme preparation yielded was compared with a previously described SP-hydrolysing enzyme from human cerebrospinal fluid (CSF) with regard to inhibition profile, protein chemical properties and kinetics. In addition, the results were compared with those of bovine pancreatic chymotrypsin (a serine protease that cleaves the carboxy-terminal side preferentially at hydrophobic amino acids). The SP peptidase activity was extracted from human spinal cords with 1% Triton X-100 in 20 mM Tris-HCI pH 7.8. After ion exchange chromatography (DEAE-Sepharose) where the enzyme activity was separated from other proteins by gradient elution, the pooled enzyme fraction was further purified by molecular sieving (Sephadex G-50). The enzyme activity was finally recovered by HPLC molecular sieving (Superdex 75 HR 10/30) using a new preparative system, AKTA-purifier, controlled by UNICORN software version 2.20.
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PMID:Purification of substance P endopeptidase (SPE) activity in human spinal cord and subsequent comparative studies with SPE in cerebrospinal fluid and with chymotrypsin. 1007 55

Electrical field stimulation (EFS)-induced non-adrenergic non-cholinergic (NANC) relaxation responses in the rabbit vaginal wall were investigated. These NANC responses were partially inhibited with the nitric oxide synthase (NOS) inhibitors N(G)-nitro-L-arginine methyl ester (L-NAME; 500 microM), N(G)-nitro-L-arginine (300 microM) or N-iminoethyl-L-ornithine (500 microM) or the selective soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, 10 microM). Application of L-NAME and ODQ concomitantly did not increase the degree of inhibition. L-NAME or ODQ were observed to be more effective at low frequencies. The resistant part of the responses was more pronounced at higher frequencies and was completely inhibited by tetrodotoxin (1 microM). Exogenous application of the peptides vasoactive intestinal peptide (VIP), pituitary adenylate cyclase activating peptide (PACAP-27 and PACAP-38), peptide histidine methionine (PHM), peptide histidine valine (PHV), helospectin-I or -II induced a relaxation response. Calcitonin gene-related peptide or substance P did not cause any relaxation. The peptidase alpha-chymotrypsin (type II; 2 units ml(-1)) did not affect non-nitrergic NANC responses, although it did inhibit relaxation responses elicited by exogenous VIP, PACAP-27, PACAP-38, PHM, PHV, helospectin-I or -II. K(+) channel inhibitors apamin (1 microM) or charybdotoxin (100 nM) when used alone or in conjunction did not affect non-nitrergic NANC responses. The non-nitrergic NANC responses were not associated with any increase in intracellular cyclic adenosine-3', 5'-monophosphate (cyclic AMP) or cyclic guanosine-3', 5'-monophosphate (cyclic GMP) concentrations. The peptide-induced relaxations were all associated with increases in cyclic AMP concentrations. These results suggest that a neuronal factor elicits non-nitrergic NANC responses in the rabbit vaginal wall. The identity of this factor remains to be established.
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PMID:Characterization of the non-nitrergic NANC relaxation responses in the rabbit vaginal wall. 1181 90

Lysergic acid diethylamide (LSD) potentiated the response of guinea-pig ileum to substance P but not to histamine. It also inhibited the disappearance of substance P when incubated with guinea-pig brain extract but not when incubated with chymotrypsin. Eserine, morphine, mescaline, chlorpromazine, ergometrine, strychnine and 2 bromo-LSD did not have this effect. Oxytocin was not destroyed by brain extract. The inhibition of the destruction of substance P by LSD could be antagonized by 2 bromo-LSD. This effect of LSD may have some relation to its pharmacological actions.
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PMID:The preservation of substance P by lysergic acid diethylamide. 1346 Feb 45

The catalytic activity of alpha-chymotrypsin on a model and a peptide substrate, in the supramolecular system "enzyme-surfactant" in water solution, has been studied by electrospray ionization mass spectrometry. Hydrolysis of N-succinyl-L-phenylalanine p-nitroanilide as the model compound, catalysed by alpha-chymotrypsin in the presence of monomeric cetyltributylammonium bromide, has been followed by UV and ESI-MS detection. Kinetic data, which are essentially identical independent of their determination techniques, show a twelve fold improvement of the enzyme catalytic efficiency when compared with the reaction carried out in the absence of the additive. Once validated, the ESI-MS technique was used to study the hydrolytic activity of the enzyme on a peptide substrate like substance P: it is worth emphasising that the spectrophotometric detection cannot be employed on peptides, where the chromophores are untouched by the hydrolytic process. Substance P hydrolyses in aqueous surfactant following dichotomic kinetics, which are initially rapid but then slow down as the reaction progress. The results presented in this paper are expected to extend studies on biocatalysis in aqueous surfactant media to a wide range of substrates, independent of their spectroscopic properties.
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PMID:ESI-MS in the study of the activity of alpha-chymotrypsin in aqueous surfactant media. 1451 37


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