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 mechanisms involved in 'priming' of the oxidase response of neutrophils are unknown. Two major problems are encountered in using circulating neutrophils; firstly, prior exposure to circulating 'priming' cytokines cannot be controlled and secondly, non-intentional 'priming' during cell separation can occur. In this study, these problems were avoided by differentiating the promyeloid leukaemic cell line, HL60, towards granulocytes using dibutyrl cyclic AMP, to produce a 'virgin cell' model system. We have demonstrated that the ability of substance P to both prime the oxidase response and induce tyrosine phosphorylation increased during differentiation. The major tyrosine-phosphorylated protein, with molecular weight of 74 kDa, was not recognised by anti-c-raf1 antibodies. Furthermore, c-raf1 expression rapidly declined during HL60 cell granulocytic differentiation. This data shows that although there was no simple relationship between c-raf quantity and priming, the data were consistent with tyrosine phosphorylation of a 74 kDa protein being important for oxidase 'priming'.
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PMID:Development of oxidase 'priming' in maturing HL60 cells: correlation with protein expression and tyrosine phosphorylation. 754 45

1. The responses of guinea-pig endocardial endothelial (EE) cells to various vasoactive substances were investigated in either the small tissue preparation or freshly isolated cells using the patch clamp technique. 2. The mean resting potential of the EE cell was -44 mV in the small tissue preparation, and applications of ATP, ADP, AMP, adenosine, histamine and substance P induced transient hyperpolarizations of -22, -21, -9, -10, -23 and -15 mV, respectively. The membrane potential of EE cells failed to respond to acetylcholine, bradykinin, thrombin, atrial natriuretic peptide, vasopressin and serotonin. 3. The whole-cell voltage clamp of dissociated cells revealed a transient increase of K+ conductance underlying the ATP and histamine responses. The agonist-induced current showed no time-dependent change during voltage steps. The response was showed no time-dependent change during voltage steps. The response was prevented by adding 10 mM EGTA to the pipette solution. 4. In the cell-attached single channel recordings, ATP induced transient K+ channel activities having a slope conductance of 34 pS. In inside-out patches, similar K+ channels were activated by applying Ca2+ of more than 0.1 microM. 5. These findings are consistent with the idea that the Ca(2+)-dependent K+ channel is involved in the hyperpolarizing response of EE cells, as described in vascular endothelial cells.
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PMID:Hyperpolarization induced by vasoactive substances in intact guinea-pig endocardial endothelial cells. 754 61

In order to determine whether nitric oxide (NO) acts directly upon nerve terminals to regulate the synaptic transmission at the level of spinal cord, effects of NO-donors on release of substance P (SP) and glutamic acid (Glu) were investigated by superfusion of synaptosomes prepared from the rat spinal cord. Basal levels of endogenous SP and Glu release were 5.99 +/- 2.50 fmol/min/mg of protein and 26.2 +/- 4.8 pmol/min/mg of protein, respectively. Exposure to a depolarizing concentration of KCI evoked 2.7- and 3.8-fold increases in SP and Glu release in a calcium-dependent manner, respectively. Sodium nitroprusside (NP) caused a reduction in the depolarization-evoked overflow of SP in a concentration-dependent manner without affecting its basal release, although it failed to affect either basal or evoked release of Glu. The reduction in SP overflow was also observed by the perfusion with S-nitroso-N-acetyl-penicillamine or membrane-permeable cyclic GMP, but not with cyclic AMP. NP caused the concentration-dependent increases in cyclic GMP levels in synaptosomes. Together with reports that excitatory amino acids stimulate NO synthase and release NO in the spinal cord, these data suggest that there may be an interaction between nerve terminals containing Glu and SP, and that NO may directly participate in the regulation of synaptic transmission in SP-containing nerve terminals, which may be mediated through the activation of guanylate cyclase and the increase in cyclic GMP levels.
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PMID:Nitric oxide regulates substance P release from rat spinal cord synaptosomes. 759 89

The effects of SR142801, a nonpeptide tachykinin neurokinin (NK3) receptor antagonist, were investigated on the functional events linked to NK3 receptor activation by using Chinese hamster ovary (CHO) cells transfected with the human NK3 receptor. Radioligand binding conducted with [125I]iodohistidyl-[MePhe7]-NKB revealed a competitive inhibition by SR142801 and its (-)-antipode SR142806 with Ki values of 0.21 +/- 0.03 and 32.0 +/- 5.0 nM, respectively. NK3 agonists such as [MePhe7]-NKB and senktide stimulated inositol monophosphate formation with EC50 values of 2.0 +/- 1.4 and 2.1 +/- 0.7 nM, respectively. SR142801 antagonized the stimulatory effect of [MePhe7]-NKB (10(-8) M) with an IC50 of 14.3 +/- 2.6 nM and of senktide (10(-8) M) with an IC50 of 4.8 +/- 1.5 nM. The [3H]arachidonic acid release induced by either [MePhe7]-NKB (EC50 of 2.6 +/- 0.2 nM) or senktide (EC50 of 4.2 +/- 2.9 nM) also was inhibited by SR142801 with IC50 values of 16.1 +/- 0.5 and 8.0 +/- 1.7 nM, respectively. The cyclic AMP accumulation induced by 10(-7) M [MePhe7]-NKB (EC50 of 54 +/- 2 nM) also was antagonized by SR142801 with an IC50 value of 4.0 +/- 0.7 nM. These antagonistic effects were stereospecific and NK3 receptor specific because the (-)-antipode, SR142806, was much less effective than SR142801 in NK3 agonist-evoked responses, whereas the nonpeptide NK1 (SR140333) and NK2 (SR48968) receptor antagonists were almost inactive. The activity of SR142801 also was evaluated on the [Ca++]i increase induced by 10(-9) M [MePhe7]-NKB.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Functional characterization of the nonpeptide neurokinin3 (NK3) receptor antagonist, SR142801 on the human NK3 receptor expressed in Chinese hamster ovary cells. 761 92

The effect of human adrenomedullin on cerebral circulation was investigated in dogs in vivo and in vitro. Bolus administration of adrenomedullin or its homologous peptides, calcitonin gene-related peptide (CGRP) and amylin, into the vertebral artery induced a dose-dependent increase in vertebral blood flow. The potencies of adrenomedullin and CGRP were similar and approximately 100 times more than that of amylin. The effects of adrenomedullin and CGRP were inhibited by CGRP8-37, an antagonist of CGRP. In contrast to substance P, adrenomedullin did not induce an increase in blood flow after prior administration of CGRP. Pretreatment with either NG-nitro-L-arginine methyl ester or indomethacin did not affect the adrenomedullin-induced increase in blood flow. Intracisternal administration of adrenomedullin induced dilation of the basilar and other major cerebral arteries in a dose-dependent manner, accompanied by an increase in the concentration of cyclic AMP in the cerebrospinal fluid. Adrenomedullin also induced relaxation of isolated basilar and middle cerebral arterial rings. These data suggest that adrenomedullin induces vasodilation of cerebral arteries and an increase in vertebral blood by acting at CGRP receptors positively coupled to adenylate cyclase, and that these effects are not dependent on nitric oxide or prostaglandin formation.
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PMID:Effects of adrenomedullin, calcitonin gene-related peptide, and amylin on cerebral circulation in dogs. 767 75

The development of newer, more potent, nonsedating H1-receptor antagonists has led to a reappraisal of the potential of this class of drugs in the treatment of asthma. Studies conducted in Japan have examined the pharmacologic profile and clinical efficacy of one of these newer agents, terfenadine. In vitro, terfenadine inhibited the release of histamine from rat peritoneal mast cells and guinea pig lung tissue and conjunctiva in response to such stimuli as compound 48/80, concanavalin A, substance P, A-23187, and the partial peptide of eosinophil major basic protein. Ketotifen had similar, though less potent, antiallergic activity in these models. Mechanisms that appear to be involved in the mediation of this inhibitory effect include the prevention of intracellular calcium ion release and calcium uptake, the inhibition of protein kinase C translocation, and the activation of adenylate cyclase and the resulting accumulation of cyclic AMP (cAMP). A multicenter, double-blind, controlled clinical trial compared the efficacy of ketotifen, 2 mg bid, with that of terfenadine, given at doses of 120 or 240 mg bid (two or four times the US recommended dose, respectively) in the treatment of mild to moderate atopic and mixed-type asthma in adults. Physician assessment of overall improvement and patient evaluation of response were somewhat better with terfenadine, particularly the 120-mg bid dose. As in other comparative studies of these two drugs, terfenadine produced less drowsiness than ketotifen.
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PMID:The Japanese perspective: effects of terfenadine in bronchial asthma: in vitro and in vivo research. 769 May 27

To determine whether neurogenic inflammation can be inhibited by cyclic AMP, which is suggested to have an inhibitory effect on neuropeptide release from airway sensory nerves, we examined plasma extravasation in the airways of anesthetized rats in vivo with Evans blue dye as a marker. Neurogenic inflammation was produced by antidromic electrical stimulation of the right vagus nerve (4 Hz, 1 ms, 4 V for 1 min). Electrical stimulation significantly increased leakage of dye in the trachea and right bronchus. Forskolin (from 0.01 to 100 pM/kg), dibutyryl cyclic AMP (db cyclic AMP; from 10 pM/kg to 100 nM/kg) and fenoterol (from 100 to 1 nM/kg) dose dependently inhibited the leakage of dye induced by electrical stimulation in the trachea and right bronchus. Substance P (1 microgram/kg) increased Evans blue dye extravasation in the same way as the leakage induced by electrical stimulation. Forskolin (from 0.1 to 1 pM/kg), db cyclic AMP (1 nM/kg) and fenoterol (10 nM/kg) failed to inhibit substance P-induced leakage, but showed significant inhibitory effects on the leakage induced by electrical stimulation in the trachea and right bronchus. However, further increases in the concentrations of forskolin, db cyclic AMP and fenoterol significantly inhibited substance P-induced leakage of dye in both tissues. These results suggest that cyclic AMP inhibits neurogenic plasma leakage by presynaptic inhibition of the release of neuropeptides from sensory nerves as well as by postsynaptic effects on the vascular endothelium.
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PMID:Inhibitory actions of cyclic AMP on neurogenic plasma extravasation in rat airways. 769 94

The possibility that pituitary adenylyl cyclase-activating peptide (PACAP) is an inhibitory neurotransmitter has been investigated in the taenia of the guinea-pig caecum. The action of PACAP on muscle contractility and its ability to alter levels of adenosine-3':5'-cyclic monophosphate (cyclic AMP) and guanosine-3':5'-cyclic monophosphate (cyclic GMP) were investigated. PACAP-1-27 was an effective agonist, giving relaxations comparable in magnitude to isoproterenol; its EC50 was 3.4 x 10(-7) M. PACAP (10(-6) M) caused an almost two-fold increase in cyclic AMP levels; but the level of cyclic GMP was not affected. The relaxation caused by PACAP was slow in onset, with a latency of 5.8 +/- 0.8 s and reached a maximum at 9.1 +/- 1.1 s after onset. The relaxation was significantly reduced by apamin (10(-6) M) and suramin (10(-4) M) but was not reduced by tetrodotoxin (10(-7) M). Relaxation of the taenia coli caused by electrical stimulation of the inhibitory nerves was greatly reduced by apamin but only slightly reduced by suramin. PACAP-like immunoreactivity (-IR) was localised immunohistochemically in varicose nerve fibres within the taenia coli and in the underlying myenteric plexus and circular muscle. Approx. 50% of vasoactive intestinal peptide (VIP)-IR nerve fibres in the taenia also had immunoreactivity for PACAP; conversely, almost all PACAP-IR fibres were immunoreactive for VIP. PACAP-IR and substance P (SP)-IR were generally in separate fibres; only about 5% of SP-IR fibres were PACAP-IR. Radioimmunoassay revealed tissue concentrations of PACAP-1-27 and PACAP-1-38 of 1.0 +/- 0.1 and 2.1 +/- 0.3 (SEM) pmol/g wet weight of tissue, respectively. Material with PACAP-1-27 immunoreactivity co-eluted with authentic PACAP-1-27 on gel filtration chromatography, and PACAP-1-38 immunoreactivity also co-eluted with the authentic peptide. This study provides structural, chemical and pharmacological evidence that PACAP could be involved in inhibitory neurotransmission to the taenia coli of the guinea-pig caecum.
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PMID:Histochemical, pharmacological, biochemical and chromatographic evidence that pituitary adenylyl cyclase activating peptide is involved in inhibitory neurotransmission in the taenia of the guinea-pig caecum. 771 25

1. The pharmacological activities of liriodenine, isolated from Fissistigma glaucescens, were determined in isolated trachea, ileum and cardiac tissues of guinea-pigs. 2. Liriodenine was found to be a muscarinic receptor antagonist in guinea-pig trachea as revealed by its competitive antagonism of carbachol (pA2 = 6.22 +/- 0.08)-induced smooth muscle contraction. It was slightly more potent than methoctramine (pA2 = 5.92 +/- 0.05), but was less potent than atropine (pA2 = 8.93 +/- 0.07), pirenzepine (pA2 = 7.02 +/- 0.09) and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP, pA2 = 8.72 +/- 0.07). 3. Liriodenine was also a muscarinic antagonist in guinea-pig ileum (pA2 = 6.36 +/- 0.10) with a pA2 value that closely resembled that obtained in the trachea. 4. Liriodenine was 10 fold less potent in atrial preparations (left atria, pA2 = 5.24 +/- 0.04; right atria, pA2 = 5.35 +/- 0.09 and 5.28 +/- 0.07 for inotropic and chronotropic effects, respectively) than in smooth muscle preparations. 5. High concentration of liriodenine (300 microM) partially depressed the contractions induced by U-46619, histamine, prostaglandin F2 alpha, neurokinin A, leukotriene C4 and high K+ in the guinea-pig trachea. The inhibitions were characterized by a rightward shift in the concentration-response curves with suppression of their maximal contraction. 6. High concentration of liriodenine (300 microM) did not affect U-46619- or neurokinin A-induced tracheal contraction in the presence of nifedipine (1 microM) or in Ca(2+)-free (containing 0.2 mM EGTA) medium. 7. Neither cyclic AMP nor cyclic GMP content of guinea-pig trachealis was changed by liriodenine (30-300 microM). 8. It is concluded that liriodenine is a selective muscarinic receptor antagonist in isolated trachea, ileum and cardiac tissues of guinea-pigs. It is more potent in smooth muscle than in cardiac preparations. It also acts as a blocker of voltage-dependent Ca2+ channels at a high concentration (300 microM).
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PMID:Pharmacological characteristics of liriodenine, isolated from Fissistigma glaucescens, a novel muscarinic receptor antagonist in guinea-pigs. 781 21

Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide with a wide range of biological activities. Recent data suggest that functional VIP receptors are expressed on various tumor cells. Somatostatin (SST) and its long-acting analogue octreotide (OCT) are potent inhibitors of tumor cell growth and secretion. In the present study, the interactions between VIP and SST/OCT on primary tumors (insulinomas, n = 3; VIPomas, n = 2; intestinal adenocarcinomas, n = 5; neuroblastomas, n = 5; papillary thyroid cancers, n = 7; carcinoids, n = 5; ductal breast cancers, n = 8; small cell lung cancers, n = 3; ACTH-producing hypophyseal adenomas, n = 5; pheochromocytomas, n = 5) as well as on tumor cell lines (A431, HT29, PANC1, COLO320, HMC1, and KU812 cells) were analyzed by use of 123I-labeled VIP and 123I-labeled Tyr-3-OCT. Cross-competition between VIP and SST/OCT for binding to tumor cells was observed. The rank-order of potency for displacement of 123I-labeled VIP binding to intact A431 cells was VIP [concentration causing half-maximal inhibition (IC50) = 2.9 +/- 1.9 (SD) nM] > OCT (IC50 = 9.3 +/- 1.7 nM) = SST > substance P = secretin (IC50 = 1 microM). Binding of 123I-labeled Tyr-3-OCT to A431 cells, in turn, was inhibited by OCT = Tyr-3-OCT (IC50 = 1.5 +/- 0.3 nM) = SST > VIP (IC50 = 4.9 +/- 1.1 nM). This rank-order of potency was also obtained for primary tumors and tumor cell lines. Furthermore, SST and OCT inhibited VIP-induced [3H]thymidine incorporation, cyclic AMP formation, and tyrosine kinase activity with IC50 values < 10 nM. Together, these data provide evidence for functional interactions between SST and VIP on various tumor cells. These interactions may involve peptide cross-competition at cellular binding sites and may have implications for the biology and pathophysiology of respective cells and disease states.
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PMID:Cross-competition between vasoactive intestinal peptide and somatostatin for binding to tumor cell membrane receptors. 790 85


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