Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of the human interleukin-1 receptor antagonist, IL-1ra, to inhibit aerosolized antigen-induced airway hyperreactivity to i.v. substance P and bronchoalveolar lavage inflammatory cell accumulation, under in vivo conditions, was assessed in guinea pigs. Pretreatment with IL-1ra (30 mg/kg i.p., administered 30 min prior to antigen challenge) inhibited increases in bronchoalveolar lavage fluid neutrophil accumulation at 1 h following aerosolized antigen (0.1% ovalbumin for 30 min) exposure. IL-1ra (30 mg/kg i.p., administered 30 min pre-antigen and 3 h post-antigen) also significantly attenuated antigen-induced increases in bronchoalveolar lavage fluid leukocytes at 6 h following antigen. However, IL-1ra (30 mg/kg i.p., administered 30 min pre-antigen as well as 6 and 12 h post-antigen) did not affect antigen-induced bronchoalveolar lavage fluid leukocyte accumulation at 24 h following antigen. A limited, but significant (P less than 0.05), reduction in antigen-induced airway hyperreactivity to 10 micrograms/kg, but not lower doses, of i.v. substance P (measured as peak increases in lung resistance in cm H2O/ml per s) at 6 h following antigen was noted in the presence of IL-1ra (30 mg/kg i.p.). In conclusion, IL-1ra inhibited antigen-induced airway hyperreactivity to i.v. substance P and bronchoalveolar lavage fluid inflammatory leukocyte influx in the guinea pig, in a time-dependent manner, suggesting that cytokines, such as IL-1, may contribute to the pathophysiology surrounding this pulmonary anaphylaxis model.
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PMID:Effect of interleukin-1 receptor antagonist on antigen-induced pulmonary responses in guinea pigs. 137 30

Eosinophils immunopositive for bombesin tetradecapeptide were detected by means of light and electron microscopy in human and rat gastrointestinal tract and pulmonary tissue. This immunoreaction was only evidenced after the use of acetic acid-containing fixative such as Bouin's fluid. The dependence of this immunostaining on fixatives and time course were extensively studied. This immunoreaction promotes mainly one epitope probably associated with the C-terminal sequence. This epitope seems also to be present in other neuropeptides such as substance P (SP) and, to a lesser extent in chemotactic factors like formyl peptide (fMLP) or eosinophil chemotactic factor of anaphylaxis (ECF-A). At the electron microscopic level, the immunopositivity was associated with eosinophil membranes.
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PMID:Bombesin-like immunoreactivity in eosinophils. A light and electron microscopic study: effect of fixatives and cross-reactivity with various compounds. 138 Dec 56

During anaphylaxis the sensitized liver can have substantial capacity for leukotriene production. However, the intrahepatic cellular source for these potent eicosanoid mediators has been unclear so far. We therefore analyzed the appropriate role of resident liver cells in organ-specific generation of leukotrienes by immunohistochemical localization of 5-lipoxygenase, by measurement of cysteinyl leukotriene production in animals or isolated livers and by histochemical monitoring of mast cells in rat, guinea pig and mouse livers, respectively. During anaphylaxis in vivo, these species all generated large amounts of leukotrienes. Immunohistochemistry with rat liver demonstrated resident mast cells as the predominant cell type in liver containing 5-lipoxygenase. Rat and guinea pig livers contained numerous mast cells and produced substantial amounts of leukotrienes on antigen challenge; in contrast, mouse livers neither showed detectable mast cells nor generated leukotrienes when stimulated analogously. Infusion of histamine or serotonin (1 mmol/L each) or of the degranulating substance P (8 mumol/L) did not elicit leukotriene generation in rat livers. Furthermore, substantial degranulation of liver mast cells by compound 48/80 (0.5 mg/kg body mass) was paralleled by only modest leukotriene formation (63 +/- 10 pmol in bile/kg body mass/30 min). These results indicate that during anaphylaxis mast cells are the main intrahepatic cells initiating leukotriene production and that such leukotriene generation is likely to be independent of mast cell degranulation or the release of histamine or serotonin.
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PMID:Resident mast cells are the main initiators of anaphylactic leukotriene production in the liver. 144

In light of current interest in substance P as a bronchoconstrictor, several pharmacologic antagonists of known mediators of anaphylaxis were tested for possible activity against this neuropeptide. Concentration-dependent contractions of the isolated guinea-pig tracheal strips to substance P (10(-8) to 10(-5) M) were elicited. These contractions were inhibited by substance P receptor antagonists, D-Arg1-D-Trp7,9-Leu11 and D-Pro2-D-Trp7,9-substance P (10(-6) to 10(-4) M). Substance P-induced contractions were not inhibited by histamine, alpha and beta adrenergic receptor antagonists or by cyclooxygenase inhibition. However, atropine enhanced contractions to substance P. Both vasoactive intestinal polypeptide (10(-7), 10(-6) and 10(-4) M) and isoproterenol (10(-7) M) were able to reverse an ongoing substance P (10(-5) M)-induced contraction. Also, at a concentration of 10(-5) M, substance P increased cyclic GMP accumulation, but had no effect on the concentration of cyclic AMP. A 15-min pretreatment with either verapamil or nifedipine (10(-8) M) had no effect on substance P-induced contractions, whereas the purported intracellular Ca++ antagonist, 8-[N,N-diethylamino]-octyl 3,4,5-trimethoxybenzoate hydrochloride (10(-4) M) produced a rightward shift of a substance P concentration-response curve. A selective calmodulin inhibitor, N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (10(-4) M) failed to affect the contraction produced by 10(-5) M substance P. When guinea-pig tracheal strips were washed and allowed to re-equilibrate in 0 Ca++ buffer, the initial maximum contractions to substance P (10(-5) M) were equal for both regular (1.8 mM) Ca++ and 0 Ca++ buffer.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of substance P-induced contractions of guinea-pig trachea. 242 83

Mice have been used in studies of the immunology or pathology of several different disorders affecting the lung. However, the value of the mouse for the analysis of pulmonary pathophysiology has been limited by the lack of methods for measuring lung function in the living animal. We report here the first method for measuring pulmonary conductance (GL) and compliance (Cdyn) in tracheostomized mechanically ventilated mice. We used this method to characterize the mouse's pulmonary responses to several putative bronchoconstrictor agonists. GL and Cdyn were decreased by intravenous infusions of methacholine, norepinephrine, or serotonin. Reproducible responses were not detected after infusions of histamine, prostaglandins D2 or F2 alpha, leukotrienes C4 or D4, substance P, or platelet-activating factor. The pattern of airway responsiveness to these agonists in the mouse is similar to that reported for the rat; in contrast to the rat, the mouse has many well-characterized strains or mutants with deficiencies of immunologic or inflammatory cells or mediators. As a result, this model offers unique advantages for identifying the roles of individual inflammatory cell types or mediators in pulmonary processes, including pulmonary anaphylaxis.
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PMID:Pulmonary responses to bronchoconstrictor agonists in the mouse. 245 8

Permeability changes in the guinea-pig skin following intradermal (i.d.) injection of tachykinin agonists or antigen were monitored through the extravasation of 99mTc-labelled human serum albumin and blood flow changes through the accumulation of 51Cr-labelled microspheres. A variety of synthetic and natural tachykinins, including substance P and neurokinins A and B, were shown to be potent inducers of permeability changes. Neurokinins A and B, but not substance P, were also shown to be apparent vasoconstrictor agents. Permeability responses in sensitized guinea pigs to i.d. injection of antigen and substance P, but not histamine, were abolished by pretreatment with the tachykinin antagonists [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-substance P and [D-Pro2, D-Trp7,9]-substance P. Interpretation of such results was complicated by the fact that such antagonists may in themselves induce mast cell activation. Depletion of substance P containing neurons by pretreatment of guinea pigs with capsaicin also produced significant inhibition of antigen-induced permeability changes. These results indicate a possible role for tachykinins, such as substance P, in cutaneous anaphylaxis in the guinea pig.
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PMID:Tachykinin involvement in cutaneous anaphylaxis in the guinea pig. 246 7

Three major lines of evidence support a role of eicosanoids and PAF in shock. Formation of each of the cyclooxygenase metabolites of arachidonate is enhanced at some point during the shock; these metabolites include PGE2, PGF2 alpha, PGI2, and TXA2. Enhanced formation of 5-HETE and the cysteinyl-LTs provides evidence for activation of the 5-lipoxygenase pathway of arachidonate metabolism, and preliminary biochemical evidence suggests that formation of PAF in anaphylactic and endotoxic shock is also enhanced. Second, TXA2, cysteinyl-leukotrienes, and, to an even greater extent, PAF are able to produce shock and death in intact animals. Third, pharmacological studies show that selective antagonists or synthesis inhibitors modify the course of the shock. While any of these lines of evidence may not by itself provide proof for a cause-effect relationship, the data taken together strongly suggest that vasoactive lipids might be involved in fundamental processes in the pathophysiology of shock. However, the role of vasoactive lipids might vary in different shock paradigms, change at various time points during the evolution of the shock, and depend on the species studied. Moreover, while the majority of the reports tend to focus on a specific substance, the metabolism of all of the eicosanoids mentioned, as well as PAF and probably other arachidonate metabolites (e.g. 15-lipoxygenase products such as lipoxins), changes during shock states. This fact probably causes most of the discrepancies in studies using specific antagonists or synthesis inhibitors to modify the state of shock. Thus, while blockade of one mediator might provide some protection, it might not be sufficient to halt or reverse the main course of the pathophysiological process. For example, the increase in vascular permeability, a fundamental phenomenon in trauma, anaphylaxis, or endotoxemia, might be mediated by PAF, LTs, PGs, peptides (e.g. kinins, substance P, CGRP) and amines (e.g. histamine in some species). Attempting to reverse such a complex phenomenon by blocking one specific factor might not be productive unless the specific substance played a key role in generation of the other factors. It seems, however, that while interactions between PGs, LTs, and PAF do occur (31, 32, 70), none of the shock states are crucially dependent on one class of the vasoactive lipids. Therefore, the therapeutic strategy should be based on multiple sites of action, either by drug combinations or multiple actions of a specific drug.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Prostaglandins, leukotrienes, and platelet-activating factor in shock. 303 39

The effect of antigen (ovalbumin) challenge on pulmonary hemodynamics, bronchoconstriction, and fluid filtration was investigated in Ringer's-perfused (non-recirculating) lungs that had been passively sensitized in vitro. Bolus ovalbumin injection (30 micrograms) produced immediate increases in pulmonary arterial pressure, peak intratracheal pressure, and lung weight within 1 min and secondary marked increases in intratracheal pressure and lung weight from 120 to 200 min. Electron microscopy of antigen-challenged isolated lungs showed evidence of both septal and intraalveolar edema. Ionophore A23187 (100 micrograms) challenge of nonsensitized lungs produced immediate pulmonary responses similar to antigen, whereas secondary increases in lung weight were smaller. Arachidonic acid pretreatment (1 microM) potentiated immediate antigen-induced increases in intratracheal pressure but did not affect pulmonary responses to ionophore challenge. Putative mediators of anaphylaxis including histamine, leukotrienes B4, C4, D4, and E4, platelet-activating factor, and substance P produced immediate changes in pulmonary arterial and/or intratracheal pressure similar to antigen challenge. Only platelet-activating factor and substance P partially mimicked the secondary edema formation noted following antigen challenge. Thus, antigen challenge in in vitro sensitized guinea pig lungs produced both immediate and secondary responses characterized by increases in vascular pressure, airway pressure, and edema formation. This occurred in the absence of circulating blood-formed elements and without a massive influx of cells. Synergism between mediators such as histamine, the leukotrienes, platelet-activating factor, and substance P released following antigen challenge may be necessary to produce the complete pathophysiological sequelae associated with antigen challenge in the perfused guinea pig lung.
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PMID:Antigen-induced edema formation, bronchoconstriction, and pulmonary vasospasm in the isolated perfused guinea pig lung. Evidence for a secondary edemagenic response. 314 5

The actions of histamine on myenteric neurones were investigated with intracellular recording methods in guinea-pig small intestine. The actions of histamine at the ganglion cell soma were: membrane depolarization, increased input resistance, suppression of post-spike hyperpolarizing potentials, augmented excitability and repetitive spike discharge. Excitability was enhanced also at spike initiation sites remote from the cell body. Both H1, and H2, receptors were involved in the response to histamine. Dimaprit mimicked the responses to histamine in 80% and 2-methylhistamine in 50% of the trials. Cimetidine was an antagonist for histamine in 82% and for dimaprit in all of the trials. Pyrilamine blocked the actions of histamine in 59% of the cells and always blocked the action of 2-methylhistamine. Histamine mimicked slow synaptic excitation in the neurones, but was ruled out as a neurotransmitter for the slow excitatory post-synaptic potential (e.p.s.p.). Histamine either did not affect the responses to 5-hydroxytryptamine, substance P and acetylcholine or it potentiated the responses to these putative neurotransmitters for slow synaptic excitation. The results support the possibility that histamine released from mast cells by circulating peptidergic messengers, by neurotransmitters or during anaphylaxis could influence enteric nervous function.
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PMID:Intracellular study of effects of histamine on electrical behaviour of myenteric neurones in guinea-pig small intestine. 614 13

Plasma extravasation was induced in rats or guinea-pigs by intravenous injections of (1) substance P (SP), (2) the C-terminal SP-hexapeptide SP(6--11), (3) serotonin (5-HT), (4) histamine, (5) bradykinin, (6) capsaicin and (7) by antigen challenge. Plasma extravasation induced by SP, SP(6--11), by 5-HT and by capsaicin was, with few exceptions, observed in the same tissues. The effect of SP was not blocked by H1 and H2 histamine receptor antagonists. The effect of i.v. capsaicin was absent in capsaicin desensitized animals. Plasma extravasation upon i.v. SP, SP(6--11), 5-HT and capsaicin was seen in the skin and in all organs containing mucous membranes except the intestinal mucosa. Plasma extravasation by histamine, bradykinin, and antigen challenge of sensitized guinea-pig was, in addition, also observed in the stomach and intestine. Plasma extravasation and bronchoconstriction by antigen challenge with 20 micrograms/kg ovalbumin was completely blocked by combined H1 and H2 histamine receptor blockade. Both responses were reduced to about the half capsaicin desensitized guinea-pigs, although the reduction of the permeability response was statistically not significant in all organs. In conclusion, several substances including anaphylaxis induce protein leakage in many tissues with differing selective distribution patterns. Anaphylactic histamine release leads to protein leakage partly via activation of sensory neurons. SP is a likely mediator of neurogenic protein leakage in many organs.
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PMID:Vascular protein linkage in various tissue induced by substance P, capsaicin, bradykinin, serotonin, histamine and by antigen challenge. 619 59


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