UNIPROT:P20366 - FACTA Search

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Query: UNIPROT:P20366 (substance P)
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Exogenous administration of lipoxin A4 (LXA4) to guinea pig isolated bronchus produced contractile effects in a concentration-dependent manner (1, 3, and 6 microM). These responses were potentiated when preparations were previously incubated with thiorphan (10 microM), an inhibitor of tachykinin breakdown, but were significantly depressed when sensory nerves were previously desensitized in vitro by capsaicin (10 microM for 15 min) challenge. Ruthenium red (10 microM for 20 min), a blocker of the cationic channel coupled to the capsaicin receptor, also produced, although in a weaker manner, a reduction in bronchomotor responses elicited by LXA4. On the other hand, preexposure to omega-conotoxin (0.1 microM for 45 min), a blocker of neuronal voltage-dependent Ca2+ channels, did not modify the LXA4 contractile effects. Furthermore, LXA4 (6 microM) superfusion of guinea pig bronchial tissue elicited a significant calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) release that was reduced by capsaicin (10 microM, 30 min) desensitization. Finally, LXA4 (10 microM) was unable to displace [3H]resiniferatoxin binding in dorsal root ganglion of rat and guinea pig. These findings support (1) a role for LXA4 in activating motor sensory function of capsaicin-sensitive nerves; (2) this activation mechanism is marginally ruthenium red-sensitive and omega-conotoxin-resistant; and (3) the interaction does not involve the recognized binding site on the vanilloid receptor. As a whole this study presents LXA4 as an endogenous mediator activating sensory nerves potentially involved in basic mechanisms of airway diseases.
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PMID:Pharmacologic and neurochemical evidence for the activation of capsaicin-sensitive sensory nerves by lipoxin A4 in guinea pig bronchus. 138 7

1. Toluene diisocyanate produced concentration-dependent contractions of the rat isolated urinary bladder. 2. The contractions were tetrodotoxin-resistant and were abolished by previous exposure of the strips to capsaicin. 3. Indomethacin (5 microM) and ruthenium red (30 microM) inhibited toluene diisocyanate-induced contractions. Responses expressed as a percentage of the response obtained with substance P, 30 nM, were respectively 141.6 +/- 24.8% and 20.1 +/- 5.1% in control and indomethacin-treated strips (P less than 0.005); 123.0 +/- 30.2% and 14.0 +/- 6.5% in control and ruthenium red-treated strips (0.01 less than P less than 0.05). 4. These results suggest that toluene diisocyanate-induced contractions of the rat isolated bladder are the result of the release of cyclo-oxygenase products which may act by activating the capsaicin receptor.
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PMID:Pharmacological modulation of the contractile response to toluene diisocyanate in the rat isolated urinary bladder. 169 99

Administration of capsaicin (8-methyl-N-vanillyl-6-nonenamide) to neonatal rats gives a long-lasting insensitivity to chemical irritants, and its potential as a specific toxin for peripheral C-fibers has made it of particular interest to neurobiologists concerned with pain mechanisms. The existence of capsaicin receptor on primary afferent sensory neurons is now evident. To deduce a receptor model for capsaicin, and propose the possible molecular interactions at the site of action, we prepared more than 50 capsaicin congeners (capsaicinoids). With these capsaicinoids, we investigated the role of functional groups in producing the long-lasting analgesia by phenylquinone writhing test and Randall-Selitto's method with ICR mice and SD rats. The structure-activity relationship of capsaicin in producing analgesia was established as follows: proper length of hydrophobic alkyl chain is 8-18 carbon atoms; 3-methoxy group of aromatic ring plays an important role but not essential; the presence of phenolic-OH is indispensable and the most suitable site is para-position; acyl amide linkage is dispensable; the linkage of amide bond bridged to the ring with CH2 is appropriate. Depletion of substance P from spinal cord and dorsal horn of rats by capsaicinoids was proved by RIA and immunohistochemistry. We succeeded in eliminating a potent acute toxicity shown by capsaicin through its structural modification.
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PMID:Neurotoxicity and long lasting analgesia induced by capsaicinoids. 192 May 42

1. Cigarette smoke increases vascular permeability in rat airways by activating release of tachykinin from capsaicin-sensitive sensory nerves. However, the mechanism by which cigarette smoke induces secretion of sensory neuropeptides is unknown. Here we hypothesized that cigarette smoke activates sensory nerve endings via a mechanism similar to that of capsaicin. 2. We studied the effects of ruthenium red, an inorganic dye which blocks the cation influx promoted by capsaicin and of the capsaicin antagonist capsazepine on the increase in vascular permeability produced by cigarette smoke, capsaicin, hypertonic saline and substance P in the trachea of pentobarbitone anaesthetized rats. We also investigated the ability of cigarette smoke to desensitize sensory nerve fibres. 3. Ruthenium red (10 mM) by aerosol blocked the increase in vascular permeability induced by capsaicin (0.5 microM) and reduced the response to cigarette smoke (5 puffs) but did not affect responses evoked by hypertonic saline (7.2%) or by substance P (10 microM) (all given by aerosol). Aerosols of capsazepine (0.1 mM) prevented extravasation by capsaicin, but did not inhibit response to cigarette smoke, hypertonic saline or substance P. Finally, pre-exposure to a high dose of cigarette smoke (10 puffs) prevented the extravasation caused by cigarette smoke (5 puffs) itself and by intravenous capsaicin (150 micrograms kg-1), but not that by intravenous substance P (10 nmol kg-1). 4. The present results show that cigarette smoke: (a) increases vascular permeability in the rat airways by a mechanism that is not antagonized by capsazepine, and is partially sensitive to rutheniun red; (b)produces desensitization of capsaicin-sensitive sensory nerves. We propose that chemical(s) contained in or agent(s) produced by cigarette smoke in the airways share partially a common pathway with capsaicin to activate peptide release from capsaicin-sensitive sensory nerves, but do not bind to the putative 'capsaicin receptor'.
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PMID:Ruthenium red, but not capsazepine reduces plasma extravasation by cigarette smoke in rat airways. 768 32

1. The ability of capsazepine, a recently developed capsaicin receptor antagonist, to prevent the effects of capsaicin on the rat isolated urinary bladder (contraction) and vas deferens (inhibition of electrically-evoked twitches) was compared to that of ruthenium red, a dye which behaves as a functional antagonist of capsaicin. 2. In the rat bladder, capsazepine (3-30 microM) produced a concentration-dependent rightward shift of the curve to capsaicin without any significant depression of the maximal response to the agonist. By contrast, ruthenium red (10-30 microM) produced a non-competitive type of antagonism, characterized by marked depression of the maximal response attainable. Similar findings were obtained in the rat isolated vas deferens in which capsazepine (10 microM) produced a rightward shift of the curve to capsaicin while ruthenium red (3 microM) depressed the maximal response to the agonist. 3. At the concentrations used to block the effect of capsaicin, neither capsazepine nor ruthenium red affected the contractile response of the rat urinary bladder produced by either neurokinin A or electrical field stimulation or the twitch inhibition produced by rat alpha-calcitonin gene-related peptide (alpha CGRP) in the vas deferens. 4. These findings provide additional evidence that both capsazepine and ruthenium red are valuable tools for exploration of the function of capsaicin-sensitive primary afferent neurones. The antagonism of the action of capsaicin by capsazepine is entirely consistent with the proposed interaction of this substance with a vanilloid receptor located on primary afferents, while the action of ruthenium red apparently involves a more complex, non-competitive antagonism.
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PMID:A comparison of capsazepine and ruthenium red as capsaicin antagonists in the rat isolated urinary bladder and vas deferens. 768 39

An isolated perfused lung model was developed in which the mechanisms of regulation of sensory neuropeptide overflow and bronchoconstrictor responses evoked by antidromic vagal nerve stimulation or various irritants could be studied. For further comparison, non-adrenergic non-cholinergic (NANC) bronchoconstriction was also studied in guinea-pig isolated bronchus and in vivo. In the isolated guinea-pig lung, spontaneous strong postmortem bronchoconstriction occurred; this had to be overcome by the beta 2-adrenoceptor agonist terbutaline. Vagal stimulation, capsaicin, resiniferatoxin (RTX), nicotine, and pH 5 buffer all caused sensory peptide release and bronchoconstriction via a capsaicin-sensitive mechanism. Bradykinin and histamine also stimulated sensory peptide release but evoked bronchoconstriction mainly via capsaicin-resistant mechanisms. Stimulation at low frequency (1 Hz) caused similar degree of sensory nerve activation (peptide release in perfused lung and NANC bronchial contraction in bronchus) as stimulation at 10 Hz. Dactinomycin and the non-peptide SR 48968 selectively blocked the bronchoconstriction induced by neurokinin 2 (NK2) receptor agonists and also depressed that induced either by vagal stimulation or capsaicin, with no prejunctional effect on the overflow of calcitonin gene-related peptide (CGRP). Furthermore, SR 48968 inhibited the bronchoconstriction to citric acid aerosol. The NK1 antagonist CP 96345 had only marginal effects on NANC bronchoconstriction. Tetrodotoxin (TTX) and omega-conotoxin (CTX) inhibited neuropeptide release and bronchoconstriction caused by vagal stimulation or a low concentration of capsaicin but only marginally attenuated the effects evoked by a high concentration of capsaicin, or nicotine. Prejunctional alpha 2-adrenoceptor or opiate receptor activation inhibited the neuropeptide release and bronchoconstriction induced by vagal stimulation or a low concentration of capsaicin. Ruthenium red had a selective inhibitory effect on the overflow of neuropeptides [CGRP, neurokinin A (NKA)] and bronchoconstriction induced by capsaicin and its analogue RTX but not on responses induced by vagal stimulation, nicotine, bradykinin and histamine. It also inhibited CGRP and NKA release and bronchoconstriction caused by pH 5 buffer in lung, as well as cough and nasal irritation provoked by citric acid in vivo. The capsaicin receptor antagonist capsazepine inhibited peptide (CGRP, NKA) release and bronchoconstriction produced by capsaicin but not that evoked by vagal stimulation, nicotine and bradykinin, suggesting selectivity. Citric acid (in vivo) and pH 5 buffer (in vitro) produced bronchoconstriction via activation of capsaicin-sensitive sensory nerves. Interestingly, capsazepine also markedly depressed peptide overflow and bronchoconstriction caused by pH 5 buffer in isolated guinea-pig lung.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of neuropeptide release from pulmonary capsaicin-sensitive afferents in relation to bronchoconstriction. 769 42

The site of action of resiniferatoxin (RTX) and capsaicin and the pharmacological consequences of the resultant tachykinin release were examined in the guinea pig trachea. RTX and capsaicin were both potent and efficacious contractors of isolated tracheal smooth muscle. RTX was about 20-fold more potent than capsaicin, with -log (M) EC50 values of 8.88 +/- 0.09 (n = 14) and 7.55 +/- 0.07 (n = 14), respectively. The putative capsaicin receptor antagonist capsazepine (10 microM) effectively inhibited responses to both RTX and capsaicin in a competitive fashion. The -log (M) pKB values for capsazepine against resiniferatoxin and capsaicin were 6.28 +/- 0.25 and 6.04 +/- 0.13, respectively. Contractile responses to RTX and capsaicin were unaffected by the NK-1 antagonist CP 96345 (0.3 microM), partially inhibited by the NK-2 antagonist SR 48968 (0.3 microM) but nearly abolished by a combination of the antagonists. Capsaicin and RTX desensitized tissues to subsequent additions of either capsaicin (1 microM) or RTX (0.1 microM). Capsaicin showed maximal desensitization at 1 microM, and RTX at 0.1 microM. This study shows that RTX is a potent activator of capsaicin-sensitive tachykinin-containing nerves in the airways. The site of action of RTX and capsaicin appears to be a receptor sensitive to capsazepine. Moreover, RTX and capsaicin both release tachykinins that act on both NK-1 and NK-2 receptor subtypes.
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PMID:Inhibition by capsazepine of resiniferatoxin- and capsaicin-induced contractions of guinea pig trachea. 830 98

Contractile and relaxant responses to capsaicin and resiniferatoxin were examined in human isolated bronchus (5-12 mm o.d.). Bronchi isolated from 10 of 16 lungs contracted in response to capsaicin. The contractions averaged 20% of maximal contraction at 1 microM and averaged > 40% maximal contraction at 300 microM (the highest concentration studied). The capsaicin-induced contractions were mimicked by resiniferatoxin (0.1-10 microM) and inhibited by the putative capsaicin receptor antagonist, capsazepine (10 microM). The contractile response to capsaicin was not affected by the potent NK-2 selective antagonist SR 48968 (0.3 microM), whereas responses to concentrations of neurokinin A (10 nM), neurokinin B (0.1 microM), substance P (1 microM), neuropeptide gamma (10 nM), and neuropeptide K (10 nM) which produced similar-size contractions were almost abolished by 0.1 microM SR 48968. The bronchi isolated from 8 of 16 lungs also exhibited relaxations in response to capsaicin. Capsaicin-induced relaxations were not inhibited by the nitric oxide synthase inhibitor L-nitro-n-arginine (10 microM). In whole-cell patch-clamp experiments on human cultured airway smooth muscle cells, capsaicin was found to enhance outward currents due to the activation of charybdotoxin-sensitive large conductance Ca2+-activated K+ channels. Neither the capsaicin-induced contractions nor the relaxations were mimicked by angiotensin II, bombesin, or calcitonin gene-related peptide at concentrations up to 1 microM. These results suggest that capsaicin and resiniferatoxin can alter smooth muscle tone, but this response does not appear to involve substance P or related neurokinins. Relaxations to capsaicin may, however, involve the activation of large conductance Ca2+-activated K+ channels.
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PMID:Tachykinin-independent effects of capsaicin on smooth muscle in human isolated bronchi. 903 24

We examined the function of putative sensory fibers that are contained in intercostal nerves and innervate interscapular brown adipose tissue (IBAT) in urethane-anesthetized rats. Warming the IBAT to 40-44 degrees C with two small heaters placed bilaterally on the skin above it attenuated the subsequent noradrenaline-induced thermogenesis (NIT) of the IBAT. In this range of warming, higher IBAT temperatures resulted in more attenuation. Denervation of IBAT blocked the effect of thermal stimulation on the NIT. Thus, activation of nerve fibers in IBAT that are sensitive to warmth or to the nociceptive effects of heat probably attenuated the NIT. Since the putative sensory fibers in the IBAT contain calcitonin gene-related peptide (CGRP) and substance P, which are thought to act in peripheral tissues, we tested the effects of injection of these neuropeptides into the IBAT. Administration of 5.2 nmol CGRP but not substance P or vehicle saline mimicked the effect of thermal stimulation of IBAT. As the neuropeptide-containing primary sensory neurons are characterized by their sensitivity to capsaicin, we also tested its effects (1 mg/kg, s.c.) and found that it also attenuated the NIT. Denervation of the IBAT or pretreatment with capsazepine, a capsaicin receptor antagonist, blocked the effect of capsaicin. We propose that temperature- and capsaicin-sensitive nerve fibers release CGRP to attenuate the NIT of brown adipocytes.
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PMID:Temperature- and capsaicin-sensitive nerve fibers in brown adipose tissue attenuate thermogenesis in the rat. 981 83

We have investigated the contractile property of cyclosporin A and FK506 in guinea-pig isolated bronchus. Cyclosporin A (10 microM) failed to significantly attenuate the excitatory non-adrenergic non-cholinergic (eNANC) and cholinergic contractile response (per cent methacholine Emax) induced by electrical field stimulation (EFS). In contrast, eNANC responses were significantly attenuated by both the neurokinin (NK)-1 and (NK)-2 receptor antagonists, N-acetyl-L-tryptophan 3,5-bis (trifluoromethyl)-benzyl and SR48968, respectively. Cyclosporin A and FK506 caused a concentration-dependent contraction in guinea-pig isolated bronchus, which was significantly attenuated by NK-1 and NK-2 receptor antagonists. The capsaicin receptor antagonist, capsazepine (10 microM) significantly reduced the contractile response to cyclosporin A and capsaicin, but not to FK506. The N-type calcium channel blocker, omega-Conotoxin (omegaCTX: 10 nM), significantly reduced the contractile response to FK506 and the eNANC response following EFS. In contrast, omega-CTX failed to significantly reduce the contractile potency to capsaicin or cyclosporin A. In bronchial preparations desensitized by repeated application of capsaicin (1 microM), the contractile responses to both cyclosporin A (100 microM) and FK506 (100 microM), were significantly reduced. In contrast, the contractile responses to substance P and neurokinin A (10 microM) were not altered. Furthermore, repeated application of cyclosporin A (100 microM) significantly inhibited the contractile response to capsaicin (1 microM). The findings from this study would indicate that cyclosporin A and FK506 mediate contraction of guinea-pig isolated bronchus secondary to the release of neuropeptides from airway sensory nerves. However, the release of sensory neuropeptides appears to be mediated via different mechanisms for cyclosporin A and FK506, the former by stimulation of the vanilloid receptor and the latter via opening of N-type calcium channels.
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PMID:Stimulation of airway sensory nerves by cyclosporin A and FK506 in guinea-pig isolated bronchus. 988 67

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