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)

We have investigated the effect of substance P (SP) and N-formyl-methionyl-leucyl-phenylanine (f-Met-Leu-Phe) on airway smooth muscle preparations isolated from male guinea pigs. Alterations in both the resting membrane potential and developed isometric force were determined. Addition of SP (10(-10) to 10(-4) M) caused a nonphasic, dose-dependent, sustained depolarization of airway smooth muscle cells, with the concomitant development of increased isometric force. In contrast, f-Met-Leu-Phe (10(-12) to 10(-6) M) induced a biphasic membrane response of airway smooth muscle cells, i.e., a dose-dependent rapid depolarization, followed by prolonged hyperpolarization. During the depolarization phase, a significant transient increase in the isometric force was observed. A selective N-formyl peptide antagonist, t-boc-phenylalanyl-leucyl-phenylalanyl-leucyl-phenylalanine, prevented the f-Met-Leu-Phe-induced changes in membrane polarity and increase in isometric force, as did amiloride (10(-5) M), the selective sodium channel blocker. However, these agents had no effect on SP-induced changes in membrane potential or isometric force. These findings suggest that airway smooth muscle of guinea pigs possess both N-formyl peptide and SP receptors but that occupation of these receptors by their respective agonists leads to functionally distinct responses.
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PMID:Differential effects of N-formyl-methionyl-leucyl-phenylalanine and substance P on the electrical and contractile properties of airway smooth muscle cells. 243 97

A monoclonal antibody that recognizes the carboxyl terminus of substance P was used to localize tachykinin-like immunoreactivity in neurons of area 17 of the adult monkey cerebral cortex. Tachykinin immunostaining was examined in normal monkeys, in monkeys receiving monocular injections of the sodium channel blocker TTX for 10 or 15 d, and in monkeys from which the crystalline lens of one eye had been removed 3 or 6 months prior to death. The immunocytochemical staining in each monkey was compared with the histochemical staining for the mitochondrial enzyme cytochrome oxidase (CO). These forms of monocular deprivation produce the most profound changes in the staining of layers II-III and IVC. In layers II-III of normal monkeys, tachykinin-immunoreactive somata are uniformly distributed by immunostained puncta are densely packed in rows of patches that correspond to the rows of CO-stained patches. Following monocular TTX injections, both the patches of CO staining in the deprived-eye columns and the corresponding patches of intense tachykinin immunostaining shrink. Quantitative analyses indicate the numerical density of immunostained somata is reduced by 50% within the deprived-eye rows of patches and is also reduced within regions surrounding the patches in both sets of ocular dominance columns. Following the removal of the lens from one eye, the CO-stained patches and the immunostained patches in one set of rows shrink and the density of immunostained somata in these rows is reduced by 60%. In the alternating rows, the CO staining between patches increases so that many of the patches fuse to form long, continuous bands. Patches of immunostained puncta also enlarge and fuse; the density of immunostained somata in these rows of enlarged patches is approximately 30% greater than normal. In layer IVC of normal monkeys, the CO staining and the tachykinin immunostaining are relatively uniform. Following monocular TTX injections the CO staining and the tachykinin immunostaining are greatly reduced in columns dominated by the injected eye, corresponding to an 80% reduction in the numerical density of immunoreactive somata. By contrast, the CO staining in layer IVC of aphakic monkeys is changed only slightly from normal and the tachykinin immunostaining appears normal. The changes in the density of immunostained somata in both layers II-III and in IVC occur even through the total density of thionin-stained neurons remains normal.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Activity-dependent regulation of tachykinin-like immunoreactivity in neurons of monkey visual cortex. 316 47

1. Nicotine produced a transient contraction of rabbit isolated iris sphincter muscle, a parasympathetic ganglion-free tissue. The response to nicotine was antagonized by hexamethonium, but was insensitive to tetrodotoxin (TTX). While single treatments with atropine, capsaicin or [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-substance P (rpwwL-SP) partially blocked the response, combined treatment abolished it. 2. Chronic treatment of animals with nicotine added to the drinking water (about 12 mg kg-1 per day) had no effect on the responsiveness to nicotine or the pharmacological properties of nicotine-induced contraction. 3. These results suggest that acetylcholine and tachykinin(s) released via sodium channel-independent mechanisms from nerve terminals of parasympathetic and primary sensory nerves, respectively, are involved in the nicotine-induced contractile response.
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PMID:Mechanism of action of nicotine in isolated iris sphincter preparations of rabbit. 322 72

N1E-115 mouse neuroblastoma cells were used to study the influence of ethanol on the 5-HT- and veratridine-induced influx of 14C-guanidinium via the 5-HT3 receptor channel and the fast sodium channel, respectively. Ethanol (10-100 mM) concentration-dependently increased the 5-HT-induced 14C-guanidinium influx, leaving the basal and veratridine (100 microM)-induced influx unaffected. The increasing effect of ethanol (100 mM) was observed at all 5-HT concentrations investigated; accordingly, ethanol increased the maximum response to 5-HT. Whereas in the absence of ethanol the concentration-response curve for 5-HT was bell-shaped, this was no longer the case when ethanol (100 mM) was present in the incubation buffer; the descending branch of the concentration-response curve for 5-HT at concentrations above 300 microM was virtually no longer observed. When, in the presence of substance P (10 microM) the 5-HT-induced 14C-guanidinium influx was already enhanced, the ability of ethanol (100 mM) to increase the 5-HT-induced influx was considerably diminished (by 72%). Preincubation of N1E-115 cells with 5-HT caused a decay of the subsequent 5-HT response ("desensitization") which was dependent on the duration of preincubation; ethanol (100 mM) did not affect the rate of this decay of the 5-HT response. The 5-HT (30 microM)-induced 14C-guanidinium influx was also increased by methanol (100 mM) and n-propanol (100 mM). The rank order of the increasing effect of the n-alkanols (at 100 mM) was: methanol < ethanol < n-propanol; i.e. the degree of enhancement increased with the lipophilicity of the alcohols.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Increasing effect of ethanol on 5-HT3 receptor-mediated 14C-guanidinium influx in N1E-115 neuroblastoma cells. 747 37

1. The 5-HT3 receptor-mediated cation influx into N1E-115 mouse neuroblastoma cells has been studied by the use of the organic cation [14C]-guanidinium. 2. 5-Hydroxytryptamine (5-HT, 30 microM) caused a time-dependent influx of [14C]-guanidinium which, in contrast to the influx elicited by veratridine (100 microM), was not inhibited by tetrodotoxin (TTX, 10 microM). The 5-HT-induced influx was potentiated by substance P and inhibited by ondansetron. 3. 5-HT and the selective 5-HT3 receptor agonists, m-chloro-phenylbiguanide, phenylbiguanide and 2-methyl-5-HT caused bell-shaped concentration-response curves; the rank order of potency was m-chloro-phenylbiguanide > 5-HT > phenylbiguanide = 2-methyl-5-HT. Among these agonists, 5-HT elicited the highest influx of [14C]-guanidinium. 5-Methoxytryptamine, an agonist at 5-HT4 receptors, showed no effect. 4. The [14C]-guanidinium influx induced by 100 microM 5-HT was not affected by methysergide (10 microM) and ketanserin (10 microM) but was inhibited by 5-HT3 receptor antagonists with the following rank order of potency: ICS 205-930 > ondansetron > MDL 72222 >> metoclopramide. 5. The 5-HT-induced [14C]-guanidinium influx was increased in the absence of Ca2+ and/or Na+ and by a reduction of the temperature from 36 degrees to 20 degrees C. 6. Preincubation with 5-HT (100 microM) caused a time-dependent and rapidly reversible decrease of the 5-HT-induced [14C]-guanidinium influx. 7. It is concluded that [14C]-guanidinium influx measurement in N1E-115 cells is a convenient method to study properties of the cation channel of the 5-HT3 receptor. This influx is independent of the fast sodium channel.
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PMID:Characterization of 5-HT3 receptors of N1E-115 neuroblastoma cells by use of the influx of the organic cation [14C]-guanidinium. 768 May 94

1. We recently described a capsaicin-sensitive vagal pathway mediating non-adrenergic, non-cholinergic (NANC) relaxations of an isolated, innervated rostral guinea-pig tracheal preparation. These afferent fibres are carried by the superior laryngeal nerves and relaxations elicited by their activation are insensitive to autonomic ganglion blockers such as hexamethonium. In the present study this vagal relaxant pathway was further characterized. 2. Relaxations of the trachealis elicited by electrical stimulation of capsaicin-sensitive vagal afferents were mimicked by bath application of capsaicin. Relaxations elicited by both methods were abolished when the tissue between the trachea and the adjacent oesophagus was disrupted. Indeed, separating the trachea from the oesophagus uncovered a contractile effect of capsaicin administration on the trachealis. 3. Capsaicin-induced, oesophagus-dependent relaxations of the trachealis were blocked by pretreatment with the fast sodium channel blocker tetrodotoxin (TTX). By contrast, capsaicin-induced contractions of the trachealis (obtained in the absence of the oesophagus) were unaffected by tetrodotoxin. 4. Substance P, neurokinin A (NKA) and neurokinin B (NKB) also elicited NANC relaxations of precontracted trachealis that were abolished by separating the trachea from the oesophagus or by TTX pretreatment. Like capsaicin, the tachykinins elicited only contractions of the trachealis following TTX pretreatment or separation of the trachea from the adjacent oesophagus. 5. Relaxations elicited by stimulation of the capsaicin-sensitive nerves were unaffected by a concentration of the tachykinin NK2 receptor-selective antagonist, SR 48968, that is selective for NK2 receptor blockade and were not mimicked by the NK2 receptor-selective agonist [beta-Ala8]-NKA(4-10). This suggests that NK2 receptors are not responsible for these relaxations. By contrast, the NK3 receptor-selective agonist, senktide analogue, and the NK1 receptor-selective agonist, acetyl-[Arg6, Sar9, Met (O2)11]-SP(6-11), elicited oesophagus-dependent relaxations of the trachealis that were abolished by oesophagus removal. Furthermore, pretreatment with the NK1-selective antagonists, CP 96345 and CP 99994, or pretreatment with a concentration of SR 48968 that also blocks NK3 receptors, markedly attenuated relaxations elicited by stimulation of the capsaicin-sensitive vagal pathways. 6. The data are consistent with the hypothesis that relaxations elicited by stimulation of capsaicin-sensitive vagal afferents involve tachykinin-mediated activation of peripheral NANC inhibitory neurones that are in some way associated with the oesophagus. The data also indicate that airway smooth muscle tone might be regulated by peripheral reflexes initiated by activation of capsaicin-sensitive afferent fibres.
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PMID:Evidence that antidromically stimulated vagal afferents activate inhibitory neurones innervating guinea-pig trachealis. 786 72

The aim of the present study was to investigate previously suggested adrenergic and tachykinin activity, as well as the cardiovascular effects, of venom from the stonefish (Synanceja trachynis). Stonefish venom (60-120 micrograms/kg, i.v.) produced dose-dependent bronchoconstriction in anaesthetised guinea-pigs. This response (100 micrograms/kg, i.v.) was significantly reduced by the neurokinin 1 (NK1) receptor antagonist CP-99,994 (1 mg/kg, i.v.). Contractile responses to venom (4 micrograms/ml) of guinea-pig isolated ileum (GPI) were significantly inhibited by a combination of the sodium channel blocking drug tetrodotoxin (1 microM) and the ganglion blocking drug mecamylamine (10 microM). However, subsequent administration of CP-99,994 (0.1 microM) did not produce further inhibition. Endogenous tachykinin depletion with capsaicin (1 microM) also significantly attenuated responses to venom (4 micrograms/ml) in GPI. Venom (4 micrograms/ml) produced increases in rate and force of contraction of rat spontaneously beating isolated atria which were significantly inhibited by the beta-adrenoceptor antagonist propranolol (5 microM) but not by noradrenergic transmitter depletion with reserpine (4.5 mg/kg, i.p.). In the presence of the alpha 1-adrenoceptor antagonist prazosin (0.3 microM), venom (6 micrograms/ml) significantly inhibited electrically evoked twitches of prostatic segments of rat vas deferens. The inhibitory effect of venom was significantly reduced by the alpha 2-adrenoceptor antagonist idazoxan (1 microM) but not by propranolol (5 microM) or the neurokinin 2 (NK2) receptor antagonist SR-48,968 (0.1 microM). Venom (60-120 micrograms/kg, i.v.) produced dose-dependent increases in mean arterial blood pressure in anaesthetised rats. This pressor response (60 micrograms/kg, i.v.) was significantly reduced by prazosin (10-50 micrograms/kg, i.v.) and the leukotriene receptor antagonist SB205312 (1 mg/kg, i.v.), significantly increased by propranolol (2 mg/kg, i.v.), but not significantly affected by the cyclo-oxygenase inhibitor indomethacin (10 mg/kg, i.v.) or the thromboxane A2/prostaglandin H2 (TP) receptor antagonist GR32191B (1 mg/kg, i.v.). Pressor responses to venom (100 micrograms/kg, i.v.) were also observed in anaesthetised rabbits. These results suggest that stonefish venom contains a component capable of stimulating the release of endogenous tachykinins with subsequent activity at NK1 receptors. The venom also appears to act via stimulation of sodium channels on sensory nerves. The venom also has activity at alpha 2-adrenoceptors and a direct action at beta-adrenoceptors. The effect of venom on blood pressure of anaesthetised rats appears to include a pressor component that is mediated, in part,by alpha-adrenoceptors and leukotriene receptors, and a depressor component that is mediated by beta-adrenoceptors. However, the pressor response does not involve action at TP receptors, or require the production of cyclo-oxygenase metabolites.
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PMID:Evidence for adrenergic and tachykinin activity in venom of the stonefish (Synanceja trachynis). 878 49

The action of lignocaine on nociceptive transmission in the spinal cord has been studied in vitro using ventral root potential (VRP) recordings from 10-12-day-old rat hemisected spinal cord preparations. Single-shock stimulation of a dorsal root at intensities sufficient to activate high-threshold C-primary afferent fibres elicited VRPs lasting for 15-20 sec in the corresponding ventral root. The VRP consisted of 3 distinct parts: the early, slow and prolonged components, as previously described (Thompson et al. 1992), where the early represents A beta fibre-evoked mono- and polysynaptic responses lasting for tens of milliseconds, the slow is a largely N-methyl-D-aspartic acid (NMDA) receptor-mediated small-calibre afferent-generated component, lasting for about 1.5 sec, and the prolonged is a neurokinin receptor-mediated long-lasting component generated by high-threshold fibres. Lignocaine superfusion (40-60 microM) significantly and reversibly reduced the slow and prolonged components of the C fibre-evoked VRP in a dose-dependent manner without any effect on the early or A beta fibre-mediated component of the VRP. The amplitude of the cumulative VRP generated by repetitive inputs (1 and 10 Hz) was also significantly reduced as was the depolarization produced by bath application of NMDA (100 microM) or substance P (SP, 1 microM) in the presence or absence of tetrodotoxin (TTX) (300 nM). At this dose range lignocaine had no effect on the compound action potential (CAP) elicited by stimulating the sciatic nerve and recorded on the dorsal root. The CAP was only significantly reduced with a 300 microM dose of lignocaine. Application of the opiate, glycine, GABAA and GABAB receptor antagonists, naloxone (1 microM), strychnine (100 microM), bicuculline (100 microM) and phaclofen (100 microM) did not alter the depressant effects of lignocaine on the VRP. Low concentrations of lignocaine have a selective action on nociceptive transmission in the spinal cord which is different and more potent than its local anaesthetic conduction blockade in the periphery. This includes a reduction of direct or synaptically driven NMDA- and NK receptor-mediated post-synaptic depolarizations indicating that this class of sodium channel blockers may be potentially useful as analgesic agents, possibly acting on TTX-resistant sodium ion channels.
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PMID:Lignocaine selectively reduces C fibre-evoked neuronal activity in rat spinal cord in vitro by decreasing N-methyl-D-aspartate and neurokinin receptor-mediated post-synaptic depolarizations; implications for the development of novel centrally acting analgesics. 886 47

To study the role of tachykinins in allergic responses in the airways of guinea pigs sensitized to ovalbumin (OVA), we examined the bronchial contractile response to allergen in the presence or absence of the tachykinin antagonist FK224 in vitro. Because neutral endopeptidase (NEP) effectively cleaves tachykinins, we incubated bronchial tissues with the NEP inhibitor phosphoramidon (10(-5) M) to maintain the activity of endogenously released tachykinins. Then we added 10(-5)% (10 microns/ml) OVA in the presence or absence of FK224 (10(-5) M). FK224 significantly inhibited OVA-induced contraction plateaued and began to relax, we added 10(-5) M phosphoramidon. In the tissue without FK224, phosphoramidon blocked the relaxation and enhanced the contraction. In contrast, in the tissues treated with FK224, phosphoramidon did not enhance the OVA-induced contraction. The enhancement of the contraction induced by phosphoramidon was not inhibited by the sodium channel blocker tetrodotoxin. These results suggest that (1) allergic response causes release of tachykinin-like substances to induce bronchial contraction in part, (2) these responses are blocked by tachykinin antagonist FK224 and (3) nerve conduction is not necessary for the release of tachykinin-like substances induced by allergic response in the guinea pig bronchus.
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PMID:Evidence that allergen-induced contraction of guinea pig bronchi is mediated in part by the release of tachykinins. 908 66

This study was undertaken to determine the effect of the immunosuppressant cyclosporin A on neurotransmitter release from non-adrenergic, non-cholinergic nerves (tachykininergic nerves) in the rabbit iris sphincter muscle. Cumulative application of cyclosporin A (0.1 to 10 microM) caused a slow onset of contraction in a concentration-dependent manner. Both FK888 (1 microM) and capsaicin (10 microM), a substance P receptor antagonist and a substance P-depleting agent, respectively, inhibited the contractile effect of cyclosporin A, whereas atropine (1 microM) had no effect. Both cyclosporin A and capsaicin (10 microM) stimulated the release of substance P-like immunoreactivity in the iris. Neither the sodium channel blocker tetrodotoxin (1 microM), the N-type voltage-dependent Ca2+ channel blocker omega-conotoxin GVIA (1 microM) nor the P-type channel blocker omega-agatoxin IVA (0.2 microM) affected cyclosporin A (1 microM)-induced contraction. In contrast, the L-type Ca2+ channel blocker nicardipine (10 microM) inhibited this contractile effect. These results suggest that cyclosporin A stimulates substance P-like tachykinin release by activating L-type voltage-dependent Ca2+ channels, resulting in contraction of the rabbit iris sphincter muscle.
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PMID:Effects of the immunosuppressant cyclosporin A on neurotransmitter release from peripheral non-adrenergic, non-cholinergic nerves. 930 79


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