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. To examine the role of epithelium in the responsiveness of tracheal smooth muscle in rabbit, we measured the contractile responses to acetylcholine (ACh), KCl, 5-hydroxytryptamine (5-HT), histamine, substance P (SP), neurokinin A (NKA), and electrical field stimulation EFS) in intact and epithelium-denuded preparations. 2. Removal of epithelium did not alter the contractile response to any agonist examined, except SP. 3. Removal of epithelium enhances the contractile response to SP. In the presence of phosphoramidon, the contractile response to SP was not significantly different in either group. The results suggest that the effect of epithelium is largely due to degradation of SP by enzymes in the epithelium. 4. Arachidonic acid metabolites did not seem to be related to the responses induced by contractile agonists or EFS. 5. In the presence of SP, the contractile responses and [3H]-choline outflow evoked by EFS were dose-dependently enhanced. Contractile responses to EFS and [3H]-choline outflow evoked by EFS were enhanced by SP significantly more than by NKA. Both were abolished by atropine or tetrodotoxin. 6. These results suggest that rabbit tracheal epithelium may modulate SP-induced contractions, both direct and indirect, by inactivation of SP. This phenomenon is widespread in mammals. The rabbit may be a useful model to examine airway cholinergic functions.
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PMID:An ubiquitous modulating function of rabbit tracheal epithelium: degradation of tachykinins. 137 1

1. Release of endothelium derived relaxing factor (EDRF) and prostacyclin (PGI2) from endothelial cells (EC) cultured from bovine aortae was measured by bioassay and radioimmunoassay, respectively, during infusions (10 min) of bradykinin (BK), adenosine diphosphate (ADP), arachidonic acid (AA), alkaline buffers and the free-bases (FB) of L-arginine or D-arginine. Release of EDRF from the luminally perfused rabbit aorta was also measured during infusions (10 min) of acetylcholine (ACh), substance P and ADP. 2. Bradykinin (10 or 30 nM) infused through the column of EC induced release of both EDRF and PGI2, neither of which was maintained for the duration of the infusion. 3. ADP (1.6 or 4 microM) infused through the column of EC induced release of a EDRF which was maintained for the duration of the infusion and a release of PGI2 which lasted for a much shorter period. 4. Arachidonic acid (30 or 90 microM) infused through the column of EC caused a sustained release of EDRF and PGI2, both of which outlasted the infusion of AA. 5. L-Arginine FB, D-arginine FB or alkaline buffer infused through the column of EC released EDRF, but only small amounts of PGI2. The release of EDRF outlasted the period of infusion and was due to an increase in the pH of the Krebs solution perfusing the EC. 6. Infusions of ACh (0.25-1 microM) or ADP (4-16 microM) caused a sustained release of EDRF from the luminally-perfused rabbit aorta, whereas infusion of substance P (3.3-10 microM) caused only a transient release of EDRF. 7. These results show that distinct patterns of EDRF release exist to different agonists in both cultured and in situ EC, and that EDRF and PGI2 do not necessarily follow the same time course of release. Furthermore, sustained release of EDRF does not require the constant infusion of the precursor, L-arginine, whereas sustained release of PGI2 only occurs when AA, the precursor of PGI2, is present in the extracellular medium.
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PMID:Different patterns of release of endothelium-derived relaxing factor and prostacyclin. 137 3

The effects on cytosolic Ca2+ concentration of 2-chloroadenosine and [L-Pro9]-substance P, a selective agonist of NK1 receptors, were investigated on astrocytes from embryonic mice in primary culture. Cells responded to [L-Pro9]-substance P with a transitory increase in cytosolic Ca2+ which was of shorter duration when external Ca2+ was removed. A transient response to 2-chloroadenosine alone occurred. When simultaneously applied, [L-Pro9]-substance P and 2-chloroadenosine evoked a prolonged elevation of cytosolic Ca2+ (up to 30 min). This phenomenon was dependent on the presence of extracellular Ca2+, but insensitive to dihydropyridines, La3+, and Co2+, excluding the implication of voltage-operated Ca2+ channels. Arachidonic acid also induced a sustained elevation of cytosolic Ca2+, but did not increase further the response evoked by [L-Pro9]-substance P and 2-chloroadenosine. The activation of protein kinase C by a diacylglycerol analogue mimicked the effect of [L-Pro9]-substance P in potentiating the 2-chloroadenosine-evoked response. Like 2-chloroadenosine, pinacidil, which hyperpolarizes the cells by opening K+ channels, prolonged the elevation of cytosolic Ca2+ concentration induced by [L-Pro9]-substance P. Conversely, depolarization with 50 mM KCl canceled the effects of either pinacidil or 2-chloroadenosine applied with [L-Pro9]-substance P. Pertussis toxin pretreatment suppressed all the effects induced by 2-chloroadenosine.
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PMID:Synergistic regulation of cytosolic Ca2+ concentration in mouse astrocytes by NK1 tachykinin and adenosine agonists. 171 34

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

1. Epithelium removal did not influence the development of spontaneous tone in guinea-pig tracheal smooth muscle mounted as open ring preparations with two adjoining cartilaginous rings in vitro. 2. Epithelium removal did not change the potency of carbachol but tended to reduce the maximal contraction. In the presence of epithelium the EC50 of carbachol was not different in tracheal open ring compared with intact tube preparations (comprising four cartilaginous rings), suggesting that the size of continuous epithelium in vitro was not critical for the potency of carbachol. 3. Substance P produced the same response in intact and rubbed tracheae. The enkephalinase inhibitor thiorphan (0.1 mM) by itself contracted the trachea and appeared to potentiate the substance P response five times more in the absence than in the presence of epithelium. Capsaicin (1 microM)-induced contractions did not differ between intact and rubbed preparations. 4. Arachidonic acid, 22 microM, variably produced small relaxations and contractions in intact as well as in rubbed tracheae. The mean effects of arachidonic acid were not significantly altered by epithelium removal. 5. Adenosine produced small contractions and dose-dependent relaxations in the presence and absence of epithelium. 6. Epithelium removal had no effect on the potency of the relaxant agonists theophylline and enprofylline. The isoprenaline curve was shifted 2 fold to the left and the terbutaline curve 1.5 fold to the right. The maximal relaxations were generally reduced in epithelium-free tissue. The reduction reached statistical significance with theophylline. 7. The present results suggest that epithelium removal is of little consequence for the pharmacology of the guinea-pig tracheal open ring preparation in vitro.
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PMID:The epithelium and the pharmacology of guinea-pig tracheal tone in vitro. 339 Jun 59

Translocation of protein kinase C (PKC) from the cytosol to the plasma membranes is believed to reflect activation of the enzyme. We have studied translocation of PKC in lactotroph-enriched anterior pituitary cell cultures by measuring the incorporation of gamma-32P from [gamma-32P]ATP into a synthetic peptide substrate, MBP4-14, and by immunoblotting of PKC isozymes. Using cells permeabilized with digitonin the effects of PKC cofactors on the distribution of the enzyme were studied. Ca2+ (50 nM) and dioctanoyl-sn-glycerol had no effect when tested alone, but in combination they caused a redistribution of PKC from the soluble to the particulate fraction. Arachidonic acid needed Ca2+ to induce translocation of PKC, while being ineffective under Ca(2+)-free conditions. Western blot analysis of partly purified PKC from lactotroph-enriched pituitary cells revealed the presence of the alpha, beta, delta and zeta isozymes. 12-O-Tetradecanoylphorbol 13-acetate (TPA) and substance P displayed different patterns of redistribution of PKC isozyme immunoreactivity from soluble to membrane-attached forms. Thus, TPA induced time- and dose-dependent (mean effective concentration (EC50) = 1 nM) translocation of the alpha, beta and delta species, while substance P stimulated time- and dose-dependent (EC50 = 1 nM) redistribution of the alpha and beta isozymes. zeta subtype immunoreactivity could not be translocated by either agonist; neither could the immunoreactivity of zeta be down-regulated by long-term treatment (24 h) with TPA. The results indicate that simultaneous activation of phospholipases C and A2 induces a synergistic activation of PKC. Finally it is suggested that substance P may exert some of its effects in lactotrophs by translocation of PKC isozymes alpha and beta.
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PMID:Translocation of protein kinase C isozymes in lactotroph-enriched rat anterior pituitary cell cultures: differential effects of substance P and phorbol ester. 752 60

Capsaicin applied to human skin provokes a response known as neurogenic inflammation. Neuropeptides (substance P, CGRP), released from afferent C-fiber terminals and histamine, secondarily released from mast cells, are supposed to participate in this reaction. We investigated the contribution of arachidonic acid and metabolic products to neurogenic inflammation, using a potent topically applied glucocorticoid and the corresponding vehicle. Arachidonic acid is liberated from membrane phospholipids by phospholipase A2, an enzyme that can be blocked by glucocorticoids. In 12 healthy volunteers, neurogenic inflammation was induced by capsaicin 1% on both upper forearms after 16 h of topical pretreatment with either prednicarbate or vehicle. Neurogenic inflammation was assessed by laser Doppler flowmetry and by planimetry of flare sizes. Prednicarbate significantly reduced the laser Doppler flow values inside the flare responses, as well as the flare sizes themselves. These results show that to some extent glucocorticoids reduce capsaicin-induced neurogenic inflammation.
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PMID:Small reduction of capsaicin-induced neurogenic inflammation in human forearm skin by the glucocorticoid prednicarbate. 831 18

1. The modulator effects of a series of neurotransmitters and related substances were tested on responses to adenosine 5'-triphosphate (ATP) at a recombinant P2x2 receptor expressed in defolliculated Xenopus oocytes. 2. Nicotine, 5'-hydroxytryptamine (5-HT), noradrenaline, adenosine, bradykinin and histamine (all 100 microM) potentiated the responses to ATP (3 microM). an effect found due to acidification of the bathing solution by these drugs. 3. Arachidonic acid, met-enkephalin, substance P, calcitonin gene-related peptide (CGRP) (all 100 microM) and nerve growth factor (NGF; 50 ng ml-1) potentiated the responses to ATP (3 microM) through a largely or wholly pH-independent effect. 4. Small acidic and alkaline shifts, as little as 0.03 pH-units, enhanced or diminished the responses to ATP, respectively. A linear relationship existed between the degree of potentiation of the ATP-induced responses caused by nicotine, 5-HT, noradrenaline, adenosine, bradykinin and histamine and the potentiation of these responses induced by the addition of acid to the superfusate. 5. Since P2x receptors on sensory neurones include P2x2 subunits, the attendant acidosis and ATP-release associated with tissue injury may play a role in sensitizing sensory nerve fibres.
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PMID:Potentiation of ATP-responses at a recombinant P2x2 receptor by neurotransmitters and related substances. 911 13

In isolated strips of the hamster urinary bladder the selective tachykinin NK2 receptor agonist [betaAla8]NKA(4-10) induced a concentration-dependent (1 nM-10 microM) contraction (EC50 104 nM) associated with significant release of prostaglandin E2 (PGE2, 50+/-17 pg/mg tissue). In mucosa-free bladder strips [betaAla8]NKA(4-10) was as potent as in the presence of mucosa (EC50 46 nM), although the evoked PGE2 release was significantly less than in controls (6+/-1.7 pg/mg tissue). Dexketoprofen (10 microM) produced a significant but limited rightward shift of the concentration/response curve to [betaAla8]NKA(4-10) both in the presence and absence of the mucosal layer: the EC50 for [betaAla8]NKA(4-10) was increased five- and threefold, respectively. The evoked PGE2 release was abolished in both cases. The selective tachykinin NK2 receptor antagonist, nepadutant (10 nM-1 microM) produced a concentration-dependent and even inhibition of both contraction and PGE2 release induced by [betaAla8]NKA(4-10). The L-type calcium channel blocker, nifedipine (1 microM) and the non-selective cationic channel blocker SKF 96365 (30 microM) both inhibited the contractile response to [betaAla8]NKA(4-10) (89+/-2 and 83+/-2% inhibition, respectively). The evoked PGE2 release was not affected by nifedipine but was almost abolished by SKF 96365. Arachidonic acid (100 microM) induced a contractile response (5.9+/-0.7 mN) associated with a large production of PGE2 (383+/-78 pg/mg tissue). The contractile response to arachidonic acid was inhibited by both nifedipine (1 microM) and SKF 96365 (30 microM) (83+/-5 and 79+/-3% inhibition, respectively). The PGE2 production induced by arachidonic acid was markedly inhibited by SKF 96365 only (about 94% inhibition). Exogenous PGE2 contracted hamster bladder strips in the presence of dexketoprofen (EC50 1 microM) and strongly potentiated the contractile response to a submaximal concentration of [betaAla8]NKA(4-10). In anaesthetized hamsters the administration of [betaAla8]NKA(4-10) (10 nmol/kg, i.v.) produced a contractile response of the urinary bladder (13+/-0.4 mmHg) that was inhibited partly by dexketoprofen (25+/-3 and 35+/-4% inhibition for 0.2 and 2 mg/kg, i.v. dexketoprofen, respectively). We conclude that activation of tachykinin NK2 receptors determines prostanoid synthesis/release in the hamster urinary bladder and that this effect is largely ascribable to structures present in the bladder mucosa. Prostanoids generated following NK2 receptor activation amplify the direct contractile effect of NK2 receptor agonists. This latter response is largely due to activation of L-type calcium channels (nifedipine-sensitive) although this source of calcium apparently is not essential for activation of prostanoid synthesis.
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PMID:Role of prostanoids in the contraction induced by a tachykinin NK2 receptor agonist in the hamster urinary bladder. 1076 62

The in vitro pharmacology of inosine (Ino), a putative anti-inflammatory compound, has been investigated in smooth muscle preparations, with emphasis on its possible interaction with known inflammatory mediators, as well as capsaicin, an inducer of "neurogenic inflammation". The highest concentration of Ino routinely studied was 1 mM, since 10 mM nonspecifically inhibited many types of smooth muscle motor responses. In the guinea pig isolated ileum or trachea, Ino (1 mM) failed to influence the excitatory effect of capsaicin. The nitric oxide (NO)-mediated relaxant effect of capsaicin in the human colonic circular muscle was not influenced by Ino. Ino only weakly reduced the contractile effect of histamine on the guinea pig ileum. Substance P-mediated nonadrenergic, noncholinergic (NANC) contractions evoked by electrical stimulation in the guinea pig ileum were inhibited by half by Ino (1 mM). Ino showed no or only a weak inhibitory effect on NANC relaxation of the rat ileum. Arachidonic acid- or leukotriene D(4)-induced contractions of the guinea pig ileum were only moderately inhibited by Ino. Collectively, these results indicate that Ino (up to 1 mM) shows no major antagonist activity at histamine H(1) receptors, leukotriene CysLT(1) receptors, the transient receptor potential channel TRPV1 or tachykinin NK(1) or NK(2) receptors, or cyclooxygenase-inhibitory activity. Therefore, its anti-inflammatory activity is probably not associated with these mechanisms. The in vitro methods used in this study are capable of detecting a wide range of biological effects and hence may be recommended as a screening procedure for potential drugs or natural products.
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PMID:In vitro pharmacology of inosine, with special reference to possible interactions with capsaicin-sensitive mechanisms and inflammatory mediators. 1979 50


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