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 possible interaction (cross talk) between the phospholipase A2 (PLA2) and inositol 1,4,5-trisphosphate/protein kinase C (PKC) signaling pathways in rat lactotroph-enriched cell cultures. Melittin, a bee venom peptide, stimulated release of [3H]arachidonic acid ([3H]AA) from [3H]AA-labeled enriched lactotrophs in a dose-dependent manner. Moreover, melittin and exogenous AA induced a redistribution of PKC catalytic activity and PKC alpha and beta immunoreactivity from the soluble to the particulate fraction in resting and substance P (SP)-stimulated cells. Melittin had no effect on phospholipase C (PLC) activity. Pretreatment of cell cultures with the PLA2 inhibitors quinacrine and aristolochic acid resulted in a dose-dependent inhibition of melittin-stimulated PKC isozyme translocation as did the inhibitor of lipoxygenase, nordihydroguaiaretic acid, whereas the cyclooxygenase inhibitor indomethacin had no effect. SP and the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) dose-dependently increased levels of [3H]AA released from cells. Pretreatment of cell cultures with quinacrine reduced the effect of SP on [3H]AA formation. After long-term treatment (24 h) of cells with TPA, the effect of TPA on [3H]AA production was not different from control, whereas SP still displayed [3H]AA-releasing abilities although not at full scale. Pretreatment of cells with thapsigargin, U 73122, methoxyverapamil, and RHC 80267, an inhibitor of diacylglycerol lipase, all resulted in reduced SP-stimulated [3H]AA liberation. Treatment of cell cultures with pertussis toxin (PTX) reduced the release of [3H]AA induced by SP, whereas PTX had no effect on SP-stimulated generation of 3H-inositol phosphates. On the basis of these results, it is concluded that (1) the PLA2 pathways interfere with the phosphoinositide-PLC signaling system at the level of PKC isozymes alpha and beta, the product responsible for this interaction being either AA or a metabolite produced by the action of lipoxygenase; (2) SP and TPA are able to activate the PLA2 pathway at a level at or beyond PLA2, and this effect is mediated, in part, through PKC alpha and beta species and (for SP) intracellular Ca2+ recruited from internal stores as well as from external sources; and (3) SP also activates PLA2 through a PTX-sensitive pathway distinct from the one coupled to phosphoinositide-PLC, which is PTX insensitive.
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PMID:Cross talk between substance P and melittin-activated cellular signaling pathways in rat lactotroph-enriched cell cultures. 923 37

We have previously reported that neuropeptide Y (NPY) inhibits responses induced by various agonists (noradrenaline, vasoactive intestinal peptide, substance P,5-hydroxytryptamine) in isolated guinea pig trachea. Although the underlying mechanisms have not been fully characterized, it was found that the NPY-evoked inhibition was specifically expressed with agents for which locally released prostaglandins (PGs) are important determinants for their myotropic activity. In the present study, we have extended these findings by examining whether NPY was capable of regulating the release of prostacyclin and thromboxane A2 induced by bradykinin (BK) from naive and ovalbumin-sensitized guinea pig perfused lungs. Our results showed that infusion of NPY (0.24 microM) through the lung significantly inhibited the release of 6-keto-PGF1 alpha (> 30%) and thromboxane B2 (50%) induced by intraarterial administration of BK (3 micrograms) from untreated and ovalbumin-sensitized guinea pig perfused lung. However, the inhibitory effect of NPY was lost in the immunological production of prostaglandins. These results suggest that NPY may act as a regulatory agent of the release of cyclooxygenase-derived products by possibly acting on events preceding phospholipase A2 activation.
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PMID:Effect of neuropeptide Y on bradykinin-induced release of prostacyclin and thromboxane from guinea pig perfused lung. 927 48

1. In vitro studies were performed to examine the mechanisms underlying substance P-induced enhancement of constriction rate in guinea-pig mesenteric lymphatic vessels. 2. Substance P caused an endothelium-dependent increase in lymphatic constriction frequency which was first significant at a concentration of 1 nM (115 +/- 3% of control, n = 11) with 1 microM, the highest concentration tested, increasing the rate to 153 +/- 4% of control (n = 9). 3. Repetitive 5 min applications of substance P (1 microM) caused tachyphylaxis with tissue responsiveness tending to decrease (by an average of 23%) and significantly decreasing (by 72%) for application at intervals of 30 and 10 min, respectively. 4. The competitive antagonist of tachykinin receptors, spantide (5 microM) and the specific NK1 receptor antagonist, WIN51708 (10 microM) both prevented the enhancement of constriction rate induced by 1 microM substance P. 5. Endothelial cells loaded with the Ca2+ sensing fluophore, fluo 3/AM did not display a detectable change in [Ca2+]i upon application of 1 microM substance P. 6. Inhibition of nitric oxide synthase by NG nitro-L-arginine (L-NOARG; 100 microM) had no significant effect on the response induced by 1 microM substance P. 7. The enhancement of constriction rate induced by 1 microM substance P was prevented by the cyclooxygenase inhibitor, indomethacin (3 microM), the thromboxane A2 synthase inhibitor, imidazole (50 microM), and the thromboxane A2 receptor antagonist, SQ29548 (0.3 microM). 8. The stable analogue of thromboxane A2, U46619 (0.1 microM) significantly increased the constriction rate of lymphangions with or without endothelium, an effect which was prevented by SQ29548 (0.3 microM). 9. Treatment with pertussis toxin (PTx; 100 ng ml-1) completely abolished the response to 1 microM substance P without inhibiting either the perfusion-induced constriction or the U46619-induced enhancement of constriction rate. 10. Application of the phospholipase A2 inhibitor, antiflammin-1 (1 nM) prevented the enhancement of lymphatic pumping induced by substance P (1 microM), without inhibiting the response to either U46619 (0.1 microM) or acetylcholine (10 microM). 11. The data support the hypothesis that the substance P-induced increase in pumping rate is mediated via the endothelium through NK1 receptors coupled by a PTx sensitive G-protein to phospholipase A2 and resulting in generation of the arachidonic acid metabolite, thromboxane A2 this serving as the diffusible activator.
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PMID:Evidence that the substance P-induced enhancement of pacemaking in lymphatics of the guinea-pig mesentery occurs through endothelial release of thromboxane A2. 928 91

The human tachykinin NK2 receptor stably expressed in Chinese hamster ovary cells (CHO-hNK2R cells) was characterized by studying the effect of neurokinin A (NKA), the preferred natural ligand, and that of other agonists and antagonists in both binding experiments and functional assays. Competition experiments using [125I]NKA showed that CHO-hNK2R cells express binding sites which have high affinity for NKA (Ki=3.4+/-0.9 nM), GR 64349 (Ki=12+/-3 nM) and [betaAla8]NKA(4-10) (Ki=21+/-8 nM) and for the antagonists MEN 10627 (Ki=0.55+/-0.2 nM), and MEN 11420 (Ki=2.4+/-0.8 nM). In contrast, the tachykinin NK1 and NK3 receptor agonists [Sar9,Met(O2)11]SP and senktide, respectively, were recognized with low affinity (Ki>10 microM). NKA (EC50=68+/-18 nM) induced a rapid and concentration-dependent increase in the intracellular level of inositoltrisphosphate (IP3). The concentration-response curve to GR 64349 (EC50=155+/-14 nM) was close to that of NKA, whereas [betaAla8]NKA(4-10) (EC50=445+/-78 nM) and SP (EC50=3197+/-669 nM) were 7- and 50-fold less potent, respectively. In addition, NKA stimulated the release of arachidonic acid and the production of prostaglandin E2 (PGE2) in a concentration-dependent manner. Also in this assay, NKA was found to be more potent than the other agonists tested (the EC50 values were 3+/-0.3, 9+/-3, 7.8+/-0.9 and 217+/-37 nM for NKA, GR 64349, [betaAla8]NKA(4-10) and SP, respectively). MEN 10627 and MEN 11420 were potent and competitive antagonists in blocking NKA-induced IP3 formation and PGE2 release: MEN 10627 and MEN 11420 displayed comparable potencies in blocking the two functional responses initiated by occupancy of the NK2 receptor by NKA. Pretreatment of the cells with pertussis toxin (500 ng/ml for 18 h) did not significantly modify the basal or stimulated phosphatidylinositol turnover but reduced the basal and NKA-induced PGE2 release by about 35%. The phospholipase C inhibitor U-73122 (10 microM) prevented the NKA-induced formation of IP3 but did not affect PGE2 release. Conversely, the phospholipase A2 inhibitor quinacrine (100 microM) blocked the release of arachidonic acid and PGE2 without affecting the NKA-stimulated formation of IP3. Chelation of extracellular calcium with 3 mM EGTA inhibited the NKA-induced PGE2 release by 81% but was without effect on basal and NKA-stimulated IP3 production. The calcium channel blockers verapamil (10 microM) and omega-conotoxin GVIA (0.1 microM) did not modify the basal PGE2 production and had no significant effect on the response to tachykinins while the blocker of non-selective cation channels, SKF-96365 (10 microM), inhibited the response to NKA by about 74%. SKF-96365 did not affect the basal or the NKA-induced IP3 formation. In conclusion, our data demonstrate that the human tachykinin NK2 receptor expressed in CHO cells displays binding affinity and functional properties which are those of a native NK2 receptor. No pharmacological evidence for heterogeneity of the human NK2 receptor was obtained in this study. Our findings indicate that the human tachykinin NK2 receptor is independently coupled to both PLC and PLA2 signaling pathways. Activation of the PLA2 pathway may be linked to the opening of a voltage-independent cation channel which activates a Ca2+-dependent PLA2.
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PMID:Independent coupling of the human tachykinin NK2 receptor to phospholipases C and A2 in transfected Chinese hamster ovary cells. 982 60

Effects of different neuroactive substances on morphine-induced respiratory depression were studied in medullary respiration-related structures using in vitro brainstem-spinal cord preparation from 1 to 4-day-old rats. Application of morphine (10 microM) reduced respiratory rhythm (fR) as measured by C4 ventral root activity. The depressant effects of morphine were reversed by acetylcholine (10 microM), substance P (50 nM), thyrotropin releasing hormone (TRH) (100 nM) and forskolin (10 microM). The adenosine receptor antagonist, theophylline (100 microM), the dopamine receptors antagonist, haloperidol (10 microM), the cyclooxygenase inhibitor, indomethacin (10 microM) and the phospholipase A(2) inhibitor, quinacrine (10 microM) had no effect on morphine-induced respiratory depression.
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PMID:Effects of neuroactive substances on the morphine-induced respiratory depression; an in vitro study. 1108 3

Inflammatory mediators acting directly on nociceptive primary afferents induce neuropeptide release. In this study we investigated interactions between bradykinin, serotonin, histamine, prostaglandin and acid pH in stimulating the release of substance P (SP), calcitonin gene-related peptide (CGRP) and prostaglandin E(2) (PGE(2)) from isolated flaps of rat back skin using enzyme immunoassays. Stimulation with bradykinin (10(-5) M) augmented the release of SP, CGRP and PGE(2) significantly. Serotonin, histamine and PGE(2) individually tested (10(-5) M) had no effect on neuropeptide release but they facilitated the bradykinin-evoked neuropeptide release. When bradykinin was combined with both serotonin and histamine, neither additional PGE(2) nor acid pH showed any further effect, suggesting that the facilitation had reached a maximum. Exposure of the skin to acid pH (6.1 or 5.2) significantly increased CGRP release. SP release was only slightly enhanced and PGE(2) release, in contrast, was suppressed by low pH stimulation, probably due to pH-dependent inhibition of phospholipase A(2). Treatment of the rats with flurbiprofen (25 mg/kg i.p.) one hour before dissection reduced PGE(2) to detection level and inhibited the CGRP secretion evoked by the combination of bradykinin, serotonin and histamine (all 10(-6) M). As this suppression could not be overcome by substitution of PGE(2) (10(-6) M), it is likely that exogenously applied PGE(2) differs in effect from endogenous, intracellularly synthesized prostaglandins that are accompanied by active intermediates and byproducts.
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PMID:Interactions of inflammatory mediators stimulating release of calcitonin gene-related peptide, substance P and prostaglandin E(2) from isolated rat skin. 1116 34

Intrathecal phospholipase A2 (PLA2) and cyclooxygenase-2 (COX-2), but not COX-1, inhibitors attenuate facilitated pain states generated by peripheral injury/inflammation and by direct activation of spinal glutamate and substance P receptors. These results are consistent with the constitutive expression of PLA2 and COX-2 in spinal cord, the spinal release of prostaglandins by persistent afferent input, and the effects of prostaglandins on spinal excitability. Whereas the acute actions of COX-2 inhibitors are clearly mediated by constitutively expressed spinal COX-2, studies of spinal COX-2 expression indicate that it is upregulated by neural input and circulating cytokines. Given the intrathecal potency of COX-2 inhibitors, the comparable efficacy of intrathecal versus systemic COX-2 inhibitors in hyperalgesic states not associated with inflammation, and the onset of antihyperalgesic activity prior to COX-2 upregulation, it is argued that a principal antihyperalgesic mechanism of COX-2 inhibitors lies with modulation of constitutive COX-2 present at the spinal level.
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PMID:The spinal phospholipase-cyclooxygenase-prostanoid cascade in nociceptive processing. 1180 83

Intradermal injection of substance P elicits an itch sensation in human subjects and an itch-associated response in mice. The substance P-induced itch-associated response in mice is not inhibited by antihistamine. Therefore, the mechanisms of substance P-induced itch-associated response are unclear. In this study, we demonstrated one of the mechanisms. Substance P induces an arachidonate cascade to produce prostaglandins and leukotriene. In this study we considered whether arachidonate metabolites are involved in the substance P-induced itch-associated response. A phospholipase A(2) inhibitor arachidoryltrifluoromethyl ketone inhibited the substance P-induced itch-associated response in mice. Pre treatment with the glucocorticoids betamethasone and dexamethasone also produced inhibition of the substance P-induced itch-associated response in mice as well as humans. The 5-lipoxygenase inhibitor zileuton, but not the cyclooxygenase inhibitors indomethacin and diclofenac, suppressed substance P-induced itch-associated response. The leukotriene B(4) receptor antagonist 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]valeric acid produced inhibition, whereas pranlukast (leukotriene C(4)/D(4)/E(4) receptor antagonist) and 5(Z)-7-[1S,2S, 3S,5R-3-(trans-b-styren)sulfonamido-6,6-dimethylbi cyclo(3,1,1)hept-2-yl]-5-heptenoic acid (EP(1) receptor antagonist) were without effect. Furthermore, when the production of leukotriene B(4) and prostaglandin E(2) was measured in skin injected with substance P and in mouse keratinocytes applied with substance P, the level of both products increased. As leukotriene B(4), but not prostaglandin E(2), also induces the itch-associated response in mice, these results suggest that leukotriene B(4) and keratinocytes, cutaneous cells which produced leukotriene B(4), play an important role in substance P-induced itch-scratch response in mice. Leukotriene B(4) receptor antagonist and 5-lipoxygenase inhibitor may be novel antipruritic drugs.
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PMID:Involvement of leukotriene B(4) in substance P-induced itch-associated response in mice. 1188 31

We previously described that recombinant interleukin-1beta (IL-1beta) induced the significant release of substance P (SP) via a cyclooxygenase (COX) pathway in primary cultured rat dorsal root ganglion (DRG) cells. In the present study, we examined the involvement of two types of phospholipase A2 (PLA2) enzymes, which lie upstream of COX in the prostanoid-generating pathway, in the IL-1beta-induced release of SP from DRG cells. The expression of type IIA secretory PLA2 (sPLA2 -IIA) mRNA was undetectable by ribonuclease protection assay in non-treated DRG cells, while in DRG cells incubated with 1 ng/mL of IL-1beta, the expression was induced in a time-dependent manner. On the other hand, type IV cytosolic PLA2 (cPLA2 ) mRNA was constitutively expressed in the non-treated DRG cells, and treatment with 1 ng/mL of IL-1beta for 3 h significantly increased the levels of cPLA2 mRNA. The IL-1beta-induced SP release was significantly inhibited by the sPLA2 inhibitor, thioetheramide phosphorylcholine (TEA-PC), and the cPLA2 inhibitor, arachidonyl trifluoromethyl ketone (AACOCF3 ). Furthermore AACOCF3 suppressed the induction of sPLA2 -IIA mRNA expression induced by IL-1beta. These observations suggested that two types of PLA2, sPLA2 -IIA and cPLA2, were involved in the IL-1beta-induced release of SP from DRG cells, and that the functional cross-talk between the two enzymes might help to control their activity in the prostanoid-generating system in DRG cells. These events might be key steps in the inflammation-induced hyperactivity in primary afferent neurons of spinal cord.
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PMID:Interleukin-1beta-induced substance P release from rat cultured primary afferent neurons driven by two phospholipase A2 enzymes: secretory type IIA and cytosolic type IV. 1195 49

We compared the mechanisms of vasorelaxation of acetylcholine and of substance P with reference to K(+) channels, and analyzed pharmacologically the nature of endothelium-derived substance(s) other than NO and prostanoids in monkey and dog coronary arteries. Coronary arteries were isolated from monkeys and dogs, and the isometric tension of the artery strips was measured. In canine coronary artery strips treated with indomethacin plus N(G)-nitro- L-arginine ( L-NA) and partially contracted with prostaglandin F(2alpha), acetylcholine induced concentration-related relaxation, which was abolished by removal of the endothelium. The relaxation was markedly suppressed but not abolished in the strips exposed to high K(+) media. Charybdotoxin plus apamin potently inhibited the relaxation to the similar extent to that by high K(+) media, whereas glibenclamide or iberiotoxin had no effect. The relaxation was markedly inhibited by quinacrine, a phospholipase A(2) inhibitor, and ketoconazole, a selective cytochrome P450 (CYP) 3A inhibitor, but not by sulfaphenazole, a selective CYP 2C inhibitor. In contrast to acetylcholine, endothelium-dependent and indomethacin-plus- L-NA-resistant relaxation induced by substance P was not inhibited by high K(+) media, charybdotoxin plus apamin, or ketoconazole. Quinacrine and AA861, a 5-lipoxygenase inhibitor, inhibited the relaxation induced by substance P. In monkey coronary artery, acetylcholine-induced relaxation resistant to indomethacin plus L-NA was abolished by endothelial denudation and by treatment with high K(+) media, charybdotoxin plus apamin, progesterone and ketoconazole, but was not affected by iberiotoxin or sulfaphenazole. Substance P did not relax monkey coronary arteries. It is concluded that endothelium-dependent, nitric oxide- and prostanoid-independent relaxation induced by acetylcholine in monkey and dog coronary arteries are mediated by charybdotoxin plus apamin-sensitive but iberiotoxin-insensitive Ca(2+)-activated K(+) channel opening substance(s), which may be CYP3A-derived arachidonic acid metabolite(s). Contrasting to the response to acetylcholine, endothelium-dependent, indomethacin-plus- L-NA-resistant relaxation induced by substance P in dog coronary artery is not associated with K(+) channel opening, and may be mediated by 5-lipoxygenase product(s).
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PMID:Mechanisms underlying endothelium-dependent, nitric oxide- and prostanoid-independent relaxation in monkey and dog coronary arteries. 1238 80


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