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)

In anaesthetized, mechanically ventilated guinea-pigs, substance P induces a bronchoconstrictor response comprising increases in airway resistance and decreases in dynamic compliance. Eicosatetraynoic acid (ETYA, 20 mg kg-1 i.v.) or BW755c (20 mg kg-1 i.v.) potentiated the substance P-induced bronchoconstriction. Neither indomethacin (1 or 5 mg kg-1 i.v.) nor aspirin (20 mg kg-1 i.v.) significantly altered the potency of substance P on bronchomotor responses. These observations are consistent with the existence of a bronchodilator lipoxygenase metabolite(s).
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PMID:Modulation of substance P-induced bronchoconstriction by lipoxygenase metabolites. 241 May 86

Substance P (0.5-8.0 micrograms/kg, i.v.) induced bronchoconstriction in anaesthetized, mechanically-ventilated guinea-pigs, comprising increases in airways resistance and decreases in dynamic compliance. These bronchoconstrictor responses were unaffected by bilateral vagotomy, pretreatment with pheniramine (2 mg/kg, i.v.) or by pretreatment with atropine (100 micrograms/kg, i.v.). Acetylcholine-induced (4-32 micrograms/kg, i.v.) bronchoconstriction was prevented by atropine pretreatment, whereas bilateral vagotomy inhibited responses to acetylcholine. Ganglionic blockade using hexamethonium (20 mg/kg, i.v.) potentiated both substance P and acetylcholine on airways resistance and dynamic compliance. Indomethacin (1 or 5 mg/kg, i.v.) did not affect substance P-induced bronchoconstriction, whereas the higher dose enhanced acetylcholine-induced increases in airways resistance. In addition, aspirin pretreatment (20 mg/kg, i.v.) did not alter the bronchoconstrictor potency for either substance P or acetylcholine. On the other hand, the combined cyclo-oxygenase/lipoxygenase inhibitors eicosatetraynoic acid (ETYA, 20 mg/kg, i.v.) and BW755C (20 mg/kg, i.v.) potentiated both acetylcholine and substance P on airways resistance and dynamic compliance. The results suggest that substance P-induced bronchoconstriction may be modulated by the sympathetic nervous system and does not appear to be influenced by vagal or histaminergic mechanisms. The failure of indomethacin or aspirin to affect substance P-induced bronchoconstriction, together with the enhancing effects of ETYA and BW755C pretreatments, provide evidence consistent with the existence of a bronchodilator mechanism which may be inhibited by compounds inhibiting lipoxygenase enzymes.
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PMID:Characterization of substance P-induced bronchoconstriction in the guinea-pig: a comparison with acetylcholine. 242 49

Addition of substance P (10(-7) to 10(-6) M) to rabbit iris sphincter muscle induced: (a) a rapid phosphodiesteratic breakdown of phosphatidylinositol 4,5-bisphosphate (PIP2) into 1,2-diacylglycerol (DG), measured as phosphatidic acid, and inositol triphosphate (IP3), measured by anion-exchange chromatography; (b) a rapid and strong contractile response, and (c) a rapid release of prostaglandin E2 (PGE2), measured by radioimmunoassay, and rapid release of 14C-labeled arachidonic acid, measured by radiochromatography. These substance P actions are concentration and time-dependent, and are blocked by substance P antagonist, [D-Pro2, D-Trp7,9]SP. The effects of substance P on arachidonic acid release and PG synthesis are not mediated through the cyclo-oxygenase and lipoxygenase pathways. Substance P exerted little effect on PGE2 release by the iris dilator muscle. We conclude that substance P, which is liberated from the sensory nerves that innervate the sphincter region of the iris and plays a role in miosis, may function as a Ca2+-mobilizing agonist in this tissue. Thus, a substance P-induced release of IP3 and formation of DG, a source for arachidonic acid in PG synthesis, followed by Ca2+ mobilization could underlie the mechanism for the biological actions, such as muscle contraction, of the neuropeptide reported in the eye. However, the precise relationship remains to be established.
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PMID:Effects of substance P on inositol triphosphate accumulation, on contractile responses and on arachidonic acid release and prostaglandin biosynthesis in rabbit iris sphincter muscle. 242 50

Guinea pigs were inoculated by nasal insufflation with parainfluenza 3 (P-3) or virus growth medium 4 days before performing in vitro pharmacologic studies on left bronchial ring segments. Cumulative dose-response studies with capsaicin revealed an enhanced contractile response after P-3 infection. The sensitivity and magnitude of contractile effects of substance P in the left bronchi were also enhanced by P-3 infection. After pretreatment of the isolated tissues with phenoxybenzamine to block histamine H1 (with metiamide to block histamine H2), muscarinic, serotonergic, and alpha adrenergic receptors, or indomethacin to block the cyclooxygenase pathway of arachidonic acid metabolism, P-3 remained effective in enhancing contractile responses, even though these pretreatments altered the sensitivity and/or magnitude of contractions produced by substance P. When ETYA or NDGA were combined with indomethacin to also block the lipoxygenase pathway of arachidonic acid metabolism, the sensitizing effect of P-3 infection was diminished or abolished, especially at larger concentrations of substance P. With combination of FPL55712 and indomethacin, the sensitizing effect of P-3 was not abolished. Contractile responses to LTC4 and LTD4 were not enhanced by P-3 infection. The data suggest a selective influence of P-3 infection on the substance P system and provide evidence for a role of the lipoxygenase pathway of arachidonic acid metabolism in the sensitizing action. Peptide leukotrienes do not appear to be the lipoxygenase products involved in this effect of virus.
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PMID:Enhancement by parainfluenza 3 infection of contractile responses to substance P and capsaicin in airway smooth muscle from the guinea pig. 244 48

In the presence of the neutral metalloendopeptidase inhibitor, phosphoramidon, substance P (SP) is a highly potent spasmogen for isolated lung parenchymal strips as well as tracheal rings from the guinea pig. We studied the mechanism of action of this peptide, and of the related tachykinin, substance K (SK), on both tissue preparations. The cyclooxygenase inhibitors, indomethacin (1 microM) or aspirin (100 microM), in combination with phosphoramidon (1 microM) effectively block SP-induced contractions in lung parenchymal strips. The lipoxygenase inhibitor, nordihydroguaiaretic acid (10 microM), the H1 antihistamine, pyrilamine (1 microM) and the anticholinergic agent, atropine (1 microM), all had no significant effect on SP-induced contractions. No detectable levels of thromboxane B2, or prostaglandins D2, E2, F2 alpha, or 6-keto-F1 alpha were released into the tissue bathing fluid. These data suggest that the contractile response of guinea pig lung parenchymal strips is mediated by cyclooxygenase metabolites, which are not released in significant concentration from the cells. In the presence of phosphoramidon, SK has a concentration-response curve similar to SP on guinea pig lung parenchymal strips. Its contractile activity is also inhibited by indomethacin but less effectively than SP. In marked contrast, the contractile responses of guinea pig tracheal tissues to the tachykinins were not affected significantly by indomethacin, alone or in combination with phosphoramidon. Additionally, tracheal tissue is 20- to 100-fold more sensitive to SK than SP in the presence or absence, respectively, of the endopeptidase inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of substance P contractile activity on isolated guinea pig lung tissues. 244 71

The role of endothelium on the responses of the perfused rabbit renal artery segments to vasoconstrictor and vasodilator agents was studied. The vasoconstrictor responses of rabbit renal arteries to phenylephrine were enhanced by endothelium destruction. Acetylcholine (ACh), calcium-ionophore (A23187) and substance P (SP), in the presence of indomethacin, induced endothelium-dependent vasodilation of the phenylephrine-constricted renal arteries. Nordihydroguaiaretic acid (NDGA), an inhibitor of lipoxygenase, significantly reduced the dilator responses to ACh, A23187 and SP, but did not reduce the responses to sodium nitrite. In conclusion, our results provide evidence for the involvement of lipoxygenase products in the endothelium-dependent vasodilation of rabbit renal arteries to ACh, A23184 and SP.
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PMID:Endothelium-dependent vasodilator actions of acetylcholine, calcium-ionophore (A23187) and substance P in perfused renal arteries from rabbits. 245 9

Acetylcholine and substance P applied to the donor tissue, dog femoral artery segments with endothelium, produced moderate relaxations of the assay tissue, endothelium-denuded dog coronary artery strips. The relaxation was attenuated markedly by treatment of the assay tissue with hydroquinone and abolished by oxyhemoglobin or methylene blue. In this bioassay system, the effect of AA861 and TMK777, new 5-lipoxygenase inhibitors, was evaluated. When the donor tissue was treated with AA861 or TMK777, the responses to acetylcholine and substance P were attenuated moderately, whereas the relaxation by nitroglycerin was not influenced by AA861. However, the inhibitors when infused just below the donor tissue did not attenuate relaxant responses to acetylcholine and substance P. Application of superoxide dismutase (SOD) to the donor tissue caused a relaxation of the assay tissue, and potentiated the relaxation by acetylcholine and substance P. AA861 and TMK777 suppressed the relaxant responses to acetylcholine and substance P, respectively, in the presence and absence of SOD to a similar extent and abolished the SOD-induced relaxation. Pyrogallol abolished the relaxation by acetylcholine, but did not inhibit the response when the donor tissue was pretreated with SOD. Therefore, it appears that AA861 and TMK777 do not degrade endothelium-derived relaxing factor (EDRF) in the perfusate via generation of superoxide anion or block the action of EDRF on vascular smooth muscle, but interfere with the synthesis and/or release of EDRF. The findings obtained so far support the idea that lipoxygenase products participate in the generation of EDRF.
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PMID:Possible involvement of 5-lipoxygenase products in the generation of endothelium-derived relaxing factor. 247 45

Footpad injection of endotoxin causes exclusive ocular inflammation in the rat. In order to clarify its physiopathologic mechanism, we studied the effect of different treatments on endotoxin-induced uveitis (EIU). Salmonella endotoxin was injected into the footpads of Lewis rats. 18 hr later, inflammation was assessed by evaluating proteins and cells in the anterior chamber; arachidonic acid (AA) metabolites, prostaglandin E2 and leukotriene B4, as well as substance P were measured by radioimmunoassay, and Ia-(MHC class II)-antigen expression in ciliary body was assessed by immunohistochemistry. The effect of inhibitors of phospholipase A2 (EPC), of lipoxygenase (azelastine) and of cyclo-oxygenase (diclofenac), as well as dexamethasone, cyclosporine (CsA) and anti-Ia antibody, were evaluated on these parameters. Phospholipase A2 inhibitor EPC and dexamethasone were most effective on inflammation: they also reduced AA metabolites very effectively and prevented Ia-expression. Lipoxygenase and cyclo-oxygenase inhibitors were partially effective on inflammation and on AA metabolites but failed to prevent Ia-expression. Immunosuppressive treatments (CsA and anti-Ia-antibody) also reduced inflammation. Our findings suggest that inflammation mediators initiate inflammation in EIU. Ia-Ag-expression is secondarily produced by mediators leading to additional inflammation due to immune mediated mechanisms.
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PMID:Immunopharmacological analysis of endotoxin-induced uveitis in the rat. 254 43

5-Hydroxytryptamine (5-HT, serotonin) stimulates phosphoinositide hydrolysis in choroid plexus by interacting with the 5-HTlc site. In the present study, the effects of 5-HT were compared with those of other agonists. 5-HT stimulates a rapid release of all three inositol sugars in a mianserin-sensitive manner. Inositol bisphosphate and inositol trisphosphate levels increase about twofold within 2.5 min, whereas inositol monophosphate levels are not appreciably elevated until 5 min. In contrast, glutamate, carbachol, histamine, substance P, and vasopressin, agents that increase phosphoinositide hydrolysis in other tissues, do not stimulate this response in choroid plexus. High concentrations of norepinephrine increase inositol phosphate release in choroid plexus, but this effect is apparently mediated by activation of the 5-HTlc site. The depolarizing agents KCl and veratrine also fail to stimulate phosphoinositide hydrolysis in choroid plexus. These results, combined with the finding that the phosphoinositide response to 5-HT is insensitive to tetrodotoxin, suggest that the effects of 5-HT are not secondary to neurotransmitter release. Furthermore, an indirect effect mediated via arachidonic acid metabolism is unlikely, since inhibitors of cyclooxygenase and lipoxygenase do not reduce the 5-HT response. We conclude, therefore, that phosphoinositide hydrolysis is the transducing mechanism of the 5-HT 5-HTlc receptor and that the choroid plexus will serve as a useful model system for studies of this receptor.
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PMID:Agonist-induced phosphoinositide hydrolysis in choroid plexus. 302 3

Ferret tracheal segments were infected with human influenza virus A/Taiwan/86 (H1N1) in vitro. After 4 days, the smooth muscle contractile responses to acetylcholine and to substance P were measured. The response to substance P was markedly accentuated, with a threefold increase in force of contraction at a substance P concentration of 10(-5) M, the highest concentration tested. In contrast, the response to acetylcholine was not affected by viral infection. Histological examination of tissues revealed extensive epithelial desquamation. Activity of enkephalinase (neutral metallo-endopeptidase, EC.3.4.24.11), an enzyme that degrades substance P, was decreased by 50% in infected tissues. Inhibiting enkephalinase activity by pretreating with thiorphan (10(-5) M) increased the response to substance P to the same final level in both infected and control tissues. Inhibiting other substance P-degrading enzymes including kininase II (angiotensin-converting enzyme), serine proteases, and aminopeptidases did not affect the response to substance P. Inhibiting cyclooxygenase and lipoxygenase activity using indomethacin and BW 755c did not affect hyperresponsiveness to substance P. Pretreating tissues with antagonists of alpha-adrenoceptors, beta-adrenoceptors, and H1 histamine receptors (phentolamine 10(-5) M, propranolol 5 X 10(-6) M, and pyrilamine 10(-5) M, respectively) had no effect on substance P-induced contraction. These results demonstrate that infection of ferret airway tissues with influenza virus increases the contractile response of airway smooth muscle to substance P. This effect is caused by decreased enkephalinase activity in infected tissues.
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PMID:Influenza infection causes airway hyperresponsiveness by decreasing enkephalinase. 304 36


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