UNIPROT:P20366 - FACTA Search

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)

Endothelium-dependent relaxation of blood vessels is produced by a large number of agents (e.g., acetylcholine, ATP and ADP, substance P, bradykinin, histamine, thrombin, serotonin). With some agents, relaxation may be limited to certain species and/or blood vessels. Relaxation results from release of a very labile non-prostanoid endothelium-derived relaxing factor (EDRF) or factors. EDRF stimulates guanylate cyclase of the vascular smooth muscle, with the resulting increase in cyclic GMP activating relaxation. EDRF is rapidly inactivated by hemoglobin and superoxide. There is strong evidence that EDRF from many blood vessels and from cultured endothelial cells is nitric oxide (NO) and that its precursor is L-arginine. There is evidence for other relaxing factors, including an endothelium-derived hyperpolarizing factor in some vessels. Flow-induced shear stress also stimulates EDRF release. Endothelium-dependent relaxation occurs in resistance vessels as well as in larger arteries, and is generally more pronounced in arteries than veins. EDRF also inhibits platelet aggregation and adhesion to the blood vessel wall. Endothelium-derived contracting factors appear to be responsible for endothelium-dependent contractions produced by arachidonic acid and hypoxia in isolated systemic vessels and by certain agents and by rapid stretch in isolated cerebral vessels. In all such experiments, the endothelium-derived contracting factor appears to be some product or by-product of cyclooxygenase activity. Recently, endothelial cells in culture have been found to synthesize a peptide, endothelin, which is an extremely potent vasoconstrictor. The possible physiological roles and pathophysiological significance of endothelium-derived relaxing and contracting factors are briefly discussed.
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PMID:Endothelium-derived relaxing and contracting factors. 254 95

The vasoactive properties of substance P (SP) were studied in isolated rabbit pulmonary artery (PA) segments in vitro. In the absence of active base-line tone, noncumulative administration of SP (10(-11) to 10(-4) M) produced dose-dependent increases in PA tension. The peak isometric tension (Tmax) with SP was similar to the Tmax response to epinephrine; however, the doses of the agonist producing a threshold contraction and 25% of Tmax (ED25) were significantly lower for SP. In the presence of active base-line tone, induced by epinephrine or 5-hydroxytryptamine, SP produced transient PA relaxation which was directly related to the magnitude of the precontracted PA tension. Blockade of neurotransmission with tetrodotoxin (1 microgram/ml) and antagonists to alpha 1-adrenergic and histamine receptor binding had no effect on the contractile response to SP. On the other hand, PA contraction to an ED50 dose of SP was 1) inhibited by a mean of 33 +/- 10% (SE) following pretreatment with the cholinesterase inhibitor, neostigmine (10(-6) M) and 2) augmented by 52 +/- 21% with the cholinergic antagonist, atropine (10(-4) M). The latter also completely blocked the relaxation response to SP in precontracted PA. Similarly, removal of the PA endothelium also abolished the relaxation response to SP. In contrast, SP-induced contraction was markedly inhibited by the cyclooxygenase inhibitor, meclofenamate (1 microgram/ml), as well as the SP antagonist, D-Pro2, D-Trp7,9-SP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vasoactive effects of substance P on isolated rabbit pulmonary artery. 258 Aug 23

A large number and variety of compounds (acetylcholine, adenosine diphosphate, adenosine triphosphate, arachidonic acid, bradykinin, Ca2+ ionophores, calcitonin gene-related peptide, histamine, hydralazine, substance P, thrombin, and vasoactive intestinal polypeptide) have been shown to relax arterial smooth muscle indirectly. The endothelium in muscular arteries from several species appears to have receptors for these vasodilators. Binding of one of these compounds to its endothelial receptors results in the release (and presumably synthesis) of substance(s) that act on arterial smooth muscle to cause relaxation. The name endothelium-derived relaxing factor (EDRF) has been proposed for the substance or substances responsible for inhibition of contraction. Studies to determine additivity of endothelium-dependent relaxing agents and sensitivity of EDRF-mediated responses to a variety of inhibitors suggest that a single factor or a single common mechanism induces relaxation of vascular smooth muscle. Pharmacological studies have been equivocal with regard to the postulated involvement of phospholipases or arachidonic acid and to the suggestion that EDRF is an oxidative, non-cyclooxygenase product of arachidonate. Experiments on transfer of EDRF and reversal of endothelium-dependent relaxation consistently indicate that EDRF is quite labile. There is convincing evidence that EDRF activates smooth muscle guanylate cyclase, which results in an increase in intracellular cyclic guanosine 3',5'-monophosphate levels. The stimulation of guanylate cyclase by EDRF provides a valuable and sensitive parameter for studies with arteries as well as cells in culture. At present, the identity of EDRF and its role in cardiovascular homeostasis are unknown.
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PMID:Endothelium-derived vascular relaxing factor. 298 29

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

Three major lines of evidence support a role of eicosanoids and PAF in shock. Formation of each of the cyclooxygenase metabolites of arachidonate is enhanced at some point during the shock; these metabolites include PGE2, PGF2 alpha, PGI2, and TXA2. Enhanced formation of 5-HETE and the cysteinyl-LTs provides evidence for activation of the 5-lipoxygenase pathway of arachidonate metabolism, and preliminary biochemical evidence suggests that formation of PAF in anaphylactic and endotoxic shock is also enhanced. Second, TXA2, cysteinyl-leukotrienes, and, to an even greater extent, PAF are able to produce shock and death in intact animals. Third, pharmacological studies show that selective antagonists or synthesis inhibitors modify the course of the shock. While any of these lines of evidence may not by itself provide proof for a cause-effect relationship, the data taken together strongly suggest that vasoactive lipids might be involved in fundamental processes in the pathophysiology of shock. However, the role of vasoactive lipids might vary in different shock paradigms, change at various time points during the evolution of the shock, and depend on the species studied. Moreover, while the majority of the reports tend to focus on a specific substance, the metabolism of all of the eicosanoids mentioned, as well as PAF and probably other arachidonate metabolites (e.g. 15-lipoxygenase products such as lipoxins), changes during shock states. This fact probably causes most of the discrepancies in studies using specific antagonists or synthesis inhibitors to modify the state of shock. Thus, while blockade of one mediator might provide some protection, it might not be sufficient to halt or reverse the main course of the pathophysiological process. For example, the increase in vascular permeability, a fundamental phenomenon in trauma, anaphylaxis, or endotoxemia, might be mediated by PAF, LTs, PGs, peptides (e.g. kinins, substance P, CGRP) and amines (e.g. histamine in some species). Attempting to reverse such a complex phenomenon by blocking one specific factor might not be productive unless the specific substance played a key role in generation of the other factors. It seems, however, that while interactions between PGs, LTs, and PAF do occur (31, 32, 70), none of the shock states are crucially dependent on one class of the vasoactive lipids. Therefore, the therapeutic strategy should be based on multiple sites of action, either by drug combinations or multiple actions of a specific drug.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Prostaglandins, leukotrienes, and platelet-activating factor in shock. 303 39

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

Formylmethionylleucylphenylalanine (FMLP) is a synthetic analogue of bacterial chemotactic factors. We studied the contraction of human airway tissue in vitro by FMLP. FMLP induced a concentration-dependent contraction of all bronchial spiral strips studied (n = 45). The maximum tension generated in response to FMLP was 86.6 +/- 7.0% (SE) of the maximum response to histamine. The contraction was not reduced by the histamine H1-receptor antagonist pyrilamine, the cyclooxygenase and lipoxygenase inhibitors indomethacin and BW755C, the muscarinic antagonist atropine, or capsaicin which depletes stores of substance P. The concentration-response curve was shifted to the right by the polypeptide antagonist N-t-BOC-phenylalanylleucylphenylalanylleucylphenylalanine and the leukotriene antagonist FPL 55712. When 2 successive FMLP concentration-response curves were performed the maximum response was significantly reduced from 114.8 +/- 9.1% of the histamine maximum to 39.3 +/- 6.1%. The contraction of human airways in vitro by an agent that is structurally and functionally similar to chemotactic peptides released from bacteria may have important implications in airway disease.
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PMID:Formyl peptide-induced contraction of human airways in vitro. 394 25

Bradykinin (Bk) induced a contraction in all small bronchi samples (diameter, 0.5 to 1 mm) from 20 patients. pD2 was 7.7 +/- 0.1 (pD2 = -log EC50) and maximal effect (Emax) was 36.2 +/- 4.7% of the maximal response to acetylcholine. The B2 agonist [Hyp3TyrMe8]Bk contracted airway smooth muscle with a pD2 of 7.8 +/- 0.2 and an Emax of 39 +/- 9%. The B1 agonist [Sar1dPhe8desArg9]Bk induced only a weak contraction at 10(-6) M. The effect of Bk was abolished by the B2 (Hoe 140) but not by the B1 [Leu8desArg9]Bk receptor antagonist. Indomethacin 10(-6) M abolished Bk-induced contraction, suggesting that cyclooxygenase products are involved in Bk action. Capsaicin 10(-5) M, which selectively depletes C fibers from airway mediators through the ruthenium red pathway, and ruthenium red 10(-5) M significantly inhibited the concentration-response curves to Bk. However, tetrodotoxin (+/-)-CP-96,345, SR 48968, and atropine did not significantly affect Bk concentration-response curves, suggesting that nerve conduction, substance P (SP), neurokinin A (NKA), and acetylcholine release are not involved in Bk action. Our data indicate that Bk contracts human distal airway smooth muscle through the Bk B2 receptor and a cyclooxygenase pathway. This effect appears to involve capsaicin and ruthenium red pathways but neither acetylcholine nor NKA and SP release.
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PMID:Contractile effects of bradykinin on the isolated human small bronchus. 750 45

We examined the mechanisms of bradykinin-induced airway microvascular leakage in guinea pig airways by measuring extravasation of Evans blue dye. Animals were pretreated with propranolol (1 mg/kg, intravenous) and atropine (1 mg/kg, intravenous) to block the beta-adrenergic and muscarinic responses, respectively. Bradykinin (250 nmol) instillation into airways significantly increased the leakage of dye in the trachea, main bronchi, and intrapulmonary airways to the same degree. The bradykinin B2-receptor antagonist HOE140 (500 nmol/kg, intravenous) did not alter basal leakage but almost completely inhibited bradykinin-mediated leakage. By contrast, the neurokinin NK1 antagonist FK888 (10 mg/kg, intravenous) partially inhibited bradykinin-induced leakage in trachea (p < 0.01) and main bronchi (p < 0.01), but had no significant effect on intrapulmonary airways. Indomethacin (5 mg/kg, intravenous) had no effect on the plasma leakage after instilled bradykinin. We concluded that the airway inflammatory response to bradykinin administered directly into the airways is mediated by bradykinin B2 receptors and partially mediated by tachykinin release from sensory nerve terminals, whereas cyclooxygenase products have no important role in the response. In the central airways, the contribution of sensory neuropeptides to the bradykinin response is greater than that caused by direct stimulation of the B2 receptor on the endothelium at the postcapillary venule of the bronchial circulation. In contrast, in the peripheral airways, the contribution of direct B2-receptor stimulation on the airway vasculature is greater than that involving sensory neuropeptides.
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PMID:Bradykinin-induced airway inflammation. Contribution of sensory neuropeptides differs according to airway site. 750 4

Substance P is involved in the modulation of arthritic pain, and more recently it has been suggested that substance P might be involved also in the immunological aspects of arthritic diseases. Substance P is present in the synovial fluid of arthritic patients, where it can induce the chemotaxis of polymorphonuclear cells (PMN) and monocytes, and the synthesis of cytokines. We thought it worthwhile to investigate the effect of non steroidal anti-inflammatory drugs (NSAIDs) on the chemotactic effect of substance P on PMN and monocytes. We evaluated the effects of NSAIDs on the chemotactic effect of two concentrations of substance P that are well within those reached by the neuropeptide in arthritic diseases. The different NSAIDs inhibit the chemotactic response of PMN with different patterns, while the effect on the chemotaxis of monocytes is much weaker. The data we present suggest that the effect of NSAIDs on the development and progress of arthritic disease could involve their capacity of blocking the chemotactic activity of substance P, and with mechanism interfere with the self-feeding pathological circle of substance P. It remains to be determined whether the effect is mediated by the block of cyclooxygenase or other less specific effects of NSAIDs on PMN and monocyte membranes.
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PMID:Inhibitory effect of NSAIDs on the chemotaxis induced by substance P on human monocytes and polymorphonuclear cells. 751 9

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