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)

Using a perfused rat hindleg system, release of tissue-type plasminogen activator (t-PA) from endothelial cells could be induced by platelet-activating factor (PAF), bradykinin, substance P, thrombin, carbachol and A23187, while this release was inhibited by mepacrine and by nor-dihydroguaiaretic acid. The PAF-induced release of t-PA was inhibited by the cytochrome P-450 mono-oxygenase inhibitors, metyrapone, ketoconazole and SKF 525A and by eicosatetraynoic acid but not by indomethacin or BW 755C, suggesting the involvement of epoxygenase products. The PAF-induced release of von Willebrand factor (vWF) was also similarly inhibited by the cytochrome P-450 monooxygenase inhibitor, ketoconazole. Phorbol ester and phospholipase C induced the release of both t-PA and vWF, while phospholipase A2 did not. The release induced by PAF and bradykinin was not influenced by pretreatment with pertussis toxin.
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PMID:The involvement of products of the phospholipase pathway in the acute release of tissue-type plasminogen activator from perfused rat hindlegs. 152 62

The pronounced synovial hyperplasia often found in the joints of patients with rheumatoid arthritis could be explained partially by the action of monocyte-macrophage polypeptides (monokines). This report demonstrates that two cytokines which may be derived from monocyte-macrophage populations, namely platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), stimulate the DNA synthesis and proliferation of human synovial fibroblast-like cells cultured in low (i.e., 1%) fetal bovine serum. Epidermal growth factor, insulin-like growth factor-I, insulin-like growth factor-II (multiplication stimulating activity) and substance P were inactive. Unlike IL-1, PDGF and FGF do not also stimulate PGE2, plasminogen activator, and hyaluronic acid levels. Thus PDGF and FGF, arising from stimulated monocyte-macrophages, may play a role in the stimulation of mesenchymal cell proliferation that often accompanies chronic inflammatory arthritic disease. The synovial cells respond to a variety of cytokines in different ways suggesting multiple-signaling pathways.
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PMID:Stimulation of human synovial fibroblast DNA synthesis by platelet-derived growth factor and fibroblast growth factor. Differences to the activation by IL-1. 270 21

Tissue segments isolated from ligament, epiligament, and synovial tissues from mature female New Zealand White Rabbits were demonstrated to constitutively secrete a plasminogen activator. Several tissues were also observed to constitutively secrete a plasminogen activator inhibitor which was detected in the form of a PA-PAI complex. Heterogeneity was observed in PA and PAI activity between the different connective tissues. Heterogeneity also existed between and within the medial collateral (MCL), lateral collateral (LCL), and the anterior cruciate (ACL) ligaments. In addition to the differences in constitutive expression of PA and PAI activity, differences in the responsiveness to the neuropeptide substance P (10(-5)-10(-9) M) were also detected. This responsiveness to substance P was displayed by an increase in PA and PAI activity in the conditioned medium. The pattern of responsiveness reflected the degree of innervation of these tissues. That is, synovium and epiligament tissue were the most responsive tissues to substance P while the MCL, LCL and ACL were less responsive to the neuropeptide. Parallel results were obtained using cell culture with fibroblasts isolated from the above mentioned tissues. That is, the pattern of responsiveness was similar between cells and tissue segments. More specifically, cells isolated from both synovium and epiligament increased their both their PA (slightly) and PAI activity following exposure to substance P. This was demonstrated at both the protein and RNA level. Thus, cells within a tissue maintain their phenotype when removed from their three-dimensional matrix. These results are unique in demonstrating that normal ligament and synovial cells and tissue respond to substance P by altering the expression of PA and PAI activity. This investigation further supports the concept that innervation may be important in normal connective tissue function.
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PMID:Plasminogen activators and plasminogen activator inhibitors in connective tissues and connective tissue cells: influence of the neuropeptide substance P on expression. 768 42

The effects on blood flow and plasma fibrinolytic and coagulation parameters of intraarterial substance P, an endothelium dependent vasodilator, and sodium nitroprusside, a control endothelium independent vasodilator, were studied in the human forearm circulation. At subsystemic locally active doses, both substance P (2-8 pmol/min) and sodium nitroprusside (2-8 microg/min) caused dose-dependent vasodilatation (p <0.001 for both) without affecting plasma concentrations of PAI-1, von Willebrand factor antigen or factor VIII:C activity. Substance P caused local increases in t-PA antigen and activity (p <0.001) in the infused arm while sodium nitroprusside did not. At higher doses, substance P increased blood flow and t-PA concentrations in the noninfused arm. We conclude that brief, locally active and subsystemic infusions of intraarterial substance P cause a rapid and substantial local release of t-PA which appear to act via a flow and nitric oxide independent mechanism. This model should provide a useful and selective method of assessing the in vivo capacity of the forearm endothelium to release t-PA acutely.
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PMID:An in vivo model for the assessment of acute fibrinolytic capacity of the endothelium. 936 92

Intra-arterial desmopressin caused dose and time dependent increases (p <0.001 for all) in forearm blood flow (all doses) and plasma tissue plasminogen activator (t-PA) concentrations (desmopressin > or = 70 ng/min). Although plasma t-PA concentrations rose in both forearms, there was a modest local release of t-PA in the infused forearm (14 ng/100 mL of tissue/min, p <0.05). At desmopressin doses > or = 300 ng/min, plasma von Willebrand factor (vWf) and Factor VIII:C concentrations rose in both forearms (p <0.001) and correlated with the rise in interleukin-6 concentrations (r = 0.92, p <0.001: r = 0.85, p = 0.002 respectively). Neither desmopressin nor substance P caused t-PA, vWf or Factor VIII:C release in the patients, although desmopressin increased plasma interleukin-6 concentrations as in healthy volunteers. We conclude that desmopressin releases t-PA, vWf and Factor VIII:C predominantly via systemic mechanisms, possibly mediated by cytokine release. Patients with type 3 vWD appear to have a generalised failure to release t-PA acutely despite a normal interleukin-6 response to desmopressin infusion.
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PMID:Local and systemic effects of intra-arterial desmopressin in healthy volunteers and patients with type 3 von Willebrand disease. Role of interleukin-6. 1095 89

We assessed forearm blood flow and plasma fibrinolytic factors in eight healthy males who received unilateral brachial artery infusions of the endothelium-dependent vasodilator, substance P, and the endothelium-independent vasodilator, sodium nitroprusside. These measurements, together with platelet aggregation studies, were performed on four occasions after double-blind randomized ingestion of placebo, methionine (0.1 mg/kg), vitamin C (2 g) and methionine plus vitamin C. Blood flow and platelet aggregation responses were unaffected by methionine loading. Substance P caused dose-dependent increases in plasma tissue plasminogen activator (t-PA) antigen (from 3.0+/-0.1 to 4.7+/-0.4 ng/ml; P<0.001) and activity (from 1.2+/-0.2 to 4.2+/-0.4 i.u./ml; P<0.001), which were augmented during acute methionine loading (4.7+/-0.4 to 5.6+/-0.5 ng/ml and 4.2+/-0.4 to 5.5+/-0.9 i.u./ml respectively; P</=0.05). Moreover, the estimated net release of t-PA was enhanced during methionine loading (two-way ANOVA; P=0.02), but this was unaffected by vitamin C supplementation. We conclude that, in the absence of alterations in endothelium-dependent vasomotion or platelet aggregation, substance P-induced t-PA release is enhanced following methionine loading. This suggests that the acute endogenous fibrinolytic capacity is augmented during acute hyperhomocysteinaemia in healthy humans via an oxidation-independent mechanism.
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PMID:Effects of acute methionine loading and vitamin C on endogenous fibrinolysis, endothelium-dependent vasomotion and platelet aggregation. 1117 Dec 80

The ability of the phospholipases A(2) (PLA(2)s) from Crotalus durissus cascavella, Crotalus durissus collilineatus and Crotalus durissus terrificus venoms and crotapotin to increase the vascular permeability in the rat skin as well as the contribution of both mast cells and sensory C-fibers have been investigated in this study. Vascular permeability was measured as the plasma extravascular accumulation at skin sites of intravenously injected 125I-human serum albumin. Intradermal injection of crotalic PLA(2)s (0.05-0.5 microg/site) in the rat skin resulted in dose-dependent increase in plasma extravascular whereas crotapotin (1 microg/site) failed to affect this response. Co-injection of crotapotin (1 microg/site) did not modify the increased vascular permeability induced by the PLA(2)s (0.05-0.5 microg/site). Previous treatment (30 min) of the animals with cyproheptadine (2 mg/kg, i.p.) markedly reduced PLA(2) (0.5 microg/site)-induced oedema. In rats treated neonatally with capsaicin to deplete neuropeptides, the plasma extravasation induced by all PLA(2)s (0.5 microg/site) was also significantly reduced. Similarly, the tachykinin NK(1) receptor antagonist SR140333 (1nmol/site) significantly reduced the PLA(2)-induced oedema. In addition, the combination of SR140333 with cyproheptadine further reduced the increased plasma extravasation by PLA(2) from C. d. cascavella venom, but not by PLA(2) from C. d. terrificus and C. d. collilineatus venoms. Our results suggest that increase in skin vascular permeability by crotalic PLA(2)s is mediated by activation of sensory C-fibers culminating in the release of substance P, as well as by activation of mast cells which in turn release amines such as histamine and serotonin.
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PMID:Inflammatory oedema induced by phospholipases A2 isolated from Crotalus durissus sp. in the rat dorsal skin: a role for mast cells and sensory C-fibers. 1278 82

Blood flow and plasma fibrinolytic factors were measured on five occasions in both forearms of eight otherwise healthy male smokers during unilateral brachial artery infusion of the endothelium-dependent vasodilator, substance P (2 to 8 pmol/min), and the endothelium-independent vasodilator, sodium nitroprusside (2 to 8 microg/min). On the first occasion, intra-arterial vitamin C was co-infused at 25 mg/min. On subsequent occasions, subjects attended after 28 and 35 days treatment with oral vitamin C (1 g daily) or placebo in a double-blind randomized crossover design still smoking but with and without acute smoke inhalation (3 cigarettes over 30 minutes). Basal plasma ascorbate concentrations increased from 37 +/- 6 micromol/L to 105 +/- 11 micromol/L following oral vitamin C supplementation (P = 0.002). Substance P caused dose-dependent increases in forearm blood flow (P < 0.001, ANOVA) and t-PA release (P < 0.05, ANOVA) that was unaffected by acute recent smoke inhalation, intra-arterial vitamin C, or oral vitamin C administration (p = ns). Likewise there were no effects on sodium nitroprusside-induced vasodilatation (p = ns). Neither acute local intra-arterial nor prolonged oral vitamin C supplementation reverses smoking-related endothelial dysfunction and impaired endogenous t-PA release. We conclude that the adverse vascular actions of smoking are not principally mediated through oxidative stress.
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PMID:Vitamin C has no effect on endothelium-dependent vasomotion and acute endogenous fibrinolysis in healthy smokers. 1517 66

Phospholipase A(2) (PLA(2)) forms are expressed in spinal cord, and inhibiting spinal PLA(2) induces a potent antihyperalgesia. Here, we examined the antihyperalgesic effects after systemic and i.t. delivery of four compounds constructed with a common motif consisting of a 2-oxoamide with a hydrocarbon tail and a four-carbon tether. These molecules were characterized for their ability to block group IVA calcium-dependent PLA(2) (cPLA(2)) and group VIA calcium-independent PLA(2) (iPLA(2)) in inhibition assays using human recombinant enzyme. The rank ordering of potency in blocking group IVA cPLA(2) was AX048 (ethyl 4-[(2-oxohexadecanoyl)amino]butanoate), AX006 (4-[(2-oxohexadecanoyl)amino]butanoic acid), and AX057 (tert-butyl 4-[(2-oxohexadecanoyl)amino]butanoate) > AX010 (methyl 4-[(2-oxohexadecanoyl)amino]butanoate) and for inhibiting group VIA iPLA(2) was AX048, AX057 > AX006, and AX010. No agent altered recombinant cyclooxygenase activity. In vivo, i.t. (30 mug) and systemic (0.2-3 mg/kg i.p.) AX048 blocked carrageenan hyperalgesia and after systemic delivery in a model of spinally mediated hyperalgesia induced by i.t. substance P (SP). The other agents were without activity. In rats prepared with lumbar i.t. loop dialysis catheters, SP evoked spinal prostaglandin E(2) (PGE(2)) release. AX048 alone inhibited PGE(2) release. Intrathecal SR141617, a cannabinoid CB1 inhibitor at doses that blocked the effects of i.t. anandamide had no effect upon i.t. AX048. These results suggest that AX048 is the first systemically bioavailable compound with a significant affinity for group IVA cPLA(2), which produces a potent antihyperalgesia. The other agents, although demonstrating enzymatic activity in cell-free assays, appear unable to gain access to the intracellular PLA(2) toward which their action is targeted.
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PMID:Systemic and intrathecal effects of a novel series of phospholipase A2 inhibitors on hyperalgesia and spinal prostaglandin E2 release. 1620 28

The increased risk for myocardial infarction and ischemic stroke in primary hypertension suggests that the condition is associated with prothrombotic mechanisms. We have shown that patients with hypertension have an impaired capacity for acute endothelial tissue-type plasminogen activator (t-PA) release, an important local protective response to prevent formation of intravascular thrombi. The aim of the present study was to investigate whether this impairment could be restored by the lowering of blood pressure. The capacity for acute t-PA release in response to intraarterial infusion of substance P at 8 pmol/min was investigated in a perfused-forearm study in 20 hypertensive patients (12 men and 8 women). Studies were performed when patients were untreated and after 8 weeks of randomized treatment with lisinopril or felodipine that lowered blood pressure by 26/10 and 24/12 mm Hg, respectively. The t-PA release response increased significantly with treatment (ANOVA, P=0.0001), with a similar effect in the 2 treatment groups. The peak release of t-PA increased from 257 (58) to 445 (77) ng/min x L/tissue(-1) (t test, P=0.02). Also, treatment shortened the average time to peak secretion from 6.7 (1.4) to 2.7 (0.3) min (t test, P=0.01). In 6 patients with a delayed secretory peak (9 minutes or later), treatment normalized the response (chi2 test, P=0.008). Antihypertensive therapy restores the capacity for acute t-PA release and improves the rapidity of the response in patients with primary hypertension. Similar responses with the 2 regimens suggest that the improvement is related to the blood pressure reduction as such. This effect may contribute to the thromboprotective effect of antihypertensive treatment.
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PMID:Impaired capacity for stimulated fibrinolysis in primary hypertension is restored by antihypertensive therapy. 1652 Apr 4


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