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)

The structural and functional features of thrombin are under discussion: combination of restricted specificity and a central regulatory role in hemostasis. Thrombin specificity is mainly connected with special regions of the enzyme molecule--an additional recognition binding site for high molecular substrates. One can consider the additional site of thrombin as a kind of the allosteric centre changing thrombin-catalyzed functions at binding with modulator. Specific site of substrate (inhibitor or receptor) is used in the role of modulator. A computer search of that modulator was fulfilled by means of the program DOTHELIX. The peptides thymosin I and substance P which have regions similar to those of hirudin were shown to inhibit thrombin activity. The kinetic data point to the noncompetitive type of inhibition. The data on the high reactivity of the thrombin-activated protein C system confirm the idea of protein C to be the first defensive mechanism when thrombin is generated in blood and interacts with thrombomodulin.
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PMID:[Regulation of thrombocyte stimulating and other activities of thrombin by modulators of the recognition site]. 172 58

We report that cultured vascular endothelial cells release into the culture medium a vasoconstrictor peptide, a substance we call an endothelium-derived constricting factor (EDCF). Conditioned medium from cultured bovine aortic and pulmonary artery endothelial cells caused sustained, dose-dependent isometric constriction of vascular rings isolated from bovine coronary and pulmonary arteries and rat and guinea pig pulmonary arteries and aortas. The medium also caused vasoconstriction when infused into isolated, perfused rabbit hearts and rat kidneys. Conditioned medium from bovine aortic intimal explants also contained constrictor activity, whereas medium from denuded intimal explants, cultured microvascular endothelial cells, vascular smooth muscle cells, or lung fibroblasts did not. Constrictor activity increased progressively in the culture medium over 2-12 h of incubation. Thrombin stimulated the release of constrictor activity; hypoxia, anoxia and meclofenamate had no effect and the calcium ionophore A23187 inhibited EDCF release. The EDCF caused a characteristic slow-onset and sustained constriction of the vascular rings that relaxed slowly over 60-90 min following removal. The constriction was not affected by inhibitors of arachidonic acid metabolism or by antagonists of serotonergic, histaminergic, alpha-adrenergic, opioid, leukotriene, angiotensin II, or substance P receptors; constriction was reversed partly by verapamil and acetylcholine and completely by nitroprusside and isoproterenol. EDCF was heat stable, not extractable into organic solvents, and completely destroyed by trypsin and neutral protease. Cycloheximide blocked the production of EDCF. These properties and the results of polyacrylamide gel filtration experiments suggested that EDCF was a peptide with a molecular weight of 3,000 daltons. These findings show that endothelial cells in culture produce a vasoconstrictor substance and support the idea that endothelial cell products play a role in mediating vascular tone.
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PMID:Endothelial cells in culture produce a vasoconstrictor substance. 311 70

To elucidate the regulation mechanism of adrenomedullin (AM) production in blood vessels, we examined the effects of 30 substances on AM production in cultured rat vascular smooth muscle cells (VSMCs). Forskolin and 8-bromo-cAMP suppressed production and gene transcription of AM. Since VSMC expresses AM receptors coupled with adenylate cyclase, AM production may be regulated by intracellular cAMP concentration. Thrombin, vasoactive intestinal polypeptide and interferon-gamma also inhibited AM production, while angiotensin II, endothelin-1, bradykinin, substance P, adrenaline, phorbol ester and fetal calf serum stimulated AM production in VSMC. These results suggest that AM production is regulated by a variety of substances, indicating complex systems regulating AM production.
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PMID:Effects of vasoactive substances and cAMP related compounds on adrenomedullin production in cultured vascular smooth muscle cells. 764 78

Release of endothelin, vasopressin and substance P from isolated rabbit tracheal epithelial cells was monitored after incubation for 2 h with thrombin (10 U/ml) in the presence and absence of cycloheximide (100 micrograms/ml) and 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (NCDC, 0.6 mM). Thrombin stimulated the release of endothelin and vasopressin. Inhibition of the thrombin-stimulated release of endothelin and vasopressin by cycloheximide (44 and 56%, respectively) and NCDC (59 and 88%, respectively) indicates that the release of these peptides is at least partially dependent on the ability of thrombin to stimulate protein synthesis and activate the phospholipase C pathway. Substance P, which is also present in tracheal epithelial cells, was not released by thrombin.
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PMID:Thrombin stimulates release of endothelin and vasopressin, but not substance P, from isolated rabbit tracheal epithelial cells. 767 94

1. Proteases regulate cells by cleaving proteinase-activated receptors (PARs). Thrombin and trypsin cleave PAR-1 and PAR-2 on neurons and astrocytes of the brain to regulate morphology, growth and survival. We hypothesized that thrombin and mast cell tryptase, which are generated and released during trauma and inflammation, regulate enteric neurons by cleaving PAR-1 and PAR-2. 2. We detected immunoreactive PAR-1 and PAR-2 in > 60 % of neurons from the myenteric plexus of guinea-pig small intestine in primary culture. A large proportion of neurons that expressed substance P, vasoactive intestinal peptide or nitric oxide synthase also expressed PAR-1 and PAR-2. We confirmed expression of PAR-1 and PAR-2 in the myenteric plexus by RT-PCR using primers based on sequences of cloned guinea-pig receptors. 3. Thrombin, trypsin, tryptase, a filtrate from degranulated mast cells, and peptides corresponding to the tethered ligand domains of PAR-1 and PAR-2 increased [Ca2+]i in > 50 % of cultured myenteric neurons. Approximately 60 % of neurons that responded to PAR-1 agonists responded to PAR-2 agonists, and > 90 % of PAR-1 and PAR-2 responsive neurons responded to ATP. 4. These results indicate that a large proportion of myenteric neurons that express excitatory and inhibitory neurotransmitters and purinoceptors also express PAR-1 and PAR-2. Thrombin and tryptase may excite myenteric neurons during trauma and inflammation when prothrombin is activated and mast cells degranulate. This novel action of serine proteases probably contributes to abnormal neurotransmission and motility in the inflamed intestine.
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PMID:Thrombin and mast cell tryptase regulate guinea-pig myenteric neurons through proteinase-activated receptors-1 and -2. 1035 15

We have investigated the ability of protease-activated receptor-1 (PAR-1), PAR-2, PAR-3 and PAR-4 agonists to induce contractile responses in isolated guinea-pig gallbladder. Thrombin, trypsin, mouse PAR-1 activating (SFLLRN-NH(2)) peptide, and mouse PAR-2 activating (SLIGRL-NH(2)) and human PAR-2 activating (SLIGKV-NH(2)) peptides produced a concentration-dependent contractile response. Mouse PAR-4 activating (GYPGKF-NH(2)) peptide, the mouse PAR-1 reverse (NRLLFS-NH(2)) peptide, the mouse PAR-2 reverse (LRGILS-NH(2)) and human PAR-2 reverse (VKGILS-NH(2)) peptides caused negligible contractile responses at the highest concentrations tested. An additive effect was observed following the contractile response induced by either trypsin or thrombin, with the addition of a different PAR agonist (SFLLRN-NH(2) and SLIGRL-NH(2), respectively). Desensitization to PAR-2 activating peptide attenuated the response to trypsin but failed to attenuate the response to PAR-1 agonists, and conversely desensitization to PAR-1 attenuated the response to thrombin but failed to alter contractile responses to PAR-2 agonists. The contractile responses produced by thrombin, trypsin, SFLLRN-NH(2) and SLIGRL-NH(2) were markedly reduced in the presence of the cyclo-oxygenase inhibitor, indomethacin, whilst the small contractile response produced by NRLLFS-NH(2) and LRGILS-NH(2) were insensitive to indomethacin. The contractile responses to thrombin, trypsin, SFLLRN-NH(2) and SLIGRL-NH(2) were unaffected by the presence of: the non-selective muscarinic antagonist, atropine; the nitric oxide synthase inhibitor, L-NAME; the sodium channel blocker, tetrodotoxin; the combination of selective tachykinin NK(1) and NK(2) receptor antagonists, (S)-1-[2-[3-(3,4-dichlorphenyl)-1 (3-isopropoxyphenylacetyl) piperidin-3-yl] ethyl]-4-phenyl-1 azaniabicyclo [2.2.2] octane chloride (SR140333) and (S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino-2-(3, 4-dichlorophenyl)-butyl] benzamide (SR48968), respectively. The results indicate that PAR-1 and PAR-2 activation causes contractile responses in the guinea-pig gallbladder, an effect that is mediated principally by prostanoid release, and is independent of neural mechanisms.
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PMID:Evidence that PAR-1 and PAR-2 mediate prostanoid-dependent contraction in isolated guinea-pig gallbladder. 1103 Jul 17

Thrombin, generated in the circulation during injury, cleaves proteinase-activated receptor 1 (PAR1) to stimulate plasma extravasation and granulocyte infiltration. However, the mechanism of thrombin-induced inflammation in intact tissues is unknown. We hypothesized that thrombin cleaves PAR1 on sensory nerves to release substance P (SP), which interacts with the neurokinin 1 receptor (NK1R) on endothelial cells to cause plasma extravasation. PAR1 was detected in small diameter neurons known to contain SP in rat dorsal root ganglia by immunohistochemistry and in situ hybridization. Thrombin and the PAR1 agonist TFLLR-NH(2) (TF-NH(2)) increased [Ca(2+)](i) >50% of cultured neurons (EC(50)s 24 mu ml(-1) and 1.9 microM, respectively), assessed using Fura-2 AM. The PAR1 agonist completely desensitized responses to thrombin, indicating that thrombin stimulates neurons through PAR1. Injection of TF-NH(2) into the rat paw stimulated a marked and sustained oedema. An NK1R antagonist and ablation of sensory nerves with capsaicin inhibited oedema by 44% at 1 h and completely by 5 h. In wild-type but not PAR1(-/-) mice, TF-NH(2) stimulated Evans blue extravasation in the bladder, oesophagus, stomach, intestine and pancreas by 2 - 8 fold. Extravasation in the bladder, oesophagus and stomach was abolished by an NK1R antagonist. Thus, thrombin cleaves PAR1 on primary spinal afferent neurons to release SP, which activates the NK1R on endothelial cells to stimulate gap formation, extravasation of plasma proteins, and oedema. In intact tissues, neurogenic mechanisms are predominantly responsible for PAR1-induced oedema.
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PMID:Agonists of proteinase-activated receptor 1 induce plasma extravasation by a neurogenic mechanism. 1148 6

Activation of protease-activated receptors (PAR) can induce vasodilation (VD) and increase of vascular permeability either directly by stimulating endothelial cells or indirectly via activation of nociceptors and subsequent release of neuropeptides (neurogenic inflammation). We aimed to estimate the relative contribution of the two pathways for stimulation with endogenous activators of PAR-2 (trypsin) and of PAR-1, 3 and 4 (thrombin) using in vivo dermal microdialysis in rats. Protein extravasation (PE) was assessed by increase of protein concentration in the dialysate, and VD was quantified by laser Doppler scanning. Both trypsin (10(-8)-10(-4) M) and thrombin (10(-6), 10(-5.5) and 10(-5) M) provoked PE and local VD in a dose-dependent manner. Trypsin (10(-4) M)-induced PE was inhibited by 87.2 +/- 21% due to the substance P (SP) NK1 receptor antagonist SR140333. VD was blocked by 58.15 +/- 10.1% in response to the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP(8-37). By contrast, CGRP(8-37) did not affect thrombin-induced VD, while blockade of SP receptors prevented the PE elicited only by low doses of thrombin (10(-6) M), being ineffective at higher thrombin concentrations. In conclusion, intradermal trypsin elicits a neurogenic inflammation in rat, probably mediated via PAR-2 activation on nociceptors and subsequent SP and CGRP release. Thrombin-induced PE and VD are mediated mainly by a non-neurogenic mechanism.
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PMID:Neurogenic components of trypsin- and thrombin-induced inflammation in rat skin, in vivo. 1636 32