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Query: UNIPROT:P35237 (thrombin inhibitor)
 2,012 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombin has been reported to inhibit neurite outgrowth from neuroblastoma cells grown in serum-containing medium after switching to serum-free medium. A test of the serum and substrate-dependence of this inhibition became possible with the development of Neurobasal/B27 serum-free medium. Inhibition of sprouting of Nb2a neuroblastoma cells by thrombin occurred from the substrate where it was bound to material adsorbed from serum. Neuritogenesis of primary hippocampal neurons was unaffected by exogenous thrombin on polylysine substrates with or without serum treatment. However, sprouting of hippocampal neurons was stimulated by treating the substrate with hirudin, a highly specific thrombin inhibitor. This suggests that hippocampal neurons are not directly responsive to added thrombin, perhaps because they produce their own thrombin.
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PMID:Exogenous thrombin inhibits neuritogenesis in cultured neuroblastoma cells but not in rat hippocampal neurons. 755 63

alpha-Thrombin is a multifunctional serine protease that has an important role in the coagulation cascade, wound healing, and inflammatory response. In this study, we show that thrombin induces IL-6 production in human epithelial cells and fibroblasts. ELISA and Northern blot analyses showed that physiologic concentrations of thrombin (0.1-1 micrograms/ml) induced IL-6 production in human lung fibroblasts, skin fibroblasts, and epithelial cells. Hirudin, a thrombin inhibitor, completely blocked IL-6 induction by thrombin. Treatment of fibroblasts with inactivated diisopropylphosphofluoridate (DIP)-alpha-thrombin, gamma-thrombin, or trypsin had no effect on IL-6 production. In contrast, treatment with the thrombin-tethered ligand receptor peptide TRP-7 (SFLLRNP) induced IL-6 production, but at lower levels than that induced by native alpha-thrombin. Finally, IL-6 pretreatment of lung or skin fibroblasts resulted in the enhanced production of IL-6 following exposure to thrombin. These results suggest that fibroblasts and epithelial cells may represent a significant source of IL-6 in the inflammatory response to tissue injury, and that cytokine production is an important biologic consequence of thrombin's interaction with its seven-transmembrane domain (STD) receptor.
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PMID:Thrombin induces IL-6 production in fibroblasts and epithelial cells. Evidence for the involvement of the seven-transmembrane domain (STD) receptor for alpha-thrombin. 760 66

Thrombin is a multifunctional serine protease that is rapidly produced from prothrombin at sites of tissue injury and catalyzes the final steps in blood coagulation. Thrombin also regulates gene expression and process outgrowth in neurons and astrocytes and stimulates proliferation of astrocytes. Since thrombin is produced immediately upon breakdown of the blood-brain barrier we examined its effects on astrocytes and neurons cultured under conditions which resemble those found in vivo following cerebrovascular injury. These studies showed that thrombin markedly protected rat primary astrocytes from cell death induced by hypoglycemia or oxidative stress. Thrombin also protected rat primary hippocampal neurons from cell death produced by hypoglycemia or growth supplement deprivation. Synthetic peptides which directly activate the thrombin receptor also protected astrocytes and neurons from these environmental insults, demonstrating that the thrombin effects were mediated through the thrombin receptor. In contrast to these results with stressed cells, high concentrations of thrombin killed both astrocytes and neurons cultured under normal conditions. All of the effects of thrombin on astrocytes and neurons were blocked by the brain thrombin inhibitor, protease nexin-1 (PN-1). This shows that the effects required the proteolytic activity of thrombin and is consistent with the known proteolytic mechanism by which thrombin activates its receptor. These results indicate that thrombin and PN-1 may regulate the viability of both astrocytes and neurons in early moments following trauma to the CNS or other conditions that alter the blood-brain barrier.
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PMID:Thrombin receptor activation protects neurons and astrocytes from cell death produced by environmental insults. 762 61

Amyloid beta-peptide (A beta) is the principal component of neuritic plaques in the brain in Alzheimer's disease (AD). Recent studies revealed that A beta can be neurotoxic by a mechanism involving free radical production and loss of cellular ion homeostasis, thus implicating A beta as a key factor in the pathogenesis of AD. However, other proteins are present in plaques in AD, including the protease thrombin and protease nexin-1 (PN1), a thrombin inhibitor. We therefore tested the hypothesis that thrombin and PN1 modify neuronal vulnerability to A beta toxicity. In dissociated rat hippocampal cell cultures the toxicity of A beta was significantly enhanced by coincubation with thrombin, whereas PN1 protected neurons against A beta toxicity. A beta induced an increase in levels of intracellular peroxides and calcium. Thrombin enhanced, and PN1 attenuated, the accumulation of peroxides and calcium induced by A beta. Taken together, these data demonstrate that thrombin and PN1 have opposing effects on neuronal vulnerability to A beta and suggest that thrombin and PN1 play roles in the pathogenesis of neuronal injury in AD.
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PMID:Opposing actions of thrombin and protease nexin-1 on amyloid beta-peptide toxicity and on accumulation of peroxides and calcium in hippocampal neurons. 764 22

Experiments were designed to examine whether thrombin affects the production of nitric oxide-like factor(s) evoked by interleukin-1 beta (IL-1 beta) in cultured smooth muscle cells from the rat aorta. IL-1 beta stimulated the release of nitrite (a stable oxidation product of nitric oxide) from cultured smooth muscle cells. Thrombin inhibited in a concentration-dependent manner the release of nitrite caused by IL-1 beta. The inhibition was prevented by hirudin (a thrombin inhibitor) and required the presence of thrombin before or during the induction period. Under bioassay conditions, the perfusates from columns containing IL-1 beta-treated smooth muscle cells relaxed detector rat aortic rings without endothelium. The addition of IL-1 beta-treated smooth muscle cells to suspensions of indomethacin-treated platelets inhibited their aggregation. Control untreated smooth muscle cells or cells treated with thrombin alone did not have such effects. The treatment of smooth muscle cells with IL-1 beta in combination with thrombin blunted both the relaxing activities of the perfusates under bioassay conditions and the inhibition of platelet aggregation. These observations indicate that thrombin inhibits the production of nitric oxide-like factor(s) evoked by the inducible nitric oxide synthase in cultured smooth muscle cells from rat aorta.
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PMID:Thrombin inhibits induction of nitric oxide synthase in vascular smooth muscle cells. 768 May 40

The new thrombin inhibitor CRC 220 was characterized in vivo for its antithrombotic effects. CRC 220 led to a dose-dependent prolongation of clotting parameters as determined in rats, rabbits, dogs, sheeps, pigs and monkeys. We evaluated the efficacy of CRC 220 to prevent thrombus formation in arteries and in the microcirculation in different animal models. In a rabbit model of tissue factor-induced coagulation activation, infusion of 0.5 mg/kg x h CRC 220 (3 hours) led to a significant prevention of fibrinogen decrease. In a rat model of lethal LPS-induced DIC CRC 220 significantly prevented the mortality rate after a 4h-infusion of 0.75 mg/kg x h. Thrombin-induced platelet aggregation in rat lungs could be prevented by the i.v. bolus injection of CRC 220. A dose of 0.3 mg/kg leads to a reduction of more than 80% of platelet deposition in the lung, significant inhibition was still observed 90 minutes after CRC 220 administration; at this time the inhibitor had already been cleared from plasma. Arterial thrombosis was induced in rabbits by squeezing and stenosis of the A. carotis. The i.v. bolus administration of CRC 220 dose-dependently prevented thrombus formation, an ED50 of 0.03 mg/kg was calculated. This dose was associated with only a minor prolongation of aPTT.
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PMID:Pharmacological characterization of a new 4-amidinophenyl-alanine thrombin-inhibitor (CRC 220). 774 May 26

Thrombin, a serine protease, plays a central role in the initiation and propagation of thrombotic events. An extensive search for new thrombin inhibitors was performed, using an unconventional approach. Screening of small basic molecules for binding in the recognition pocket of thrombin led to the discovery of (aminoiminomethyl)piperidine (amidinopiperidine) as a weak, but intrinsically selective, thrombin inhibitor. Elaboration of this molecule provided compounds which inhibit thrombin with Ki's in the range of 20-50 nM and with selectivities of 1000-4000 against trypsin. These inhibitor compounds show a new and unexpected binding mode to thrombin. Modification of the central building block and then of one of the hydrophobic substituents led to the discovery of a new family of thrombin inhibitors which has reverted to the former binding mode to thrombin. This last class of compounds shows inhibitory activities in the picomolar range, low toxicity, and a short plasma half life which favors its use for an intravenous application. From this series of thrombin inhibitors, 19f(Ro 46-6240) was selected for clinical development as an antithrombotic agent for intravenous administration.
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PMID:Design and synthesis of potent and highly selective thrombin inhibitors. 796 50

Thrombin is involved in the pathogenesis of venous and arterial thrombosis. This study addressed the question of the relative importance of thrombin in the early and late phases of thrombogenesis. The effect of Ro 46-6240 (1.43 mg/kg bolus and 0.1 mg/kg per minute i.v.), a novel, selective thrombin inhibitor on thrombogenesis induced by rabbit aorta subendothelium, was measured ex vivo in a perfusion chamber model after a short (5-minute) and long (30-minute) exposure time to rabbit native blood. The role of the perfusion time was assessed at shear rates of 100/s, 650/s, and 2600/s. These shear rates mimic blood flow conditions found in veins, arteries, and small or stenosed arteries, respectively. Fibrin deposition and platelet thrombus formation on subendothelium were evaluated by microscopic morphometry. In the presence of Ro 46-6240, fibrin deposition was abolished at both perfusion times and at all shear rates. In the 5-minute experiments, thrombus height was reduced by Ro 46-6240 at shear rates of 100/s (85%) and 650/s (35%) but not at a shear rate of 2600/s, whereas thrombus area was not affected at any shear rate. In contrast, both thrombus height and thrombus area were reduced (60% to 90%) by Ro 46-6240 in the 30-minute perfusion groups at all wall shear rates. The antithrombotic effect of Ro 46-6240 after 30-minute perfusion was confirmed by the minimal increase in the pressure difference between the entrance and the exit of the perfusion chamber compared with the control groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Thrombin plays a key role in late platelet thrombus growth and/or stability. Effect of a specific thrombin inhibitor on thrombogenesis induced by aortic subendothelium exposed to flowing rabbit blood. 806 9

The vasoactive mechanisms of the serine protease alpha-thrombin were examined in isolated coronary arteries from dogs. In resting coronary arteries with endothelium, alpha-thrombin caused concentration-dependent contractions that were characterized by an initial transient relaxation followed by slowly developing sustained contractions. The vascular actions of alpha-thrombin were mimicked by the thrombin receptor-activating peptide (TRAP) SFLLRNP, a synthetic peptide based on the cleaved terminus of the thrombin receptor domain. Treatment of the arteries with N omega-nitro-L-arginine or removal of endothelium abolished the transient relaxations and enhanced the contractions, indicating that the transient relaxations were mediated by the concurrent release of endothelium-derived nitric oxide. alpha-Thrombin that had been catalytically inactivated with the irreversible inhibitor by use of D-Phe-Pro-Arg-chloromethyl ketone did not cause contractions, indicating the requirement of proteolytic cleavage by alpha-thrombin to induce contractions. In contrast to TRAP, alpha-thrombin-induced contractions were blocked by hirudin (a specific thrombin inhibitor), nifedipine and diltiazem (Ca2+ channel blockers), or staurosporine and calphostin C (protein kinase C inhibitors). Unlike alpha-thrombin, which undergoes homologous desensitization, TRAP failed to cause desensitization to subsequent stimulation by alpha-thrombin or TRAP. These observations support the hypothesis that vasoactive actions of alpha-thrombin are mediated by a mechanism that involves cleavage at the active site to expose a new NH2 terminus that activates the thrombin receptor. Further, the dissociation between alpha-thrombin and the synthetic receptor peptide in signal transduction and dissimilar desensitizing properties suggest the existence of distinct thrombin receptor subtypes and/or signaling events in vascular smooth muscle.
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PMID:Distinct receptors and signaling pathways in alpha-thrombin- and thrombin receptor peptide-induced vascular contractions. 815 40

Thrombin contracts vascular smooth muscle and stimulates its proliferation. Using a specific thrombin inhibitor, hirudin, we studied whether thrombin contributes to the pulmonary vasoconstriction and vascular proliferation that occurs in pulmonary hypertension. Hirudin was infused intravenously (0.2 mg/h/kg) by minipumps in nine rats during a 3-wk exposure to hypobaric hypoxia (HH). Vehicle (normal saline) was infused in eight hypoxic control (HC) and seven normoxic control (NC) rats. Sufficient hirudin delivery was confirmed by a failure of undiluted plasma from HH, but not from NC and HC, to clot in response to thrombin. When the plasma samples were diluted 1:10, the thrombin time was significantly prolonged in HH when compared with that in both NC and HC. Although hirudin slightly reduced mean pulmonary arterial pressure in open-chest rats, there was no significant difference between the hypoxic groups in total pulmonary resistance, right ventricle weight, morphologic remodeling of lung vessels, or the perfusion pressure-flow relationship in isolated lungs. Vasoconstrictor responses of isolated lungs to angiotensin II and acute hypoxic challenges were not affected by hirudin treatment. We conclude that hirudin, in a dose sufficient to reduce thrombin's catalytic effect on fibrinogen, does not significantly prevent the development of chronic hypoxic pulmonary hypertension.
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PMID:Chronic hypoxic pulmonary hypertension. Is thrombin involved? 821 23


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