Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cardiac sarcolemmal Na+/H+ exchanger extrudes intracellular H+ in exchange for Na+, in an electroneutral process. Of the 6 mammalian exchanger isoforms identified to date, the Na+/H+ exchanger (NHE)-1 is believed to be the molecular homolog of the sarcolemmal Na+/H+ exchanger. The exchanger is activated primarily by a reduction in intracellular pH (intracellular acidosis), although such activation is subject to modulation by a variety of endogenous mediators (e.g., catecholamines, thrombin, endothelin) through receptor-mediated mechanisms. A large body of preclinical evidence now suggests that inhibition of the sarcolemmal Na+/H+ exchanger attenuates many of the unfavorable consequences of acute myocardial ischemia and reperfusion. Much of this evidence has been obtained with recently developed potent, selective inhibitors of the exchanger, such as HOE-642 (cariporide) and its structurally related congener HOE-694, in studies using both in vitro and in vivo models of ischemia and reperfusion in a variety of species. The data from these studies indicate that Na+/H+ exchange inhibition leads to a decreased susceptibility to severe ventricular arrhythmia, attenuates contractile dysfunction, and limits tissue necrosis (i.e., decreases infarct size) during myocardial ischemia and reperfusion. Such protection is likely to arise, at least in part, from attenuation of "Ca2+ overload," which has been linked causally with all of these pothologic phenomena. The consistent and marked cardioprotective benefit that has been observed with cariporide and related compounds in preclinical studies suggests that Na+/H+ exchange inhibition may represent a novel and effective approach to the treatment of acute myocardial ischemia in humans.
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PMID:Rational basis for use of sodium-hydrogen exchange inhibitors in myocardial ischemia. 1048 75

The effects of recombinant soluble P-selectin glycoprotein ligand-1 (rsPSGL.Ig) were studied after 120 min of splanchnic artery occlusion and 120 min of reperfusion (SAO/R). SAO/R rats administered a low-affinity mutant form of rsPSGL.Ig exhibited signs of severe circulatory collapse with marked hypotension, a survival time of only 37+/-16 min, and significant increases in intestinal myeloperoxidase (MPO) activity (P<0.01). In addition, SAO/R rats given rsPSGL.Ig low-affinity mutant showed severe endothelial dysfunction characterized by a blunted vasorelaxation to the endothelium-dependent vasodilator acetylcholine in comparison to sham-operated controls (30+/-9% vs. 97+/-3%). Administration of rsPSGL.Ig (0.5 mg/kg) significantly improved mean arterial blood pressure and increased survival time to 107+/-13 min (P <0.01). rsPSGL.Ig treatment also resulted in a significant attenuation in both intestinal MPO activity as well as the SAO/R-induced decline in endothelium-dependent vasorelaxation of superior mesenteric artery rings (P<0.01). In addition, rsPSGL.Ig attenuated in vitro neutrophil adherence to thrombin-stimulated superior mesenteric artery endothelium to a comparable degree as a P-selectin monoclonal antibody. These data suggest that rsPSGL.Ig provides beneficial effects by preserving endothelial function and attenuating neutrophil-endothelial cell interactions in the splanchnic circulation following ischemia-reperfusion.
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PMID:Acute mesenteric ischemia and reperfusion: protective effects of recombinant soluble P-selectin glycoprotein ligand-1. 1048 98

Propionyl-L-carnitine (PrC) has been shown to exert beneficial effects in the treatment of myocardial and peripheral ischemia in man. These conditions are associated with the activation of circulating neutrophils and platelets. To determine whether PrC could affect the synthesis of lipid mediators known to influence neutrophil and platelet functions, we explored the effects of PrC on the synthesis of platelet-activating factor (PAF) and arachidonic acid (AA) metabolites. Preincubation (90 min) of human neutrophils with PrC (0.1-100 microM) inhibited the synthesis of PAF and of a PAF analog (1-alkyl-1'enyl-2-acetyl-sn-glycero-3-phosphoethanolamine: AEGPE) induced in vitro by the calcium ionophore A23187. In contrast, concentrations of PrC up to 100 microM did not influence the uptake of exogenous AA or the A23187-induced release of AA and eicosanoids from neutrophils in vitro. PrC (1 microM) also inhibited PAF synthesis from human platelets stimulated in vitro with thrombin, but had no effect on thrombin-induced aggregation. Oral administration of PrC (2 g/day for two weeks) to five normal volunteers resulted in a significant inhibition of PAF and AEGPE synthesis by neutrophils stimulated with A23187 ex vivo, with no effect on AA or eicosanoid release. These data indicate that PrC selectively inhibits in vitro and ex vivo PAF synthesis from human neutrophils and platelets without influencing AA metabolism or eicosanoid release. This effect of PrC might represent an additional mechanism by which this molecule can exert protective effects in tissue ischemia and in other inflammatory diseases associated with neutrophil and platelet activation.
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PMID:Inhibition of platelet-activating factor synthesis in human neutrophils and platelets by propionyl-L-carnitine. 1048 38

Disseminated intravascular coagulation frequently occurs after global ischemia and reperfusion due to cardiac arrest. The present study was performed to demonstrate the role of tissue factor for coagulation pathway activation, as well as to investigate the precise time course of tissue factor pathway inhibitor (TFPI) during and after cardiopulmonary resuscitation (CPR). Thirty-two of out-of-hospital cardiac arrest patients were classified into two groups, those who achieved return of spontaneous circulation (ROSC) (n=13) and those without ROSC (n=19). Ten normal healthy volunteers served as control subjects. Serial levels of tissue factor and TFPI were measured during and after cardiac arrest and CPR. In patients with ROSC, cardiac arrest and CPR led to persistent increases in the levels of tissue factor that peaked 6 hours after arrival at the Emergency Department. Tissue factor levels in patients without ROSC also showed marked elevations compared to those of the control subjects. In both groups, the levels of TFPI were significantly lower than those in the control subjects. However, we could not find differences in the levels of the two markers between the patients with ROSC and those without ROSC. In conclusion, we demonstrated persistent elevation of the tissue factor levels associated with low TFPI during and after CPR in patients with out-of-hospital cardiac arrest. These results indicate the activation of the extrinsic coagulation pathway without adequate TFPI generation, which may contribute to thrombin activation and fibrin formation after whole-body ischemia and reperfusion.
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PMID:Tissue factor and tissue factor pathway inhibitor levels during and after cardiopulmonary resuscitation. 1057 88

Thrombin activity has been implicated as a mechanism for failed reperfusion and reocclusion following thrombolysis. Aggregating platelets provide a phospholipid surface on which prothrombin is cleaved to form thrombin. We examined markers of thrombin generation and activity in patients enrolled in a randomized, placebo-controlled, dose escalating trial of the platelet glycoprotein IIb-IIIa inhibitor eptifibatide (Integrilintrade mark) administered concomitantly with tissue plasminogen activator for the treatment of myocardial infarction. Measurements were obtained at baseline, at 90 minutes, and at 6, 12, and 24 hours after starting therapy. Eptifibatide inhibited platelet aggregation in response to 20 microM ADP. Levels of fibrinopeptide A (FPA), thrombin-antithrombin complexes (TAT), and prothrombin fragment 1.2 (F1.2) were not lower in patients treated with eptifibatide than in the control group. In the course of dose escalation, two groups of patients received the same 135 microg/kg bolus of eptifibatide, one with and one without a heparin bolus. FPA levels were dramatically lower in the heparin-treated patients. Levels of FPA, TAT, and F1.2 were not higher in patients with than in those without recurrent ischemia, or in patients without than in those with Thrombolysis in Myocardial Infarction (TIMI) grade 3 angiographic flow at 90 minutes. These data suggest that thrombin generation and activity persist following thrombolysis, despite inhibition of platelet aggregation, and that treatment with inhibitors of thrombin activity may be required even when glycoprotein IIb-IIIa inhibitors are used.
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PMID:Inhibition of platelet aggregation with a glycoprotein IIb-IIIa antagonist does not prevent thrombin generation in patients undergoing thrombolysis for acute myocardial infarction. 1059 Jan 83

Although both intracerebral and subdural hematomas induce brain edema, previous studies have indicated that they may have different cerebrovascular effects. Our own investigations have demonstrated that while subdural hematomas (SDH) are associated with ischemia this is not the case following intracerebral hematomas (ICH). Previous studies have demonstrated a decrease in energy-dependent transport of glutamine across the blood-brain barrier (BBB) following focal cerebral ischemia. The present study investigates this further by examining the effects of SDH, ICH, and intracerebral thrombin injections, an agent involved in ICH-induced injury, on blood to brain glutamine transport. The injection of 200 microL of blood into the subdural space induced a marked reduction in glutamine transport (Ki, influx rate constant) into the cerebral cortex at 4 and 24 h following SDH (sham, 105+/-4% of contralateral cortex; SDH 4 h, 63+/-5%, p<0.01; SDH 24 h, 47+/-12%, p<0.05). There were no significant changes in glutamine Ki in subcortical areas following SDH. Following ICH (200-microL clot); however, there were only modest decreases in glutamine Ki in subcortical areas (sham, 98+/-2% of right cortex; ICH 4 h, 91+/-5%, p<0.01; ICH 24 h, 91+/-2%, p<0.05). Intracerebral injection of thrombin (5U) had minimal effect on glutamine Ki, in subcortical areas, at 4 h and induced a modest decrease in transport at 24 h (sham, 98+/-2% of right cortex; thrombin 4 h, 98+/-2%; thrombin 24 h, 86+/-2%, p<0.05). The present studies demonstrate marked differences in the effects of ICH and SDH on BBB function.
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PMID:Effect of intracerebral and subdural hematomas on energy-dependent transport across the blood-brain barrier. 1059 21

This pilot study was designed to determine whether the low molecular weight heparin, enoxaparin, could be used for elective percutaneous coronary intervention (PCI) to provide antithrombotic effects without the full systemic anticoagulation that occurs with the use of unfractionated heparin. Sixty patients were randomized to receive intravenous enoxaparin (1 mg/kg bolus dose) or unfractionated heparin at the time of coronary intervention. Laboratory testing was performed at baseline, 5 minutes, and 4 hours after study drug to test if a single bolus dose of intravenous enoxaparin can consistently achieve therapeutic antithrombotic effect, thus eliminating the need for multiple doses of heparin and closely monitoring levels of anticoagulation during PCI. Thirty percent of patients who received unfractionated heparin required a second bolus of intravenous heparin to achieve the target-activated clotting time of 300 seconds before PCI. Enoxaparin showed antithrombotic properties comparable to that of unfractionated heparin as measured by anti-Xa levels, with less inhibition of thrombin (factor IIa) at the time points measured (p <0.0001). Angioplasty success rates, in-hospital ischemia, bleeding, and vascular complications were similar in both groups. Thus, intravenous enoxaparin has predictable and effective antithrombotic effects during elective PCI. Although the level of anticoagulation attained with enoxaparin is significantly lower than that after unfractionated heparin, no increase in ischemic complications were noted. The use of a single bolus of intravenous enoxaparin, without the need for measuring the activated clotting time or titrating heparin anticoagulation, has the potential for simplifying the performance and perhaps enhancing the safety of PCI.
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PMID:Usefulness of intravenous enoxaparin for percutaneous coronary intervention in stable angina pectoris. 1060 10

Thrombolytic therapy has become a standard treatment for selected patients with acute myocardial infarction (MI). Various thrombolytic agents have been shown to decrease mortality. However, current thrombolytic agents still suffer significant shortcomings, such as a low optimal reperfusion rate delayed reperfusion. and incomplete myocardial perfusion. Furthermore, cyclic flow variations and reocclu.sions remain a significant cause of late morbidity and mortality. In thrombolysis with tissue plasminogen activator (t-PA), heparin seems to play an important role. However, it has several features that suggest that it may not be the optimal adjunct to thrombolytics, including weak and indirect action on thrombin, little access to clot-bound thrombin, inhibition by acute-phase plasma proteins, and its direct stimulation of platelet aggregation. Argatroban (NOVASTAN(R)), a small-molecule, synthetic, direct thrombin inhibitor, has several potential advantages over heparin, and prior studies suggest superior thrombin inhibition with favorable pharmacokinetic and pharmacodynamic properties warranting further investigation The Myocardial Infarction using NOVASTAN (R) and t-PA (MINT) study is a phase II, single-blind, angiographic trial directly comparing heparin versus two doses of argatroban in 120 patients with ST-elevation MI who present within 6 hours of symptom onset. The primary objective of the MINT trial is to assess the TIMI grade 3 flow and TIMI Frame Count at 90 minutes after the initiation of t-PA. This trial will also evaluate the safety of the combination of t-PA, argatroban, and aspirin. The incidence of clinical or silent ischemia, will be monitored. All patients will be followed up to 30 days for the composite endpoint of death, nonfatal recurrent myocardial infarction, coronary artery bypass surgery, PTCA, recurrent ischemia, and shock/new-onset heart failure.
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PMID:A Randomized, Blinded Study of Two Doses of Novastan(R) (Brand of Argatroban) Versus Heparin as Adjunctive Therapy to Recombinant Tissue Plasminogen Activator (Accelerated Administration) in Acute Myocardial Infarction: Rationale and Design of the Myocardial Infarction using Novastan(R) and T-PA (MINT) Study. 1060 50

Activated factor X (FXa) is a trypsinlike serine protease involved in the cascade of blood coagulation. The monocyte chemoattractant protein-1 (MCP-1) may be important in the pathophysiology of liver ischemia-reperfusion injury. We investigated the effects of a selective FXa inhibitor, DX-9065a, on MCP-1 expression after ischemia-reperfusion in the rat liver. Liver ischemia was induced in rats by occluding the portal vein for 30 min. DX-9065a was injected intravenously 5 min before vascular clamping. Serum concentrations of MCP-1 were measured by enzyme-linked immunosorbent assay. The levels of MCP-1 mRNA in the liver after reperfusion were determined by northern blot analysis. In vitro MCP-1 production by peritoneal macrophages in response to alpha-thrombin was examined. Serum concentrations of MCP-1 increased and peaked at 6 hr after reperfusion. However, pretreatment of animals with DX-9065a resulted in significantly smaller increases in the serum concentration of MCP-1 after reperfusion in a dose-dependent manner. Pretreatment with DX-9065a significantly reduced MCP-1 mRNA levels in the liver after ischemia-reperfusion. In vitro MCP-1 production by peritoneal macrophages was enhanced by alpha-thrombin. In addition, DX-9065a significantly reduced tissue factor mRNA levels in peripheral monocytes after ischemia-reperfusion, compared to untreated animals. In conclusion, a selective inhibitor of FXa, DX-9065a, limited MCP-1 production after ischemia-reperfusion of the rat liver.
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PMID:A synthetic selective inhibitor of factor Xa, DX-9065a, reduces monocyte chemoattractant protein-1 expression after ischemia-reperfusion injury in rat liver. 1063 May 15

We have considered the extracellular serine protease thrombin and its receptor as endogenous mediators of neuronal protection against brain ischemia. Exposure of gerbils to prior mild ischemic insults, here two relatively short-lasting occlusions (2 min) of both common carotid arteries applied at 1-day intervals 2 days before a severe occlusion (6 min), caused a robust ischemic tolerance of hippocampal CA1 neurons. This resistance was impaired if the specific thrombin inhibitor hirudin was injected intracerebroventricularly before each short-lasting insult. Thus, efficient native neuroprotective mechanisms exist and endogenous thrombin seems to be involved therein. In vitro experiments using organotypic slice cultures of rat hippocampus revealed that thrombin can have protective but also deleterious effects on hippocampal CA1 neurons. Low concentrations of thrombin (50 pM, 0.01 unit/ml) or of a synthetic thrombin receptor agonist (10 microM) induced significant neuroprotection against experimental ischemia. In contrast, 50 nM (10 units/ml) thrombin decreased further the reduced neuronal survival that follows the deprivation of oxygen and glucose, and 500 nM even caused neuronal cell death by itself. Degenerative thrombin actions also might be relevant in vivo, because hirudin increased the number of surviving neurons when applied before a 6-min occlusion. Among the thrombin concentrations tested, 50 pM induced intracellular Ca(2+) spikes in fura-2-loaded CA1 neurons whereas higher concentrations caused a sustained Ca(2+) elevation. Thus, distinct Ca(2+) signals may define whether or not thrombin initiates protection. Taken together, in vivo and in vitro data suggest that thrombin can determine neuronal cell death or survival after brain ischemia.
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PMID:The protease thrombin is an endogenous mediator of hippocampal neuroprotection against ischemia at low concentrations but causes degeneration at high concentrations. 1068 55


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