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)

Low molecular weight heparin (LMWH) has similar efficacy to unfractionated heparin with less hemorrhagic complications. We studied the neuroprotective effect of LMWH on a rat model of focal-ischemia. Our results revealed that treatment with LMWH at 1 and 3 h following thrombotic MCA occlusion reduced brain edema and infarct size and improved clinical outcome. Treatment with LMWH initiated at 6 h after thrombin injection only partially ameliorated brain damage.
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PMID:Posttreatment with low molecular weight heparin reduces brain edema and infarct volume in rats subjected to thrombotic middle cerebral artery occlusion. 972 98

The pathophysiology of ischemia-reperfusion injury and the role played by the interaction of plasma proteins, including complement, with reperfused endothelium remains incompletely understood. Venular endothelial changes due to hypoxia followed by reoxygenation (H-R) are vital because venules are the primary site of fluid accumulation and polymorphonuclear leukocyte deposition due to inflammation. This investigation focused on whether H-R potentiates the response to permeability inducing agents found in activated plasma. Activated complement was studied by using zymosan activated plasma (ZAP). Permeability changes were assessed by quantitating rate of clearance of albumin across the monolayers. H-R alone did not change permeability relative to the normoxic condition. ZAP at 2% in normoxic cells increased albumin clearance from 2 +/- 0.2 to 9 +/- 1. 0 microL/h, which increased significantly to 13.5 +/- 2.0 microL/h when given to hypoxia-reoxygenation challenged monolayers. The permeability response to ZAP was dose related and not present with heat inactivated ZAP. ZAP at 2% altered the structure of the cytoskeleton of the human umbilical vein endothelial cells (HUVEC). However, addition of monoclonal anti-complement antibodies or addition of soluble complement receptor-1 did not attenuate ZAP-induced HUVEC permeability. Addition of zymosan-activated serum did not alter the permeability and addition of heparin inhibited the ZAP-induced changes in permeability, suggesting that these changes were mediated via thrombin and not complement. The increase in monolayer permeability due to ZAP was prevented by increasing intracellular adenosine-3',5'-cyclic monophosphate. These findings suggest that HUVEC monolayers challenged with H-R are more susceptible to increases in permeability induced by activated plasma components.
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PMID:Hypoxia-reoxygenation potentiates zymosan activated plasma-induced endothelial injury. 973 93

Thrombosis is responsible for most of the acute manifestations of coronary artery disease, including unstable angina and non-Q-wave myocardial infarction. Antithrombotic therapy with antiplatelet agents and anticoagulants plays a major role in decreasing the risk of ischemic events in such patients. As thrombin generation plays a key role in the pathogenesis of thrombosis, recent studies have focused on thrombin inhibition in the management of acute ischemia. Heparin is the most widely used anticoagulant in the acute phase. Heparin given in therapeutic doses intravenously has been shown to be more effective than aspirin in decreasing the risk of death or myocardial infarction in patients with unstable angina. Low-molecular-weight heparin (LMWH) has improved pharmacologic and pharmacokinetic properties over standard heparin and this may provide greater efficacy and safety. LMWH may be given at fixed subcutaneous dose without monitoring and, therefore, is of greater clinical utility and is more cost-effective than standard heparin. Several LMWHs have been evaluated in the management of acute coronary syndromes and have shown equivalent or improved efficacy compared with standard heparin. As heparin in combination with aspirin is now the treatment of choice in acute unstable coronary syndromes, LMWH could potentially improve the outcome in such patients.
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PMID:Clinical potential of antithrombotic drugs in coronary syndromes. 973 74

We investigated whether antithrombin (AT) can reduce ischemia/reperfusion (I/R)-induced injury of rat liver by promoting prostacyclin release from endothelial cells. Although intravenous administration of AT (250 U/kg) markedly reduced hepatic injury, neither dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, nor Trp49-modified AT, which lacks affinity for heparin, had any effect. Hepatic levels of 6-keto-PGF1, a stable prostacyclin (PGI2) metabolite, were increased significantly after I/R of the rat liver. AT significantly increased the hepatic level of 6-keto-PGF1, whereas neither DEGR-Xa nor Trp49-modified AT increased it. Hepatic tissue blood flow was markedly reduced after I/R. Although AT significantly increased the hepatic tissue blood flow after I/R, neither DEGR-Xa nor Trp49-modified AT increased the blood flow. Hepatic levels of cytokine-induced neutrophil chemoattractant (CINC) and myeloperoxidase (MPO) were significantly increased after hepatic I/R. The levels of these two indicators were reduced by AT but were unaffected by either DEGR-Xa or Trp49-modified AT. Pretreatment of animals with indomethacin (IM) completely inhibited the protective effects of AT on the I/R-induced hepatic damage and the leukocyte activation as well as the AT-induced increase in hepatic 6-keto-PGF1 levels after I/R. Iloprost, a stable analog of PGI2, exhibited effects similar to those of AT and also significantly inhibited the exacerbation of liver injury, the decrease in hepatic tissue blood flow, and the increases in hepatic CINC and MPO levels seen in rats subjected to I/R but pretreated with IM. These findings suggest that AT may prevent I/R-induced hepatic injury by increasing the hepatic levels of PGI2 through the interaction of AT with cell-surface glycosaminoglycans, thus increasing hepatic tissue blood flow and inhibiting leukocyte activation in animals subjected to I/R.
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PMID:Antithrombin reduces ischemia/reperfusion injury of rat liver by increasing the hepatic level of prostacyclin. 986 57

A number of models of focal ischemia have been created to mimic acute middle cerebral artery (MCA) occlusion. In the present series of experiments, we report our observations on the thrombin model of MCA occlusion and the neuroprotective effects of intraarterial thrombolysis with two doses of urokinase (2500 and 5000 units/kg). In all experiments male Wistar rats were used and the animals were allowed to recover for 48 h before assessment of neurobehavioral performance on a four-point scale. The extent of cerebral hemispheric damage was calculated as the percentage of brain infarction using TTC staining. Occlusion of the MCA was effected by the introduction of an autologous blood clot into the internal carotid artery (ICA) approximately 2 mm from the origin of the MCA. This clot was formed by the drawing of 10 microl of blood into a bovine thrombin (20 microg per animal) containing intraarterial catheter, which was inserted into the right ECA. After standing for 15 min to allow clot formation, the catheter was advanced gently through the ICA to the site of injection. MCA occlusion produced a consistent large infarction in all animals. Urokinase infusion (i.a. ) was started 2 h after arterial occlusion in the initial series. In animals treated with low dose urokinase infusion there was mild protection. Animals treated with high dose urokinase infusion showed a highly significant improvement in the motor recovery and a decrease in the extent of infarction compared to control animals. In the final group, the infusion of urokinase was delayed for 3 h. While producing protection in some animals, it also produced intracerebral hemorrhage in two of eight animals. Thus delay of infusion to 180 min increased the risk of hemorrhage. This model may in the future be used to test the protective effects of combination therapy with thrombolysis and neuroprotective medications.
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PMID:Intraarterial urokinase produces significant attenuation of infarction volume in an embolic focal ischemia model. 987 71

Generalized atherosclerosis and coronary artery disease (CAD) are associated with endothelial dysfunction and during acute myocardial ischemia platelet activation has been reported. Activated platelets exert activated fibrinogen receptors (GP IIb/IIIa) and express CD 62p being regarded as reliable marker for platelet activation. Patients with angiographically proven CAD performed a bicycle exercise test until the onset of angina or ST-segment depression. We studied the ischemia-induced alterations in fibrinogen binding to activated platelet GP IIb/IIIa receptors and CD 62p expression. Therefore, the basal fibrinogen binding to GP IIb/IIIa and CD 62p expression and the thrombin-concentration for half-maximal platelet activation before and after exercise testing were determined. Additionally, inhibition of thrombin-induced platelet activation by increasing concentrations of the prostacyclin-analog iloprost and the NO-donor SIN-1 was examined. In patients with CAD, a significantly reduced basal activation and a highly significant reduction in sensitivity towards thrombin was measured. The thrombin-induced expression of GP IIb/IIIa and CD 62p was significantly diminished in patients with CAD after physical exercise and their platelets were significantly more sensitive towards the inhibitory effects of iloprost and SIN-1. These data demonstrate a significant reduction in platelet activation in response to physical exercise in patients with CAD and advanced atherosclerosis. Despite exercise induced myocardial ischemia as evidenced by angina and ECG-changes, the platelets are not generally activated, as it could be expected. Thus, patients with myocardial ischemia experienced a reduced platelet activity and enhanced sensitivity towards prostacyclin (PGI2) and nitric oxide, probably due to an augmented release of endogenous platelet inhibitory mediators.
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PMID:Increased platelet sensitivity toward platelet inhibitors during physical exercise in patients with coronary artery disease. 995 Feb 58

In this study, we evaluated the role of proteolytic enzymes belonging to the coagulation, fibrinolytic, and plasma contact systems in the early postoperative phase after orthotopic liver transplantation (OLT). Twenty-nine patients were studied at the time of OLT and during the first 2 postoperative weeks. Blood samples were collected daily after OLT and analyzed for kallikrein-like activity (KK), functional kallikrein inhibition (KKI), plasmin-like activity (PL), and alpha2-antiplasmin (AP). In addition, prekallikrein (PKK), prothrombin (PTH), antithrombin III (AT III), plasminogen (PLG), prothrombin/antithrombin III complexes (TAT), prothrombin fragment 1 + 2 (F1 + 2), and plasmin/alpha2-antiplasmin complexes (PAP) were measured. Nineteen patients experienced biopsy-verified acute rejections (AR) and ten patients had uneventful courses and served as controls. Plasma analyses showed that the contact, coagulation, and fibrinolytic systems were activated during OLT. Following OLT, continuous thrombin and plasmin generation was observed, and these effects were more pronounced in the group having an uneventful course than in patients with AR. Factors that could possibly affect plasma proteolytic activity, such as blood product usage during and after OLT and cold ischemia time of the liver graft, did not differ between the groups, nor did the routine liver function tests, alanine aminotransferase (ALT) and aspartate aminotransferase (AST).
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PMID:Plasma proteolytic activity in liver transplant rejection. 1036 91

The cardiac sarcolemmal Na+/H+ exchanger (NHE) extrudes one H+ in exchange for one Na+ entering the myocyte, utilizing for its driving force the inwardly directed Na+ gradient that is maintained by the Na+/K+ ATPase. The exchanger is quiescent at physiological values of intracellular pH but becomes activated in response to intracellular acidosis. Recent evidence suggests that a variety of extracellular signals (e.g., adrenergic agonists, thrombin, and endothelin) also modulate sarcolemmal NHE activity by altering its sensitivity to intracellular H+. Since sarcolemmal NHE activity is believed to be an important determinant of the extent of myocardial injury during ischemia and reperfusion, regulation of exchanger activity by endogenous ligands associated with ischemia is likely to be of pathophysiological importance.
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PMID:Regulation of cardiac sarcolemmal Na+/H+ exchanger activity by endogenous ligands. Relevance to ischemia. 1041 45

The Na(+)/H(+) exchanger is a pH-regulatory protein present in the plasma membrane of cardiomyocytes and other cell types. In response to intracellular acidosis, the protein removes one intracellular proton in exchange for an extracellular sodium. The protein consists of a membrane transporting domain and a regulatory cytosolic domain. The regulatory cytosolic domain mediates the stimulation of the membrane domain. Hormonal stimulation of myocardial cells results in activation of the antiporter, possibly through protein kinases and other regulatory proteins. Several hormones and growth factors have been shown to stimulate the antiporter in the myocardium, including endothelin, thrombin, angiotensin II, and alpha(1)-adrenergic stimulation. The exact mechanisms involved in this stimulation are as yet unclear, and may be important in regulation of the Na(+)/H(+) exchanger during ischemia and reperfusion.
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PMID:Functional and cellular regulation of the myocardial Na+/H+ exchanger. 1048 Dec 9

The cardiac sarcolemmal Na(+)/H(+) exchanger (NHE) extrudes one H(+) in exchange for one Na(+) entering the myocyte, utilizing for its driving force the inwardly directed Na(+) gradient maintained by the Na(+), K(+)-ATPase. The exchanger is quiescent at physiological values of intracellular pH but becomes activated in response to intracellular acidosis. Recent evidence suggests that a variety of extracellular signals (e.g., adrenergic agonists, thrombin, endothelin, and oxidant stress) also modulate sarcolemmal NHE activity by altering its sensitivity to intracellular H(+). Because sarcolemmal NHE activity is believed to be an important determinant of the extent of myocardial injury during ischemia and reperfusion, regulation of exchanger activity by factors that are associated with ischemia is likely to be pathophysiological importance.
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PMID:Regulation of cardiac sarcolemmal Na+/H+ exchanger activity: potential pathophysiological significance of endogenous mediators and oxidant stress. 1048 Dec 11


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