Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antiaggregatory and antithrombotic actions of MK-0383, a low molecular weight, nonpeptide antagonist of the platelet glycoprotein IIb/IIIa, were evaluated in a variety of canine models. Inhibition of ex vivo platelet aggregation responses to ADP and collagen were observed after the acute sequential i.v. administrations of 10 to 500 micrograms/kg or 360-min continuous i.v. infusions of 1 to 10 micrograms/kg/min of MK-0383. Hemostatic function normalized within 30 (platelet response to collagen, template bleeding times) to 90 min (platelet response and sensitivity to ADP) after the termination of 360-min i.v. MK-0383 infusions, suggesting no protracted, direct effects on platelet function. With acute sequential i.v. administrations of MK-0383, platelet response to ADP was abolished without significant extension of bleeding time. In a model of platelet-dependent cyclic flow reductions in injured, stenosed left circumflex coronary artery, the bolus i.v. administrations of 300 and 1000 micrograms/kg of MK-0383 totally abolished cyclic flow reductions for periods of 18 +/- 1 and 37 +/- 5 min, respectively. In a model of electrically induced left circumflex coronary artery occlusive thrombosis, 10 micrograms/kg/min i.v. of MK-0383 initiated 15 min before electrical injury prevented occlusive thrombosis in three of six preparations despite continued electrical stimulation of the vessel for 300 min, delayed occlusion in three of six preparations (160.3 +/- 5.5 min) and reduced thrombus mass (5.1 +/- 1.3 mg), compared to the development of occlusive thrombosis in six of six saline-treated preparations (50.5 +/- 8.7 min; 19.1 +/- 3.0 mg). When administered as an adjunct to thrombolytic agents in the presence of background heparin for lysis of electrically induced left circumflex coronary artery occlusive thrombus, 10 micrograms/kg/min i.v. of MK-0383 initiated 15 min before tissue-type plasminogen activator or streptokinase increased the incidence of (tissue-type plasminogen activator: eight of nine MK-0383 vs. three of eight saline; streptokinase: eight of eight MK-0383 vs. two of eight saline) and accelerated reperfusion, and reduced the incidence of acute thrombotic reocclusion during continued MK-0383 infusion. These findings indicate significant antithrombotic potential for MK-0383 alone or as an adjunct to thrombolytic therapy in the treatment of coronary artery ischemic syndromes.
 ...
PMID:Nonpeptide glycoprotein IIb/IIIa inhibitors. 5. Antithrombotic effects of MK-0383. 781 34

We have studied the relationships between whole blood and plasma serotonin (5-hydroxytryptamine, 5-HT), its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) and serum lipids, platelet aggregation in the whole blood and in the platelet-rich plasma (PRP), and some fibrinolytic parameters in monkeys. Plasma 5-HT was found to be positively related to 5-HT- and ADP-induced platelet aggregation, tissue plasminogen activator (tPA) activity, serum cholesterol and LDL-cholesterol, whereas 5-HT in cerebrospinal fluid correlated inversely with serum cholesterol. Plasminogen activator inhibitor (PAI) activity was positively related to LDL. Euglobulin clot lysis time was related to both tPA and PAI activities. The significance of these findings and the possible role of 5-HT in atherogenesis and hemostasis are discussed.
 ...
PMID:Correlations between platelet aggregation, fibrinolysis, peripheral and central serotonergic measures in subhuman primates. 775 51

Rupture of the lipid-rich atheromatous plaque, intraplaque hemorrhage, and intraluminal thrombus are three pathological hallmarks most commonly recognized in the infarct-related coronary artery at the site of acute myocardial infarction. Rupture of the atheromatous plaque is closely related to but does not fully explain the genesis of occlusive intracoronary thrombus formation and thus the development of acute myocardial infarction. Besides a variety of hematologic disorders, one should emphasize the role of the platelet-derived mediators that promote an environment where thrombosis and vasoconstriction occur, including TXA2, serotonin, ADP, platelet-derived growth factor, tissue factor, and the diminished availability of those natural endogenous substances that inhibit platelet aggregation, such as EDRF, tissue plasminogen activator, and PGI2. PGI2 released from vascular endothelial cells is extremely unstable. Our group provided the first evidence that HDL stabilizes PGI2 through the newly discovered function of Apo A-I, which is associated with the surface of HDL particles and identified as PGI2 stabilizing factor. Decrease in HDL-associated Apo A-I in patients with unstable angina and during the acute phase of myocardial infarction indicates that HDL plays an important role in preventing coronary atherosclerosis and intracoronary thrombus formation by stabilizing PGI2 in addition to the generally accepted biochemical property of HDL to prevent the accumulation of cholesterol by mobilizing free cholesterol from tissues or macrophages. There is also a PGI2 synthesis-stimulating factor in serum that has not yet been identified chemically. EDRF or nitric oxide provides another important regulating system in the vessel wall. Lipoproteins are inhibitors of endothelium-dependent relaxation of rabbit aorta.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Pathogenesis of acute myocardial infarction. Novel regulatory systems of bioactive substances in the vessel wall. 804 17

The influence of erythropoietin therapy on platelet function and fibrinolysis was evaluated in 12 anemic hemodialysis patients. Six months of therapy with human erythropoietin (50 to 80 IU/kg initially) raised the hemoglobin level to 10.8 g/dl but did not increase platelet activity in vivo as measured by beta-thromboglobulin or platelet factor 4. There was no change in the platelet aggregation thresholds in vitro for ADP, adrenaline, thrombin or collagen during treatment. Platelet number and volume were also unaffected. Fibrinolytic activity intensified as erythropoietin treatment proceeded, with a fall of euglobulin clot lysis time and rise in the activity of t-PA. PAI-1 levels also showed a downward trend, without reaching significance. Thus erythropoietin treatment in modest doses does not seem to adversely influence the hemostatic system in patients on hemodialysis.
 ...
PMID:The effect of erythropoietin on platelet function and fibrinolysis in chronic renal failure. 805 Aug 4

Clopidogrel is a thienopyridine derivative and a potent inhibitor of ADP-induced platelet aggregation. We compared clopidogrel with aspirin as an adjunctive treatment to tissue-type plasminogen activator (t-PA) for thrombolysis and reocclusion. Thrombosis was induced in coronary arteries of 32 dogs by injuring the endothelium with an electric charge. Coronary blood flow velocity was monitored by a pulsed Doppler flow probe placed around the artery. After the artery had been occluded by a thrombus for 3 continuous hours, each animal was given one of the following intravenous treatments: 1) t-PA (80 micrograms/kg + 8 micrograms.kg-1.h-1) and heparin (200 U/kg) (group 1, n = 7); 2) t-PA, heparin, and aspirin (5 mg/kg) (group 2, n = 8); 3) t-PA, heparin, and clopidogrel (5 mg/kg) (group 3, n = 9); and 4) t-PA, heparin, and clopidogrel (10 mg/kg + 2.5 mg.kg-1.h-1) (group 4, n = 8). After treatment, thrombolysis developed in 45 +/- 12 min in group 1, 39 +/- 10 min in group 2, 39 +/- 10 min in group 3, and 27 +/- 10 min in group 4 (compared with group 1, P > 0.05). After thrombolysis, reocclusion occurred in 5 of 5 dogs in group 1 and 7 of 7 in group 2, but only 2 of 7 in group 3 and none of 7 in group 4 (compared with groups 1 and 2, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Clopidogrel is more effective than aspirin as adjuvant treatment to prevent reocclusion after thrombolysis. 806

Plasminogen and tissue-type plasminogen activator bind to the platelet surface, and as a result, the catalytic efficiency of plasminogen activation is significantly enhanced. The plasmin that is generated on or near the platelet is known to affect a number of platelet surface events. For this reason, we examined the effect of plasmin on platelet-surface plasminogen activation and its determinants. Specifically, we measured the effects of plasmin treatment of platelets (1 caseinolytic unit/mL for 1 h at 37 degrees C) on plasminogen, tissue-type plasminogen activator, and plasmin binding to the unactivated and ADP-activated platelet surface; and on the kinetics of plasminogen activation on the platelet surface. Following plasmin treatment, the number of plasminogen binding sites on unactivated platelets increased by 78% (from 46,000 +/- 4000 to 88,000 +/- 9000 sites/platelet), while the number of tissue-type plasminogen activator sites did not change, and the number of diisopropyl fluorophosphate (DFP)-inactivated plasmin (DFP-plasmin) binding sites decreased by 31% (from 92,000 +/- 11,000 to 65,000 +/- 7000 sites/platelet); the dissociation constants (Kds) for each of these binding processes did not change significantly following treatment. On ADP-activated platelets, plasmin treatment increased the number of plasminogen binding sites by 41% (from 188,000 +/- 17,000 to 265,000 +/- 25,000 sites/platelet), decreased the number of plasmin binding sites by 28% (from 219,000 +/- 41,000 to 157,000 +/- 24,000 sites/platelet), and did not affect the number of tissue-type plasminogen activator sites; again, the Kds for each of these binding processes did not change significantly following treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Kinetics and mechanism of platelet-surface plasminogen activation by tissue-type plasminogen activator. 813 Feb 11

An antithrombotic action of the protein C (PC) activator from the venom of Agkistrodon blomhoffi ussuriensis on the model of platelet-dependent thrombosis in the arteriovenous shunt in rats was under investigation. Administration of the PC activator to rats resulted in a dose-dependent prolongation of the thrombus formation time, in a decrease in PC and factor V levels in blood and in APTT prolongation. There were no changes in the tissue-type plasminogen activator level and in the ADP- or epinephrine-induced platelet aggregation, but platelet adhesion to glass decreased. The possible mechanism of the antithrombotic action of the PC activator appeared to be the factor V inactivation mediated by protein C activation and the decrease in platelet adhesion.
 ...
PMID:[The antithrombotic action of a protein C activator from the venom of Agkistrodon blomhoffi ussuriensis in thrombus formation in an extracorporeal shunt in rats]. 820 48

In 12 healthy young men, strenuous cycling exercise in the supine position, caused platelet aggregability to decrease and the ADP threshold to rise from 7.0 microM resting, to 9.5 exercising (P < 0.01). At the same time, fibrinolytic activity increased markedly: euglobulin clot lysis time shortened from 178 to 68 min, PAI-1 fell from 8.91 to 5.16 IU ml-1, and t-PA rose from 0.56 to 3.95 IU ml-1, all three values were significant to P < 0.01. When the erect posture was assumed after lying at ease for 1 h after exercise, it did not increase platelet activity as expected, but caused a modest increase of fibrinolytic activity. These results suggest that supine exercise will not affect the haemostatic system adversely.
 ...
PMID:Effect of supine exercise on platelet aggregation and fibrinolytic activity. 820 49

The experiments reported here were carried out to define in greater detail actin's stimulation of plasmin generation by t-PA. Actin did not alter t-PA's hydrolysis of a synthetic substrate, and thus is unlikely to have a direct effect upon t-PA's proteolytic activity. When studied in a single-stage assay, actin accelerated t-PA-mediated plasmin generation from both Glu-plasminogen and Lys-plasminogen, indicating the central role of ternary complex formation. Although actin does not appear to bind two-chain urokinase (tcu-PA), it stimulates tcu-PA's cleavage of Glu-plasminogen. This finding suggests that actin alters the conformation of Glu-plasminogen to an open form. The failure of actin to increased plasmin generation by tcu-PA acting on Lys-plasminogen, which is in an open configuration, is consistent with this interpretation. Immunoglobin G, which shares with actin the property of binding to Glu-plasminogen after nicking by plasmin, did not stimulate tcu-PA's cleavage of Glu-plasminogen, indicating the uniqueness of actin's effects and suggesting interactions between actin and plasminogen at multiple binding sites. Unlike fibrin and heparin, whose stimulation of t-PA is related to polymer length actin is able to stimulate t-PA when presented in either a monomeric or polymeric form. Denaturation of actin by exposure to urea and guanidine increased its ability to stimulate plasmin generation by t-PA. Because actin's structure is maintained by a noncovalently bound adenine nucleotide (ATP or ADP), exposure to ATP/ADPases found in plasma and on cell membranes might also result in its denaturation. Actin treated with an enzyme functionally similar to such ecto-ATP/ADPases, potato apyrase, was more potent than native actin in stimulating plasmin generation by t-PA. The effects of apyrase were blocked by the addition of the plasma actin-binding proteins, gelsolin and the vitamin D-binding protein (DBP). Thus, denaturation of actin may occur in under physiologic conditions, with potential biological consequences. Actin thus appears to be unique with regard to its interactions with the fibrinolytic system and plasma actin-binding proteins may serve to protect the host from the effects of denatured actin.
 ...
PMID:Actin stimulates plasmin generation by tissue and urokinase-type plasminogen activators. 823 51

Inhibition of the platelet glycoprotein (GP) IIb/IIIa receptor with the murine monoclonal antibody 7E3 abolishes ex vivo platelet aggregation, reduces thrombogenicity, and sustains arterial recanalization with recombinant tissue-type plasminogen activator (rt-PA). A chimeric murine/human Fab fragment of 7E3 (c7E3-Fab) has a markedly reduced immunogenicity, but its potency as an adjunct for thrombolysis with rt-PA has not been evaluated. The effects of a single intravenous bolus injection of aspirin (17 mg/kg) or c7E3-Fab (0.45 mg/kg) on thrombolysis and reocclusion induced with rt-PA were studied in groups of six baboons with femoral arterial thrombosis and superimposed high-grade stenosis. This dose of c7E3-Fab blocked 96 +/- 1% of the platelet GPIIb/IIIa receptors and abolished ADP-induced platelet aggregation. Bolus intravenous injections of rt-PA (0.25 mg/kg) were repeated at 15-minute intervals until reperfusion occurred (maximum of four injections). In the aspirin group, reperfusion was obtained within 51 +/- 16 minutes (mean +/- SD) but was rapidly followed by reocclusion within 6 +/- 9 minutes and by cyclic reflow and reocclusion. In the c7E3-Fab group, reperfusion was obtained within 25 +/- 8 minutes (P < .01 versus aspirin group) and was associated with a delayed reocclusion of 63 +/- 63 minutes (P < .05 versus aspirin group). Template bleeding times remained unchanged in the aspirin/rt-PA group but were markedly prolonged (to > 30 minutes) in the c7E3-Fab/rt-PA group.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:A chimeric murine/human antibody Fab fragment directed against the platelet GPIIb/IIIa receptor enhances and sustains arterial thrombolysis with recombinant tissue-type plasminogen activator in baboons. 824 Nov 5


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>