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)

1. We have investigated the effect of sodium nitroprusside (NP) and glyceryl trinitrate (GTN) on fibrinolysis in anaesthetized rabbits ex vivo and in vitro by measurement of euglobulin clot lysis time (ECLT), plasma levels of tissue plasminogen activator (t-PA) activity, plasma t-PA antigen levels and plasminogen activator inhibitor (PAI-1) activity. 2. In vivo, NP (30 micrograms kg-1), GTN (30 micrograms kg-1) and prostacyclin (3 micrograms kg-1) caused similar transient decreases in left ventricular systolic pressure. However, while prostacyclin induced near-maximal inhibition of ex vivo platelet aggregation, NP or GTN had no effect. 3. Ex vivo, NP caused a significant decrease in ECLT and an increase in plasma t-PA activity. 4. Intravenous co-administration of t-PA (30 micrograms kg-1) with NP caused substantial prolongation of plasma t-PA activity, without affecting t-PA antigen levels. 5. In whole blood in vitro, NP (30 micrograms kg-1) prevented the time-dependent increase in PAI-1 activity and inhibited inactivation of added t-PA (10 ng ml-1). 6. We propose that NP exhibited fibrinolytic activity through increased t-PA activity as a result of inhibition of PAI-1 release from platelets. These results could have important therapeutic consequences when t-PA and nitrate treatments are combined.
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PMID:Sodium nitroprusside modulates the fibrinolytic system in the rabbit. 212 49

Endothelial cells produce at least three substances that can attenuate the platelet aggregation response: tissue-type plasminogen activator; the platelet inhibitory prostaglandins I2 and E1; and endothelium-derived relaxing factor, one form of which exhibits properties of nitric oxide. Since platelet aggregates formed in vivo are involved in the initiation of many clinically important occlusive vascular syndromes, we tested the hypothesis that these endothelial products act synergistically to disperse platelet aggregates. Our data reveal that tissue-type plasminogen activator, prostaglandin E1, and nitroglycerin (an organic nitrate activator of guanylate cyclase analogous to endothelium-derived relaxing factor) act synergistically to disaggregate platelets and do so in part by modulation of platelet cyclic nucleotides. These data suggest a potential mechanism by which the endothelium protects against the formation of platelet aggregates in vivo and offer a potential strategy for improving the efficacy of thrombolytic therapy.
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PMID:Synergistic disaggregation of platelets by tissue-type plasminogen activator, prostaglandin E1, and nitroglycerin. 250 9

Treatment of ischemic deficits caused by vasospasm relies on enhancing cardiac output, inducing arterial hypertension, and expanding the intravascular volume in an attempt to improve CBF. Different treatment protocols exist from institution to institution to achieve these goals. The role of calcium-channel blockers now is well established. The newest focus on prevention of vasospasm includes tPA and a variety of anti-inflammatory drugs and potential neuroprotective drugs under research. Endovascular therapy for vasospasm has an increasing role in treating patients who are unable to tolerate induced hypertension or aggressive volume augmentation. We will return to our index case of the 63-year-old woman with SAH caused by an ACoA aneurysm to review some major management issues. After placing a ventriculostomy and slowly lowering ICP, the patient became alert and was fully oriented. She had aneurysm surgery on hospital day 2, with an uncomplicated immediate postoperative course. A Swan-Ganz catheter, placed for intraoperative monitoring, was kept in place and she was hydrated with 125 mL/hour of normal saline, achieving a PAWP of 10 to 16 mm Hg. Her mean arterial blood pressure without pharmacologic intervention was 95 to 110 mm Hg. She had continued clinical improvement with resolution of her left hemiparesis. On hospital day 5, her ventriculostomy was clamped because cerebrospinal fluid drainage was minimal. The following morning, the patient was arousable only to deep pain and her left side was flaccid. An emergent CT scan demonstrated no new hemorrhage, no increase in ventricular size, and no infarct. Vasospasm was considered the most likely cause. Hypertensive therapy was about to be initiated with a phenylephrine drip, but within an hour she was fully alert and moving all extremities equally. A search for other potential causes of neurologic decline was undertaken and revealed a phenytoin level of 5.5. It was thought that the patient most likely had had a seizure and that her clinical deterioration represented a postictal state. She received a bolus infusion of phenytoin. On hospital day 7, the patient became confused, insisting that her nurse was her son and ordering him out of her "apartment." Lower extremity weakness was detected. CT scan was unchanged. Phenylephrine was started but she developed precordial lead ST elevation and elevated cardiac enzymes. Topical nitrate therapy was initiated and phenylephrine was discontinued. The patient underwent emergent cerebral angiography, which demonstrated moderate to severe bilateral ACA spasm and moderate right MCA spasm.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Management of aneurysmal subarachnoid hemorrhage. 747 15

Recent studies have strengthened the arguments for the use of angiotensin-converting enzyme (ACE) inhibitors in the early postinfarct period. Those with clinically detectable heart failure, and hence at highest risk, will benefit most, as shown in the AIRE study, but those at lower risk with left ventricular dysfunction still have some benefit, theoretically through ventricular remodeling. In patients in the very early stages of acute myocardial infarction, three trials have shown discordant results. In CONSENSUS-II, intravenous enalaprilat followed by oral enalapril gave no benefit, rather causing excess hypotension and a possible increase in mortality. In ISIS-4 and GISSI-3, mortality improved by 0.46% and 0.8%, respectively, with risk reductions of 9% and 11%. Added transdermal nitrate in GISSI-3 gave a total reduction of 17%. In view of the risk of hypotension (20% in ISIS-4, compared with placebo 10%), very early ACE inhibition will probably only be used for selected patients. Logically, one target group would be those seen 7-24 hours after the onset of symptoms, particularly 7-12 hours, at which time captopril alone gave a reduction of 14.5% in risk. These mortality differences compare favorably with those recently found when comparing tPA and streptokinase in the GUSTO study.
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PMID:The new trials: AIRE, ISIS-4, and GISSI-3. Is the dossier on ACE inhibitors and myocardial infarction now complete? 794 63

Experiments were performed to examine the effect of the major fibrinolytic protease, plasmin, on the production of nitric oxide from interleukin-1 beta (IL-1 beta)-treated cultured human and rat aortic smooth muscle cells. Incubation of vascular smooth muscle cells with IL-1 beta resulted in significant accumulation of nitrite and nitrate in the culture media. Plasmin, either added exogenously or generated by the reaction of tissue plasminogen activator with plasminogen, potentiated the IL-1 beta-mediated release of nitrite and nitrate from smooth muscle cells in a concentration-dependent manner, without affecting the production of nitrite and nitrate from cells untreated with IL-1 beta. This potentiating effect was abolished when plasmin was incubated with the protease inhibitor, alpha 2-antiplasmin. The perfusates from columns containing IL-1 beta-treated smooth muscle cells relaxed detector blood vessels without endothelium, and the addition of IL-1 beta-treated smooth muscle cells to suspensions of indomethacin-treated platelets inhibited their aggregation. Untreated smooth muscle cells or cells treated with plasmin alone did not have such effects. However, the simultaneous treatment of smooth muscle cells with IL-1 beta and plasmin markedly enhanced both the relaxing activities of the perfusates and the inhibition of platelet aggregation. Treatment of smooth muscle cells with NG-nitro-L-arginine inhibited the cytokine-mediated effects as well as the potentiating effect of plasmin. These results demonstrate that the plasmin can enhance the production of nitric oxide by IL-1 beta-treated vascular smooth muscle cells.
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PMID:Plasmin potentiates induction of nitric oxide synthesis by interleukin-1 beta in vascular smooth muscle cells. 844 74

Magnesium (Mg) has shown the ability to inhibit arterial thrombus formation in some experimental animal studies. This effect may be due to an inhibition of platelet reactivity as in vitro studies have demonstrated that Mg inhibits platelet aggregation. In order to evaluate the in vivo effect of Mg in humans measurements of platelet activity, fibrinolytic activity, as well as measurements of prostacyclin (PGI2), and nitric oxide (NO) release were performed after infusion of magnesium sulphate (MgSO4) in healthy volunteers. In a placebo controlled, cross-over study in 14 healthy male subjects, 8 mmol MgSO4 was given as an intravenous bolus over 15 min followed by 3 mmol MgSO4/h. The mean S-Mg concentration increased from 0.85 to 1.50 mM during the Mg infusion period. A transient decrease in blood pressure was observed during the initial bolus infusion of Mg. Haemodynamic parameters were otherwise unstable. The bleeding time increased by 48% during the Mg infusion (p < 0.005), and in accordance with this, ex vivo platelet aggregation in platelet rich plasma was significantly inhibited, both following collagen (p = 0.02) and ADP (p = 0.04) stimulation. There were no significant changes in plasma beta-thromboglobulin concentration or the excretion of 2,3-dinor-thromboxane B2 in the urine. Neither tissue plasminogen activator (t-PA)activity, tissue plasminogen activator (t-PA)antigen nor plasminogen activator inhibitor (PAI)antigen changed during the Mg infusion period. There was no sign of increased release of PGI2 from the vessel wall as judged by urinary concentration of 2,3-dinor-6-keto-prostaglandin F1 alpha. Nor was there any sustained increase in the release of NO, measured as nitrate concentration in urine. However, a transient increase in NO release was observed during one sample period. In conclusion a reduced platelet activity and increased bleeding time, was found during Mg infusion in healthy volunteers. Fibrinolytic activity showed no changes. An anti-platelet effect may in part be responsible for the beneficial effect of Mg, described in patients with acute myocardial infarction (MI) and preeclampsia.
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PMID:Magnesium inhibits platelet activity--an infusion study in healthy volunteers. 882 90

Vasotropic, haemostatic and haemorheological parameters have been investigated in 17 patients suffering from migraine without aura in comparison with 11 sex and age matched healthy control subjects. NO metabolites (NO2- and NO3-), endothelin (ET-1), tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI-1), fibrinogen, D-dimer, fibrinopeptide A, beta thromboglobulin (beta-TG), blood viscosity, plasma viscosity, haematocrit (Htc) and red blood cell (RBC) filterability index (FI) were determined during headache free periods. Migraineurs NO3- and ET-1 plasma levels, compared to control values, showed a significant decrease and increase respectively; fibrinogen, beta-TG and D-dimer appeared slightly lowered in migraineurs, while Htc remained in the normal limits; tPA, PAI-1 and FI were significantly reduced, while fibrinopeptide A, blood viscosity and plasma viscosity at a low shear rate (shr) exhibited a significant rise. Data obtained support the involvement of endothelial, haemostatic and haemorheological functions in the pathogenesis of migraine.
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PMID:Endothelial, haemostatic and haemorheological modifications in migraineurs. 886 51

Patients with atrial fibrillation have been reported to exhibit abnormal hemostasis. Since nitric oxide (NO) exerts antithrombotic effects and attenuates platelet function, we evaluated two indicators of plasma NO levels, the plasma levels of nitrite and nitrate (NOx), and the levels of cGMP in platelets. We also examined whether indicators of plasma NO levels were associated with abnormalities in parameters related to platelet function, blood coagulation, and fibrinolysis. We evaluated 45 patients with chronic sustained atrial fibrillation (33 men and 12 women, age range 63 +/- 2 years) compared with 45 sex- and age- (+/- 2 years) matched nonhospitalized subjects with sinus rhythm. There were no significant differences between the two groups in the incidence of risk factors for stroke except for ischemic heart disease or in echocardiographic parameters. Plasma levels of NOx measured using the Greiss reagent (mean [interquartile range]: 15.6 [9.5 to 25.7] versus 24.1 [14.2 to 40.8] mumol/L, n = 45) and the platelet cGMP levels (0.33 [0.16 to 0.67] versus 0.63 [0.31 to 1.29] pmol/10(9) platelets, n = 9) were significantly (P < .05) lower in the patients with atrial fibrillation than in the control subjects. Plasma levels of D-dimer, beta-thromboglobulin, and fibrinogen were significantly (P < .05) higher in the patients with atrial fibrillation. The two groups did not differ as to the plasma levels of tissue plasminogen activator or plasminogen activator inhibitor-1. Our findings suggest that a decrease in plasma NO levels may account for the hemostatic abnormalities observed in patients with atrial fibrillation.
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PMID:Plasma levels of nitrite/nitrate and platelet cGMP levels are decreased in patients with atrial fibrillation. 940 10

Among cardiovascular diseases, hypertension, angina pectoris, acute myocardial infarction and ischemic stroke present a circadian pattern with a greater incidence of unfavourable events between awakening and noon. Chronotherapy aims to use drugs that release their active principles at different times during the day, according to biological needs. In chronotherapy of cardiovascular diseases, a particular attention has been paid to slow-release drugs that assure a 24 hours therapeutic effect with once a day administration. In primary hypertension well controlled by monotherapy (dipper hypertensives), the morning administration of long-acting beta-blockers and calcium antagonists has shown to control blood pressure over 24 hours, whereas ACE-inhibitors have proved more effective when administered at evening. In secondary hypertension (non dipper hypertensives) the administration of calcium antagonists is more effective at evening. Patients with severe hypertension need polytherapy. In that case, at least one of the antihypertensive drugs should be given at evening to lower night blood pressure values, which are particularly elevated also during sleep, and so to prevent an excessive blood pressure rise on awakening. In chronic monotherapy of ischemic heart disease, long-acting beta-blockers and calcium antagonists have shown to be equally effective when they are administered at morning, whereas slow-release nitrates, which need a nitrate-free interval, are to be administered either at morning or at evening, according to the expected time of onset of anginal pain. ASA seems to reduce the morning incidence of acute myocardial infarction, while tissue-type plasminogen activator presents a circadian variation of its thrombolytic activity with a higher efficacy between noon and midnight.
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PMID:[Application of chronotherapy to cardiovascular diseases]. 979 79

Clinical effects of recombinant human erythropoietin (rHuEPO) such as thrombosis, convulsions, hyperviscosity, hypertension, and angiogenic effect in culture cells have been described. We studied the rHuEPO effect on endothelial damage markers and endothelial function markers: tissue-type plasminogen activator (t-PA), nitrate (NO3), thrombomodulin (TM), and von Willebrand factor (vWF). Twenty-six peritoneal dialysis patients treated with rHuEPO and 19 controls were included. The study design for rHuEPO patients consisted of four periods: long-term treatment (rHuEPO-1); 2 months of withdrawal (rHuEPO-2); and 4 months on 5000 IU/week rHuEPO subcutaneously, with markers being measured after 2 months (rHuEPO-3) and after 4 months (rHuEPO-4). After 2 months of rHuEPO withdrawal, a decrease in hemoglobin level appeared (11+/-1.8 g/dL to 9.2+/-1.5 g/dL, p < 0.01). After rHuEPO reintroduction, this value reached 10.6+/-1.5 g/dL at two months, and 11.1+/-1.4 g/dL at four months. A significant increase in t-PA ratio was observed from two months without rHuEPO to two months on rHuEPO, returning to previous values after four months. Similarly, TM increased for patients with creatinine clearances (CrC) < 5 mL/min. No changes in the higher-than-normal plasma vWF levels were found during the various periods. A statistically significant lower value was found in controls compared with rHuEPO-4 patients. A statistically significant increase in NO3 levels was observed in the pre-venous occlusion (VO) test immediately after the re-introduction of rHuEPO. This increment returned to prior values four months after rHuEPO was reintroduced. Our results show that rHuEPO treatment causes an increase in some endothelial damage markers (TM, t-PA) and modifies endothelial function markers (t-PA ratio, NO3). These changes might favor thrombosis and atherosclerosis.
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PMID:Effects of recombinant human erythropoietin on functional and injury endothelial markers in peritoneal dialysis patients. 1040 11


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