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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the efficacy of tissue-type plasminogen activator (t-PA) for coronary thrombolysis is well established, its direct cardioprotective effect - independent of its thrombolytic effect - is still controversial. In addition, the potentiation of t-PA's direct cardioprotective effect by thromboxane A2 synthetase inhibitor has recently been reported. In this study, the authors examined whether t-PA alone or in combination with DP1904, a thromboxane A2 synthetase inhibitor, is able to salvage ischemic myocardium via a direct action on myocardium. In addition, the effect of these interventions on intramyocardial hemorrhage in reperfused infarcts was assessed. A branch of the coronary artery of the rabbit was occluded for 30 mins and then reperfused for 72 h. Myocardial infarct size and 'area at risk' were determined by histology and fluorescent particles, respectively. The extent of intramyocardial hemorrhage was graded using scores. Rabbits were divided into three groups: control, t-PA and DP1904 plus t-PA. The t-PA was administered intravenously at 500 iu/kg/min for 30 mins starting 5 mins prior to reperfusion. DP1904 was injected intravenously at a dosage of 10 mg/kg every 24 h starting 2 hr prior to coronary occlusion. Mortality was similar and hemodynamic parameters and area at risk were comparable between all three groups. The myocardial infarct size as a percentage of area at risk was 44.5 +/- 3.8% (mean +/- standard error) (n = 9) in the control group, 41.6 +/- 4.6% in the t-PA group (n = 8) and 51.3 +/- 5.2% in DP1904 plus t-PA group (n = 8), not significantly different (ANOVA). Neither were the hemorrhage scores significantly different between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tissue-type plasminogen activator alone or in combination with thromboxane A2 synthetase inhibitor for ischemic myocardium. 212 35

We have previously shown that plasma levels of endothelium-derived tissue-type plasminogen activator (t-PA) increase during mental stress. The aim of the study was to investigate in vivo release in an intact human muscle vascular bed. Eleven healthy young males (22-36 yrs) were studied at rest and during 10 min of mental stress (forced arithmetic). Net release or uptake were assessed by arterio-venous (AV) concentration gradients across the forearm of t-PA antigen and t-PA activity, and plasminogen activator inhibitor antigen type 1 (PAI-1). Forearm blood flow was measured by venous occlusion plethysmography. At rest, there was a positive AV-difference of t-PA activity across the forearm indicating a net release of t-PA activity of approximately 3.7 fmol x min-1 x 100 ml-1 (Wilcoxon's signed rank test vs 0, p = 0.01). However, t-PA antigen showed a variable release pattern. On the average, there was a net release of 0.17 ng x min-1 x 100 ml-1 after 60 min of rest (Wilcoxon vs 0, p = 0.07). PAI-1 antigen showed net release at rest. In response to stress, forearm blood flow increased from 1.9 to 2.9 ml x min-1 x 100 ml-1 (ANOVA, p = 0.007), and net release of t-PA activity increased to 9.8 fmol x min-1 x 100 ml-1 (ANOVA, p = 0.01 compared with rest). Arterial and venous plasma t-PA levels also increased significantly during stress (ANOVA, p < 0.01). t-PA antigen showed a similar but less pronounced release pattern during stress.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vivo release of tissue-type plasminogen activator across the human forearm during mental stress. 783 66

These experiments were designed to study the effect of resistance exercise on parameters pertinent to the hemostatic and fibrinolytic systems. Seven normal healthy subjects (6 male, 1 female, 25 +/- 3 yr mean SD) were studied under three conditions: control (C) [no exercise], high volume resistance exercise (HVRE), and low volume resistance exercise (LVRE), which were randomized for each subject, with 7 d separating tests. Both HVRE and LVRE trials encompassed the performance of five sets of nine exercises. After establishing one repetition maximum (1 RM), the HVRE involved the performance of moderate resistance, higher repetition, and shorter resting periods, whereas LVRE involved the use of high resistance, lower repetition, and longer resting intervals. Heart rate (HR) was monitored at rest and continuously during trials and venous blood was removed with minimum stasis, before and immediately after HVRE, LVRE, and before and after 38 min of supine rest (C). The blood was enzymatically analyzed for lactic acid (LA) and assayed using chromogenic substrates for the determination of tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI), and Factor VIII (FVIII) activities. Global fibrinolysis (GF) was also screened in the fibrin plate and hematocrit ratios were employed to calculate percent plasma volume changes. Values were corrected for changes in plasma volume then data were analyzed using repeated measures ANOVA. There were no significant (P > 0.05) changes in the parameters measured in the resting condition over the three testing occasions and no significant differences (P > 0.05) were observed during the control experiment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fibrinolytic and hemostatic parameter response after resistance exercise. 849 88

Hypertriglyceridemia is linked to impaired fibrinolytic function, and lipid-lowering treatment with fibric acid derivatives could hypothetically improve fibrinolysis in this condition. We therefore conducted a double-blind, placebo-controlled, crossover study of gemfibrozil treatment on fibrinolytic function in 21 men with combined hyperlipoproteinemia. Measurements were performed at rest and during mental stress and after venous occlusion. The patients had clearly disturbed fibrinolytic function, with elevated plasminogen activator inhibitor-1 (PAI-1) activity at rest ( approximately 25 U/mL; reference, <15 U/mL). Gemfibrozil reduced plasma total and VLDL cholesterol as well as all triglyceride fractions, whereas HDL cholesterol increased (P <.001 for all). Total triglyceride levels were reduced by 57 +/- 4% (from 5.3 to 2.1 mmol/L). Fasting serum insulin levels were not altered by gemfibrozil treatment. Plasma levels of PAI-1 activity and tissue-type plasminogen activator (TPA) activity or antigen were unaffected by gemfibrozil treatment both at rest and during the provocations. The levels of D-dimer, plasmin/antiplasmin complex, and fibrinogen were also uninfluenced by gemfibrozil treatment. Mental stress elevated plasma TPA (P=.0036) and lowered PAI-1 (P=.0012) activity during placebo but not gemfibrozil treatment (P=.28 and P=.17, respectively), but treatment effects did not differ by ANOVA on delta values (ie, stress minus rest). Venous occlusion reduced PAI-1 activity, whereas TPA and plasmin/antiplasmin complex increased during both treatments. Thus, gemfibrozil treatment did not improve fibrinolysis or lower fibrinogen levels in men with combined hyperlipoproteinemia despite marked reduction of plasma triglyceride levels. It seems unlikely that improved fibrinolysis explains the primary preventive effect of gemfibrozil.
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PMID:Gemfibrozil treatment of combined hyperlipoproteinemia. No improvement of fibrinolysis despite marked reduction of plasma triglyceride levels. 862 72

The plasminogen activator (PA)-plasmin proteolytic system has recently received considerable attention because of its participation in a wide variety of biological activities and in pathological conditions involving tissue destruction. Excessive mechanical stress such as occlusal trauma is associated with alveolar bone loss in severe periodontitis. Therefore, mechanical stress may involve degradation of the extracellular matrix by occlusal trauma through activation of the PA-plasmin proteolytic system. We examined the effects of mechanical stress on PA activity, gene expressions of tissue type (t) PA, urokinase type (u) PA and PA inhibitor-1 (PAI-1) in human PDL cells. Human PDL cells were cultured on flexible-bottomed culture plates and placed on a Flexercell Strain Unit. The cells were flexed at 6 cycles (5 s strain, 5 s relaxation) at 9% and 18% elongation for 5 d. Application of tension-force induced significantly higher PA activity in stressed PDL cells than in non-stressed controls, and did so in a time- and magnitude-dependent manner (p < 0.001, ANOVA). Western-blot analysis revealed that the high level of activity was due to tPA and not uPA. Gene expression of tPA mRNA in stressed PDL cells, as examined by RT-PCR, increased on d 5. These findings suggest that tPA may be involved in periodontal metabolism in response to mechanical stress.
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PMID:Effect of tension-force on plasminogen activator activity from human periodontal ligament cells. 913 97

The purpose of this study was to evaluate fibrinolytic potential at rest and after a fibrinolytic stressor in men with a history of myocardial infarction (MI) compared with an age- and activity-matched group of men without coronary artery disease (CAD). All men were currently enrolled in exercise programs. Tissue-type plasminogen activator (TPA) and plasminogen activator inhibitor 1 (PAI-1) activity and antigen levels were measured at rest and after a maximal exercise test. A 2 x 2 (group x time) ANOVA with repeated measures was used to evaluate fibrinolytic potential. Bivariate regressions were conducted to evaluate relations between fibrinolytic potential and maximal oxygen uptake (VO2max). Age was similar between groups (CAD, 57.5 +/- 6.6; non-CAD, 58.1 +/- 7.3 years); however, VO2max was higher in non-CAD subjects (36.2 +/- 6.2 vs 27.5 +/- 5.9 mL.kg-1.min-1). Mean +/- SEM resting TPA and PAI-1 activities were similar between CAD and non-CAD subjects (TPA, 2.8 +/- 0.2 vs 2.8 +/- 0.2 IU/mL; PAI-1, 15.9 +/- 3.1 vs 13.1 +/- 4.1 AU/mL). Both groups showed similar significant increases in TPA activity with exercise (P < .05), and postexercise TPA activity was also similar (CAD, 9.1 +/- 2.0 IU/mL; non-CAD, 11.7 +/- 2.6 IU/mL). Both groups also showed similar significant decreases in PAI-1 activity with exercise (P < .05) and no differences in postexercise PAI-1 activity (CAD, 13.2 +/- 2.5 AU/mL; non-CAD, 10.4 +/- 3.6 AU/mL). Significantly higher resting TPA antigen levels were seen in CAD (14.8 ng/mL) than non-CAD (10.2 ng/mL) subjects (P < .05), but neither group showed significant changes with exercise (CAD, 12.9 ng/mL; non-CAD, 11.8 ng/mL). Resting PAI-1 antigen was similar in the two groups (CAD, 71.4 ng/mL; non-CAD, 74.2 ng/mL) and did not significantly change with exercise (CAD, 77.9 ng/mL; non-CAD, 72.3 ng/mL). VO2max was positively correlated with postexercise TPA activity (r = .52, P < .05) and negatively correlated with resting TPA antigen (r = -.43, P < .05). Resting TPA antigen was also directly correlated with body mass index (r = .63, P < .05). The finding that functional fibrinolytic activity was not different in physically active men with and without CAD contrasts with previous reports. This suggests that matching subjects on the bases of age and habitual physical activity status and controlling exercise intensity are important factors to consider when evaluating fibrinolytic potential.
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PMID:Fibrinolytic activity is similar in physically active men with and without a history of myocardial infarction. 919 61

Systemic administration of desmopressin (DDAVP) induces increased plasma levels of tissue-type plasminogen activator (t-PA), coagulation factor VIII, and von Willebrand factor (vWF). However, the mechanisms behind these responses are not known. We tested the hypothesis that DDAVP acts as a local stimulator of acute endothelial release of t-PA and vWF independently of central pathways. Healthy, young, nonsmoking male volunteers were studied. In a first study (n = 7), DDAVP and placebo were administered as randomized single-blind stepwise intrabrachial artery infusions (0.7, 7.0, and 70 ng/min). In a another subset of subjects (n = 4), a constant-rate DDAVP infusion of 70 ng/min was administered for 20 minutes in the brachial artery of the nondominant arm with the dominant arm as control. To rule out that the observed t-PA release was flow-dependent, 4 additional subjects received stepwise intra-arterial infusions of both DDAVP (7.0, 21, and 70 ng/min) and sodium nitroprusside (SNP; 0.5, 2.5, and 10 micrograms/min). Brachial venoarterial plasma concentration gradients and forearm plasma flow were used to determine net release/uptake rates of t-PA and vWF. At baseline, the average net release rate of t-PA was 6.7 ng/min across the whole forearm vascular bed, whereas there was no detectable basal release of vWF. Stepwise infusion of DDAVP induced a massive regulated release of t-PA with a peak after 15 minutes on the highest dose-step (ANOVA; P < .0001). The average maximum net release rate was 178 ng/min, and the total amount of t-PA released was, on the average, 3,000 ng. The majority was released in its active form. Constant-rate DDAVP infusion again markedly increased t-PA release in the infusion arm but had no effect whatsoever in the control arm. In contrast, DDAVP did not stimulate a local release of vWF in either study. Central hemodynamics were unchanged during infusions despite a local vasodilatory response with DDAVP. Endothelium-independent flow stimulation by SNP did not elicit any local t-PA release. We conclude that DDAVP induces a massive acute flow-independent release of t-PA, without the simultaneous release of vWF, in the human forearm vascular bed. The lack of a t-PA response in the control arm, as well as the unaltered central hemodynamics with DDAVP, confirms that the observed regulated t-PA release is local and independent of central mechanisms.
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PMID:Evidence of a local mechanism for desmopressin-induced tissue-type plasminogen activator release in human forearm. 942 6

Increased plasma renin activity (PRA) has been associated with an increased risk of myocardial infarction (MI), whereas angiotensin-converting enzyme (ACE) inhibition appears to reduce the risk of recurrent MI in patients with left ventricular dysfunction. These observations may be partially explained by an interaction between the renin-angiotensin system (RAS) and fibrinolytic system. To test this hypothesis, we examined the effect of salt depletion on tissue-type plasminogen activator (tPA) antigen and plasminogen activator inhibitor-1 (PAI-1) activity and antigen in normotensive subjects in the presence and absence of quinapril (40 mg BID). Under low (10 mmol/d) and high (200 mmol/d) salt conditions there was significant diurnal variation in PAI-1 antigen and activity and tPA antigen. Morning (8 AM through 2 PM) PAI-1 antigen levels were significantly higher during low salt intake compared with high salt intake conditions (ANOVA, F=5.8, P=0.048). PAI-1 antigen correlated with aldosterone (r=0.56, P<10(-7)) during low salt intake. ACE inhibition significantly decreased 24-hour (ANOVA for 24 hours, F=6. 7, P=0.04) and morning (F=24, P=0.002) PAI-1 antigen and PAI-1 activity (F=6.48, P=0.038) but did not alter tPA antigen. Thus, the mean morning PAI-1 antigen concentration was significantly higher during low salt intake than during either high salt intake or low salt intake and concomitant ACE inhibition (22.7+/-4.6 versus 16. 1+/-3.3 and 16.3+/-3.7 ng/mL, respectively; P<0.05). This study provides evidence of a direct functional link between the RAS and fibrinolytic system in humans. The data suggest that ACE inhibition has the potential to reduce the incidence of thrombotic cardiovascular events by blunting the morning peak in PAI-1.
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PMID:Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1. 985 58

We have observed marked interindividual differences in release rates of tissue-type plasminogen activator (t-PA) among healthy subjects. The objective of the current study was to test the hypothesis that there is an association between a genetic variation at the t-PA locus and the in vivo release rate of t-PA. Fifty-one healthy males were studied at rest in the morning and 27 of these were also subjected to a mental stress test. Net release rates of total t-PA across the forearm vascular bed were calculated as the product of the venoarterial concentration gradient and forearm plasma flow. Zygosity for an Alu-repeat polymorphism in intron 8 of the t-PA gene was determined by a polymerase chain reaction. Basal t-PA release rates differed markedly by genotype (ANOVA, P<0.05); subjects homozygous for the insertion had a significantly higher release rate (mean 10.9 ng. min-1. L-1, n=19) than both heterozygotes (4.5 ng. min-1. L-1, n=26) and subjects homozygous for the deletion (0.9 ng. min-1. L-1, n=6). After 2 minutes of mental stress release rates had increased approximately 2-fold in all groups. Arterial and venous plasma levels of t-PA were unrelated to genotype. In conclusion, the current results provide the first evidence of an association between a common genetic variation at the t-PA locus and interindividual differences in net release rates of t-PA in vivo. The relationship is not reflected by circulating steady-state plasma levels and can thus not be disclosed by conventional venous plasma sampling.
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PMID:Gene polymorphism of t-PA is associated with forearm vascular release rate of t-PA. 997 31

We assessed forearm blood flow and plasma fibrinolytic factors in eight healthy males who received unilateral brachial artery infusions of the endothelium-dependent vasodilator, substance P, and the endothelium-independent vasodilator, sodium nitroprusside. These measurements, together with platelet aggregation studies, were performed on four occasions after double-blind randomized ingestion of placebo, methionine (0.1 mg/kg), vitamin C (2 g) and methionine plus vitamin C. Blood flow and platelet aggregation responses were unaffected by methionine loading. Substance P caused dose-dependent increases in plasma tissue plasminogen activator (t-PA) antigen (from 3.0+/-0.1 to 4.7+/-0.4 ng/ml; P<0.001) and activity (from 1.2+/-0.2 to 4.2+/-0.4 i.u./ml; P<0.001), which were augmented during acute methionine loading (4.7+/-0.4 to 5.6+/-0.5 ng/ml and 4.2+/-0.4 to 5.5+/-0.9 i.u./ml respectively; P</=0.05). Moreover, the estimated net release of t-PA was enhanced during methionine loading (two-way ANOVA; P=0.02), but this was unaffected by vitamin C supplementation. We conclude that, in the absence of alterations in endothelium-dependent vasomotion or platelet aggregation, substance P-induced t-PA release is enhanced following methionine loading. This suggests that the acute endogenous fibrinolytic capacity is augmented during acute hyperhomocysteinaemia in healthy humans via an oxidation-independent mechanism.
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PMID:Effects of acute methionine loading and vitamin C on endogenous fibrinolysis, endothelium-dependent vasomotion and platelet aggregation. 1117 Dec 80


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