Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that both mental stress and administration of the muscarinic receptor agonist methacholine induce an acute release of tissue-type plasminogen activator (t-PA) across the human forearm. There are data indicating that the regulated acute release of t-PA from the endothelium is closely interrelated with release of von Willebrand factor (vWF). The aim of the present study was to simultaneously determine basal and stimulated in vivo release rates of t-PA and vWF in an intact human muscle vascular bed. Eighteen healthy young males were studied at rest and during 10 min of mental stress (forced arithmetic). A subsample of ten subjects also received a step-wise i.a. infusion of methacholine (0.1-0.8-4.0 microg/min). Forearm blood flow was determined by venous occlusion plethysmography and interconverted to forearm plasma flow (FPF) using individual hematocrits. Net release/uptake rates of t-PA and vWF were calculated as the product of the arteriovenous concentration gradient and FPF. At rest there was a net release of both t-PA antigen and activity. In contrast, there was no significant local net release of vWF antigen across the forearm. Net release rates of t-PA roughly doubled in response to the stress test (0.4 to 0.8 and 0.2 to 0.5 ng x min(-1) x 100 ml(-1) for t-PA antigen and activity, respectively, p <0.05 for both). Local administration of methacholine induced a more than 10-fold increase in the net release rates of t-PA (0.6 to 9.6 and 0.3 to 6.6 ng x min(-1) x 100 ml(-1) at the highest dose step for antigen and activity respectively, p <0.01 for both). In contrast, neither mental stress nor local administration of methacholine induced a significant net release of vWF antigen across the forearm. The results demonstrate that the processes of acute release of t-PA and vWF are not necessarily linked in vivo in man.
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PMID:Sympathoadrenal activation and muscarinic receptor stimulation induce acute release of tissue-type plasminogen activator but not von Willebrand factor across the human forearm. 926 90

Experimental data indicate large between-organs variations in rates of synthesis of tissue-type plasminogen activator (t-PA), which may reflect important differences in the capacity for constitutive and stimulated t-PA release from the vascular endothelium. In this report we describe a new multiple-organ experimental in vivo model for simultaneous determinations of net release/uptake rates of t-PA across the coronary, splanchnic, pulmonary, and hepatic vascular beds. In eleven intact anesthetized pigs, blood samples were obtained simultaneously from the proximal aorta, coronary sinus, pulmonary artery, and portal and hepatic veins. Plasma flows were monitored separately for each vascular region. Total plasma t-PA was determined by ELISA with a porcine t-PA standard. Regional net release/uptake rates were defined as the product of arteriovenous concentration gradients and local plasma flows. The net release of t-PA across the splanchnic vascular bed was very high, with a mean output of 1,919 ng total t-PA x min(-1) (corresponding to 90 ng per min and 100 g tissue). The net coronary t-PA release was 68 ng x min(-1) (30 ng x min(-1) X 100 g(-1)). Pulmonary net fluxes of t-PA were variable without any significant net t-PA release. The net hepatic uptake rate was 4,855 ng x min(-1) (436 ng x min(-1) x 100 g(-1)). Net trans-organ changes of active t-PA mirrored those of total t-PA. The results demonstrate marked regional differences in net release rates of t-PA in vivo. The experimental model we present offers new possibilities for evaluation of regional secretion patterns in the intact animal.
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PMID:An experimental multiple-organ model for the study of regional net release/uptake rates of tissue-type plasminogen activator in the intact pig. 930 69

We recently showed that muscarinic receptor stimulation causes a marked increase in the net release of tissue-type plasminogen activator (TPA) antigen and activity across the human forearm in vivo, in conjunction with endothelium-dependent vasodilation. Because hypertension has been associated with endothelial dysfunction, the aim of the study was to compare forearm TPA release and vasodilation in response to muscarinic stimulation in normotensive (NC) and borderline hypertensive (BH) subjects. The study was performed in 10 apparently healthy young men with BH and 10 male NC subjects. Methacholine (MCh: 0.1, 0.8, and 4.0 micrograms/min) and sodium mitroprusside (SNP: 0.5, 2.5, and 10 micrograms/min) were administered in randomized order as double-blind, stepwise, intrabrachial artery infusions. Forearm blood flow was assessed by plethysmography. Net release/uptake was calculated as the product of the arteriovenous concentration gradient and forearm plasma flow. Vasodilator responses to MCh were similar in both groups (P = NS), whereas the decrease in forearm vascular resistance in response to SNP was somewhat less in BH subjects (P = .005). At rest, both groups showed a significant arteriovenous gradient and net release of TPA antigen across the forearm (P < .05 throughout). However, in contrast to the significant net increment in TPA activity across the forearm in the NC group (P < .018), BH subjects had no basal forearm increment in TPA activity (NC vs BH, P = .006). Arterial and venous plasma levels of plasminogen activator inhibitor 1 (PAI-1) antigen and activity were higher in BH subjects (P < or = .05 throughout), who in contrast to NC subjects, also had a significant forearm net release of PAI-1 antigen (P = .006). Across the whole group, there was a significant inverse relation between arterial PAI-1 antigen levels and increment in TPA activity across the forearm (r = -.57, P = .008) but no relation to TPA antigen release. In response to MCh infusion, both the net release of TPA antigen and increment in TPA activity increased markedly and to similar extents in both groups (P < .01 throughout). SNP infusion had no effect on either TPA antigen release or increment in TPA activity in the NC group but elicited a significant net release of TPA antigen and increase in TPA activity in the BH group (P < .05). Both circulating levels and local release of PAI-1 antigen were significantly correlated to fasting plasma insulin. Endothelium-dependent vasodilation and endothelial TPA release in response to muscarinic receptor stimulation were preserved in BH subjects. At rest, BH subjects had higher circulating PAI-1 antigen levels and a corresponding decrease in circulating levels and local increment of TPA activity. In contrast to NC subjects, BH subjects responded with a TPA release also in response to increased flow, which may indicate an enhanced endothelial cell responsiveness to fluid shear stress.
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PMID:Endothelium-dependent vasodilation and tissue-type plasminogen activator release in borderline hypertension. 943 82

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 determined the influence of oral contraceptives (OC) on the capacity of the endothelium to release tissue-type plasminogen activator (t-PA). Twenty-three healthy premenopausal women were studied: 12 nonusers and 11 users of OC. Net endothelial release rates of t-PA were calculated as the product of the arteriovenous concentration gradient and forearm plasma flow in response to intra-arterial bradykinin (BK: 12.5-50 ng. 100 ml tissue(-1) x min(-1)) and sodium nitroprusside (SNP: 1.0-4.0 microg x 100 ml tissue(-1) x min(-1)). Net release of t-PA antigen and increment in t-PA activity across the forearm to BK increased (P < 0.01) in a dose-dependent fashion and to similar extents in the nonusers and users of OC. At the highest BK dose, net release of t-PA antigen was 64.5 +/- 8.2 and 66.2 +/- 15.4 ng x 100 ml tissue(-1) x min(-1) in the nonusers and users of OC, whereas the net increment in t-PA activity was 18.6 +/- 3.0 and 16.0 +/- 2.0 IU. 100 ml tissue(-1) x min(-1), respectively. There was no effect of SNP on t-PA release in either group. These results indicate that endothelial t-PA release is not altered in premenopausal women who use oral contraception.
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PMID:Influence of oral contraceptive use on endothelial t-PA release in healthy premenopausal women. 1238 32

The capacity of the vascular endothelium locally to release tissue-type plasminogen activator (t-PA) is critical for effective endogenous fibrinolysis. We determined the influence of ageing and regular aerobic exercise on the net release of t-PA across the human forearm in vivo using both cross-sectional and intervention approaches. First, we studied 62 healthy men aged 22-35 or 50-75 years of age who were either sedentary or endurance exercise-trained. Net endothelial release rates of t-PA were calculated as the product of the arteriovenous concentration gradient and forearm plasma flow to intra-arterial bradykinin and sodium nitroprusside. Second, we studied 10 older (60 +/- 2 years) healthy sedentary men before and after a 3 month aerobic exercise intervention. Net endothelial t-PA release was significantly blunted with age in the sedentary men. At the highest dose of bradykinin the increase in t-PA antigen release was approximately 35 % less (P < 0.05) in the older (from -1.0 +/- 0.4 to 37.8 +/- 3.8 ng (100 ml tissue)(-1) min(-1)) compared with young (from 0.1 +/- 0.6 to 56.6 +/- 9.2 ng (100 ml tissue)(-1) min(-1)) men. In contrast, the endurance-trained men did not demonstrate an age-related decline in the net release of t-PA antigen. After the exercise intervention, the capacity of the endothelium to release t-PA increased approximately 55 % (P < 0.05) to levels similar to those of the young adults and older endurance-trained men. Regulated endothelial t-PA release declines with age in sedentary men. Regular aerobic exercise may not only prevent, but could also reverse the age-related loss in endothelial fibrinolytic function.
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PMID:Effects of ageing and regular aerobic exercise on endothelial fibrinolytic capacity in humans. 1250 96

The capacity of vascular endothelium to locally release tissue-type plasminogen activator (t-PA) represents an important endogenous defence mechanism against intravascular fibrin deposition and thrombosis. We determined the influence of chronic and acute oestrogen administration on endothelial t-PA release in postmenopausal women. Sixty-three healthy postmenopausal women were studied: 31 non-users (age 58 +/- 1 years) and 32 users of hormone replacement therapy, including oestrogen alone (ORT: 62 +/- 2 years; n = 15) and in combination with progesterone (HRT: 57 +/- 1 years; n = 17). Net endothelial t-PA release was determined in vivo, in response to intrabrachial infusions of bradykinin and sodium nitroprusside. To examine the acute effects of oestrogen on endothelial t-PA release, bradykinin and sodium nitroprusside dose-response curves were repeated in the presence of 17 beta-oestradiol in 20 of the 31 non-users. Net endothelial release of t-PA was ~30 % higher (P < 0.01) in women taking ORT (from 2.0 +/- 1.0 to 83.6 +/- 9.2 ng (100 ml tissue)-1 min-1) compared with those taking HRT (from 1.4 +/- 0.4 to 63.5 +/- 5.6 ng (100 ml tissue)-1 min-1) and those not taking supplementation (1.0 +/- 0.7 to 63.0 +/- 4.7 ng (100 ml tissue)-1 min-1). Intra-arterial infusion of 17 beta-oestradiol significantly potentiated bradykinin-induced t-PA release. Net endothelial release of t-PA was approximately 45 % higher (P < 0.01) after (from 1.0 +/- 0.8 to 87.4 +/- 9.9 ng (100 ml tissue)-1 min-1) versus before (1.2 +/- 0.6 to 60.8 +/- 5.6 ng (100 ml tissue)-1 min-1) acute 17 beta-oestradiol administration. Our results suggest that oestrogen has a direct modulatory effect on the capacity of the endothelium to release t-PA in healthy postmenopausal women. However, progesterone appears to oppose the favourable influence of oestrogen on endothelial fibrinolytic capacity.
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PMID:Acute and chronic effects of oestrogen on endothelial tissue-type plasminogen activator release in postmenopausal women. 1281 79

Release of tissue-type plasminogen activator (t-PA) from the vascular endothelium is paramount to endogenous thrombolysis potential. In addition to its vasodilator effects, nitric oxide (NO) has important antithrombotic properties, such as inhibition of platelet aggregation. It is currently not clear whether NO influences the capacity of the endothelium to release t-PA. The authors determined whether net endothelial t-PA release is regulated, at least in part, by NO. Endothelial t-PA release was determined, in vivo, in response to intrabrachial infusions of bradykinin (12.5-50.0 ng.100 mL tissue-1.min-1) in the presence and absence of the NO synthase inhibitor, NG-monomethyl-l-arginine (l-NMMA; 5 mg/min) in 12 healthy men. Net release of t-PA across the forearm vascular bed was calculated as the product of arteriovenous concentration gradient and forearm plasma flow. The vasodilator response to bradykinin was significantly blunted ( approximately 30%) with l-NMMA. Although there was no effect of l-NMMA on basal t-PA release, acute release of t-PA to bradykinin was higher (P < 0.01) after (from -0.2 +/- 0.5 to 105.2 +/- 9.4 ng.100 mL tissue-1.min-1) versus before (from -0.4 +/- 0.7 to 48.7 +/- 7.3 ng.100 mL tissue-1.min-1) the administration of l-NMMA. Thus, in the absence of NO endothelial t-PA release was enhanced. These results suggest a potential regulatory influence of NO on bradykinin induced endothelial t-PA release.
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PMID:Endothelial release of tissue-type plasminogen activator in the human forearm: role of nitric oxide. 1288 37

To investigate beta2 -adrenergic agonist-mediated effects on coronary fluxes of local fibrinolytic factors, healthy anaesthetised and instrumented pigs (n=10) were studied during infusion of isoprenaline (IPR) into the left main coronary artery. Coronary net fluxes of total t-PA antigen, active t-PA and total PAI-1 antigen were determined at baseline and at 3, 5, 7 and 10 minutes of IPR infusion. During IPR, net release of total t-PA increased in a biphasic pattern with transiently high levels at 3 (+440 %) and 7 minutes (+620%) and returned towards baseline at 10 minutes. Net coronary release of active t-PA increased with maximum levels at 3 minutes (+50%). Baseline coronary net flux of total PAI -1 showed a decrease which was most pronounced at 10 minutes. To conclude, a fast beta2 agonist-mediated local release of t-PA into the coronary vasculature was demonstrated. For total t-PA, this response was characterised by a biphasic release profile.
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PMID:Intracoronary beta2 receptor activation induces dynamic local t-PA release in the pig. 1459 73

Endothelial release of tissue-type plasminogen activator (t-PA) regulates fibrinolysis and is considered to be a primary endogenous defense mechanism against thrombosis. Adiposity is associated with an increased risk of atherothrombotic events. We determined the influence of overweight and obesity on the capacity of the vascular endothelium to release t-PA and the effects of regular aerobic exercise on endothelial t-PA release in previously sedentary overweight and obese adults. First, we studied 66 sedentary adults: 28 normal-weight (BMI < 25 kg/m2); 22 overweight (BMI > or = 25 and < 30 kg/m2); and 16 obese (BMI > or = 30 kg/m2). Net endothelial t-PA release was determined in vivo in response to intrabrachial infusions of bradykinin (BK) and sodium nitroprusside. Second, we studied 17 overweight and obese adults who completed a 3-mo aerobic exercise intervention. Net release of t-PA in response to BK was approximately 45% lower (P < 0.01) in overweight (from 0.1 +/- 0.4 to 41.7 +/- 4.9 ng x 100 ml tissue(-1) x min(-1)) and obese (-0.1 +/- 0.6 to 47.7 +/- 5.2 ng x 100 ml tissue(-1) x min(-1)) compared with normal-weight (0.1 +/- 0.8 to 77.5 +/- 6.7 ng x 100 ml tissue(-1) x min(-1)) adults. There was no difference in t-PA release between the overweight and obese groups. Exercise training significantly increased t-PA release capacity in overweight and obese adults (from -0.3 +/- 0.5 to 37.1 +/- 4.9 ng x 100 ml tissue(-1) x min(-1) before training vs. 1.0 +/- 0.9 to 65.4 +/- 6.3 ng x 100 ml tissue(-1) x min(-1) after training) to levels comparable with those of their normal-weight peers. These results indicate that overweight and obesity are associated with profound endothelial fibrinolytic dysfunction. Importantly, however, regular aerobic exercise can increase the capacity of the endothelium to release t-PA in this at-risk population.
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PMID:Endothelial t-PA release is impaired in overweight and obese adults but can be improved with regular aerobic exercise. 1598 56


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