| 1. |
- Björkman, Jan-Arne, et al.
(författare)
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Cardiac sympathetic nerve stimulation triggers coronary t-PA release.
- 2003
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Ingår i: Arteriosclerosis, thrombosis, and vascular biology. - 1524-4636. ; 23:6, s. 1091-7
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: This study was undertaken to determine whether stimulation of sympathetic cardiac nerves induces release of the thrombolytic enzyme tissue-type plasminogen activator (t-PA) in the coronary vascular bed. METHODS AND RESULTS: Anesthetized pigs were studied in an open chest model. Bilateral vagotomy was performed, and sympathetic cardiac nerves were activated by electrical stimulation (1 and 8 Hz). To evaluate possible mediating effects of increased heart rate and enhanced local blood flow, tachycardia was induced by pacing and hyperemia by local infusion of sodium nitroprusside and clevedipine. Furthermore, to study the effects of alpha- and beta-adrenergic receptor stimulation, phenylephrine and isoprenaline were infused locally. In response to low- and high-frequency sympathetic stimulation, mean coronary net release of total t-PA increased approximately 6- and 25-fold, respectively. Active t-PA showed a similar response pattern. Neither tachycardia nor coronary hyperemia stimulated t-PA release. In contrast, beta-adrenergic stimulation by isoprenaline induced an approximately 6-fold increase in coronary t-PA release, whereas no significant change in release rates occurred in response to alpha-adrenergic stimulation by phenylephrine. CONCLUSIONS: Stimulation of cardiac sympathetic nerves induces a marked coronary release of t-PA, and part of this response may be mediated through stimulation of beta-adrenergic receptors.
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| 2. |
- Hrafnkelsdottir, Thordis, 1965, et al.
(författare)
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Regulation of local availability of active tissue-type plasminogen activator in vivo in man
- 2004
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Ingår i: J Thromb Haemost. - 1538-7933. ; 2:11, s. 1960-8
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Tidskriftsartikel (refereegranskat)abstract
- Free, biologically active tissue-type plasminogen activator (tPA) is the main initiator of intravascular fibrinolysis, but little is known about the regulation of active tPA on the organ level. The aim was to investigate if the local availability of active tPA on the organ level depends on the local release rate of tPA or the arterial input of tPA and plasminogen activator inhibitor type 1 (PAI-1). Also, we wanted to evaluate if plasma levels predict capacity for endothelial release of fibrinolytic proteins. Invasive perfused-forearm studies were performed in 96 healthy subjects. Local release rates of fibrinolytic proteins were assessed at baseline and during endothelial stimulation. Stimulation by methacholine and desmopressin induced a 6- and 12-fold increase in total tPA release rates, respectively. With increasing local release rates of tPA a gradually closer correlation emerged between the total tPA secretion and the forearm output of active tPA (from r = 0.102, ns to r = 0.85, P < 0.0001). Forearm availability of active tPA was not related to arterial input of either tPA or PAI-1. Release rates and plasma levels of tPA were not correlated. Baseline release rates of active tPA increased to noon. The major determinant for the local availability of active tPA is the capacity of the endothelium to release tPA rather than the arterial input of PAI-1 or tPA. Despite a molar excess of PAI-1, the majority of tPA released during stimulation does not undergo local inactivation. The capacity to release tPA locally cannot be predicted from its plasma concentration.
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| 3. |
- Ladenvall, Per, 1972, et al.
(författare)
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Tissue-type plasminogen activator -7,351C/T enhancer polymorphism is associated with a first myocardial infarction.
- 2002
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Ingår i: Thrombosis and haemostasis. - 0340-6245. ; 87:1, s. 105-9
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Tidskriftsartikel (refereegranskat)abstract
- We recently identified a polymorphic Sp1 binding site in an enhancer at the tissue-type plasminogen activator (tPA) locus (tPA -7,351C/T), which was associated with vascular tPA release. Subjects homozygous for the -7,351C allele had twice the tPA release rate compared to subjects carrying the -7,351T allele. In this study we tested the hypothesis that the tPA -7,351C/T polymorphism is associated with myocardial infarction (MI). In a population-based prospective nested case-control study within northern Sweden, genotypes were determined among 61 MI cases and 120 controls. In a multivariate model, the tPA -7,351C/T polymorphism (OR 2.68 for T allele carriers; 95% CI 1.31-5.50), tPA antigen (OR 1.16; 95% CI 1.07-1.25) and apo A-I (OR, 0.997; 95% CI 0.995-0.999) were independently associated with a first MI. These findings suggest that genetic markers of local tPA release and circulating steady-state tPA levels carry independent prognostic information.
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| 4. |
- Jern, Christina, 1962, et al.
(författare)
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Evidence of a net release of tissue-type plasminogen activator across the human cerebral vasculature.
- 2004
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Ingår i: Thrombosis and haemostasis. - 0340-6245. ; 91:5, s. 1019-25
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Tidskriftsartikel (refereegranskat)abstract
- We have earlier described models for measuring local net release rates of tissue-type plasminogen activator (t-PA) in vivo across skeletal, coronary, pulmonary, and splanchnic vascular beds. Aim of the present study was to investigate whether there is a net release of t-PA across the human cerebral vascular bed and whether an acute regulated release can be induced by sympathoadrenal activation. Fourteen male subjects undergoing elective coronary artery bypass grafting were investigated prior to surgery and during sternotomy-induced sympathoadrenal activation. Blood samples were obtained simultaneously from the radial artery and the jugular bulb. Blood flow velocity in the middle cerebral artery (V(MCA)) was determined by transcranial Doppler. Cerebral net release of t-PA was calculated as the arterio-venous concentration gradient times V(MCA). Prior to surgery there was a significant cerebral net release of t-PA (131 and 42 ng/min for t-PA antigen and activity, respectively). The release was significantly induced by sternotomy (to 271 and 80 ng/min, respectively). No significant cerebral net release of plasminogen activator inhibitor type 1 (PAI-1) was detected throughout the experiment. The results show that there is a basal net release of t-PA across the human cerebral vascular bed and that sympathoadrenal activation induces a local regulated release of t-PA.
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| 5. |
- Jood, Katarina, 1966, et al.
(författare)
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Body mass index in mid-life is associated with a first stroke in men: a prospective population study over 28 years
- 2004
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Ingår i: Stroke. - 1524-4628. ; 35:12, s. 2764-9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: Data on the association between obesity and stroke are still limited. We examined the possible association between mid-life body mass index (BMI) and risk of stroke in the prospective Multifactor Primary Prevention Study in Goteborg, Sweden. METHODS: 7402 apparently healthy men aged 47 to 55 at baseline were followed-up over a 28-year period. Incidence of fatal and nonfatal stroke was recorded in a local stroke registry through the Swedish National Register on Cause of Death and the Swedish Hospital Discharge Registry. RESULTS: A total of 873 first strokes were recorded, including 495 ischemic, 144 hemorrhagic, and 234 unspecified strokes. Compared with men with low normal weight (BMI, 20.0 to 22.49 kg/m2), men with BMI >30.0 kg/m2 had a multiple adjusted hazard ratio of 1.93 (95% CI, 1.44 to 2.58) for total stroke, 1.78 (95% CI, 1.22 to 2.60) for ischemic stroke, and 3.91 (95% CI, 2.10 to 7.27) for unspecified stroke. There was no significant association between BMI and hemorrhagic stroke. Adjustment for potential mediators, eg, hypertension, diabetes and serum cholesterol levels, attenuated but did not eliminate the risk. CONCLUSIONS: In this prospective population-based study of men, increased BMI in mid-life was associated with an increased risk for total, ischemic, and unspecified stroke, but not with hemorrhagic stroke. The result supports the role of mid-life BMI as a risk factor for stroke later in life and suggests a differentiated effect on stroke subtypes.
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| 6. |
- Ladenvall, Per, 1972, et al.
(författare)
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Genetic variation at the human tissue-type plasminogen activator (tPA) locus: haplotypes and analysis of association to plasma levels of tPA.
- 2003
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Ingår i: European journal of human genetics : EJHG. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 11:8, s. 603-10
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Tidskriftsartikel (refereegranskat)abstract
- Tissue-type plasminogen activator (tPA) plays a key role in thrombus dissolution and plasma levels of tPA have been associated with cardiovascular disease. We have previously resequenced regulatory and coding regions of the human tPA gene (PLAT) and identified eight single-nucleotide polymorphisms (SNPs). In a small experimental study, four common variants were associated with invasively determined vascular tPA release rates. The aim of the present study was to investigate whether there is an association between genetic variants at this locus and plasma levels of tPA. To this end, 240 Swedish individuals without cardiovascular disease were typed for the eight SNPs and an Alu insertion polymorphism at the PLAT locus, as well as for a polymorphism in the plasminogen activator inhibitor type 1 (PAI-1) promoter (PAI-1 -675 4G>5G). Stepwise regression analysis, with established predictors of plasma tPA including plasma PAI-1 and genetic variants, showed that neither genotypes nor haplotypes were major contributors to plasma tPA. The results also showed that the level of linkage disequilibrium was high at the PLAT locus, as demonstrated by the fact that only three haplotypes had a frequency above 5%. In conclusion, in the present study neither genetic variation at the PLAT locus nor the PAI-1 -675 4G>5G polymorphism was strong predictors of plasma tPA levels, which suggests that variations in other genes contribute to the heritability of this phenotype. The results also show that three haplotypes at the PLAT locus accounted for nearly 90% of the chromosomes and that they could be defined by typing only two SNPs.
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| 7. |
- Nyberg, Annette, 1967, et al.
(författare)
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Pulmonary net release of tissue-type plasminogen activator during porcine primary and secondary acute lung injury.
- 2004
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Ingår i: Acta anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 48:7, s. 845-50
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Tissue-type plasminogen activator (tPA) is a key mediator of fibrinolysis. Matching of pulmonary perfusion and ventilation is a critical denominator of oxygenation in acute lung injury (ALI). This study investigates pulmonary venoarterial plasma tPA gradients in association with acute ALI induced by bronchoalveolar lavage (BAL) and endotoxinemia (ETX). METHODS: Twenty-one anaesthetized, ventilated pigs were allocated to control (CTRL, n=5), bronchoalveolar saline lavage (BAL, n=8) or infusion of Escherichia coli endotoxin (ETX, n=8). Total tPA was analyzed in plasma (ELISA calibrated for porcine tPA). The inflammatory response was assessed by TNFa levels (ELISA). All variables were assessed at baseline and 2 h following ALI. RESULTS: Bronchoalveolar lavage and ETX induced similar increases in pulmonary shunt whereas pulmonary vascular resistance was significantly more increased in ETX animals. Cardiac output remained stable in BAL animals but decreased in ETX animals. The pulmonary venoarterial tPA plasma gradient increased in ETX animals, yielding a positive pulmonary net flux of tPA, which was absent in BAL animals. TNFalpha levels increased in ETX, but not in BAL, animals. A significant correlation was observed between TNFalpha and tPA plasma levels in ETX animals. All variables remained unchanged in CTRL animals. CONCLUSION: Plasma changes of tPA levels support a pulmonary release of tPA in early experimental ALI induced by acute ETX but not lavage, and are related to the inflammatory response. Despite increased vascular fibrinolytic capacity in ETX animals, pulmonary dysfunction was not different from BAL animals. The results demonstrate the close relation between inflammation and coagulation in early ALI.
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| 8. |
- Osterlund, Barbro, et al.
(författare)
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Intracoronary beta2 receptor activation induces dynamic local t-PA release in the pig.
- 2003
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Ingår i: Thrombosis and haemostasis. - 0340-6245 .- 2567-689X. ; 90:5, s. 796-802
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 9. |
- Tjärnlund, Anna, 1974, et al.
(författare)
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Rapid genotyping of haemostatic gene polymorphisms using the 5' nuclease assay.
- 2003
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Ingår i: Thrombosis and haemostasis. - 0340-6245. ; 89:5, s. 936-42
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Tidskriftsartikel (refereegranskat)abstract
- Hemostatic gene polymorphisms have been shown to be associated with arterial and venous thrombotic disease. To date these polymorphisms have mainly been detected by labor-intensive conventional gel based methods. Aim of the present study was to design and optimize high throughput 5' nuclease assays for the detection of a set of 10 single-nucleotide polymorphisms (SNP) in genes of importance for hemostasis: plasminogen activator inhibitor type 1 -675 4G>5G, thrombin activatable fibrinolysis inhibitor Ala147Thr and 1,542C>G, beta-fibrinogen -455G>A, von Willebrand factor -1,051A>G, factor VII Arg353Gln, factor XIII Val34Leu, prothrombin 20,210G>A, tissue factor pathway inhibitor -287T>C, and methylenetetrahydrofolate reductase 1,298A>C. Specificity of each genotyping assay was confirmed by sequence-based typing and reproducibility was evaluated by repeated genotyping. The genotyping protocols presented here may serve as a valuable tool for clinical researchers interested in exploring associations between these SNPs and thrombotic disease.
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