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J Am Coll Cardiol, 2003; 41:333-339
© 2003 by the American College of Cardiology Foundation
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CLINICAL STUDY: ENDOTHELIAL FUNCTION

Acute systemic inflammation enhances endothelium-dependent tissue plasminogen activator release in men

Stanley Chia, MB, ChB (Hons), MRCP*,*, Christopher A. Ludlam, MB, ChB, PhD, FRCP, FRCPath{dagger}, Keith A. A. Fox, BSc (Hons), MB, ChB, FRCP, FESC* and David E. Newby, BA, BSc (Hons), PhD, BM, DM, MRCP*

* Cardiovascular Research, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
{dagger} Department of Haematology, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom

Manuscript received June 5, 2002; revised manuscript received September 16, 2002, accepted September 20, 2002.

* Reprint requests and correspondence: Dr. Stanley Chia, Cardiovascular Research, Department of Cardiology, Royal Infirmary of Edinburgh, Lauriston Place, Edinburgh EH3 9YW, United Kingdom.
schia{at}ed.ac.uk


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: The purpose of this study was to investigate in vivo the effects of acute systemic inflammation on the endogenous fibrinolytic capacity in men.

BACKGROUND: Systemic inflammation and endogenous fibrinolysis play a major role in the pathogenesis of coronary artery disease. Although previous studies have shown impaired endothelium-dependent vasomotor function, the effects of inflammation on the endothelial release of the fibrinolytic factor tissue plasminogen activator (t-PA) are unknown.

METHODS: In a double-blind randomized placebo-controlled crossover trial, we administered a mild inflammatory stimulus, Salmonella typhi vaccine, or saline placebo to eight healthy men on two separate occasions. Six hours after vaccination, blood flow and plasma fibrinolytic variables were measured in both arms during intrabrachial infusions of bradykinin (40 to 1,000 pmol/min), acetylcholine (5 to 20 µg/min), and sodium nitroprusside (2 to 8 µg/min).

RESULTS: Compared with placebo, the S. typhi vaccination caused a rise in white cell count (11.1 ± 0.5 x109/l vs. 7.9 ± 0.8 x109/l; p = 0.004) and plasma interleukin-6 concentrations (6.9 ± 1.4 pg/ml vs. 1.6 ± 0.4 pg/ml; p = 0.01) in addition to a significant augmentation of t-PA antigen (45 ± 9 ng/100 ml/min at peak dose vs. 24 ± 8 ng/100 ml/min at peak dose; p = 0.016, analysis of variance) and activity (104 ± 15 IU/100 ml/min vs. 54 ± 12 IU/100 ml/min; p = 0.006, analysis of variance) release during bradykinin infusion. Forearm blood flow increased in a dose-dependent manner after bradykinin, acetylcholine and sodium nitroprusside infusions (p < 0.001), but this was unaffected by vaccination.

CONCLUSIONS: Our results showed that acute systemic inflammation augmented local forearm t-PA release in men, which suggests that acute inflammation may invoke a protective response by enhancing the acute endogenous fibrinolytic capacity in healthy men. Further studies are needed to clarify whether this response is impaired in patients with cardiovascular disease.

Abbreviations and Acronyms
  ANOVA
  analysis of variance
  CRP
  C-reactive protein
  FBF
  forearm blood flow
  IL-6
  interleukin-6
  PAI-1
  plasminogen activator inhibitor type 1
  t-PA
  tissue-type plasminogen activator

Atherosclerosis is widely recognized to be an inflammatory disease process involving dysfunction of the vascular endothelium (1). This dysfunction leads to increased expression of leukocyte adhesion molecules, reduced anticoagulant activity and the release of growth factors, inflammatory mediators, and cytokines. Continued inflammation leads to leukocyte and monocyte recruitment, arterial damage, and atherogenesis. Additional cycles of damage cause plaque expansion and disruption that may lead to angina, crescendo angina, and acute coronary syndromes.

Recent epidemiological and observational studies have suggested a link between systemic inflammation and coronary artery disease. Infections by organisms, such as Chlamydia pneumoniae and herpes simplex virus type 1, appear to be associated with an increased risk of cardiovascular mortality (2), and approximately 4% of bacteremic patients will develop acute myocardial infarction within a month of infection (3). Increased cardiovascular mortality also is seen after respiratory tract infections (4), severe illnesses requiring intensive care (5), and surgery (6). Markers of systemic inflammation, such as C-reactive protein (CRP), serum amyloid A, interleukin-6 (IL-6), and tumor necrosis factor-alpha, are elevated in patients with cardiovascular disease and are associated with an adverse prognosis and recurrent coronary events (7–10). Moreover, in previously healthy individuals, elevated plasma CRP and IL-6 concentrations predict the development of cardiovascular disease (11–13). Indeed, reflecting its anti-inflammatory action, the preventative benefits of aspirin in reducing cardiovascular risk are proportional to the plasma CRP concentration (11). These data collectively suggest two patterns of association: a link between chronic inflammation and the slow process of atherogenesis and an association between acute systemic inflammation and a transiently increased risk of an acute cardiovascular event.

The vascular endothelium plays a vital role in the control of blood flow, hemostasis, fibrinolysis, and inflammation (14), and impaired endothelial function is implicated in the pathogenesis of coronary artery disease. Tissue plasminogen activator (t-PA) is a fibrinolytic factor released from the endothelium through the translocation of a dynamic intracellular storage pool and regulates the degradation of intravascular fibrin (15). If endogenous fibrinolysis is to be effective, then the rapid mobilization of t-PA from the endothelium is essential because thrombus dissolution is much more effective if t-PA is incorporated during, rather than after, thrombus formation (16,17). However, in the presence of pro-inflammatory states or an imbalance in endogenous fibrinolysis, such microthrombi may propagate, ultimately leading to arterial occlusion and tissue infarction (18).

We have previously described an in vivo model to assess the acute release of t-PA in men (19) and demonstrated an association between t-PA release and endothelial dysfunction (20,21). Hingorani et al. (22) also have recently shown that acute inflammation causes dysfunction of endothelium-dependent vasodilation in humans. However, there have been no studies to assess directly the acute local fibrinolytic capacity after acute inflammation. Therefore, the aim of this study was to test the hypothesis that the acute fibrinolytic capacity is altered by a mild systemic inflammatory response generated by typhoid vaccination.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Subjects.   Eight healthy nonsmoking men between 20 and 27 years of age participated in the study, which was undertaken with the approval of the local research ethics committee and in accordance with the Declaration of Helsinki. The written informed consent of each subject was obtained before entry into the study.

All subjects were normotensive without a history of diabetes mellitus and vascular or coronary artery disease. None of the subjects had undergone typhoid vaccination in the previous year or received vasoactive or nonsteroidal anti-inflammatory drugs in the week before the study. All subjects abstained from alcohol for 24 h and from food and caffeine-containing drinks for at least 4 h before each forearm study. All studies were performed in a quiet, temperature-controlled room maintained at 22 to 25°C.

Drugs
An inflammatory response was generated with a typhoid vaccination using Salmonella typhi capsular polysaccharide vaccine 0.025 mg (Typhim Vi, Aventis Pasteur MSD, Berkshire, United Kingdom). Pharmaceutical-grade bradykinin (Clinalfa, Läufelfingen, Switzerland), acetylcholine (Clinalfa), and sodium nitroprusside (David Bull Laboratories, Faulding, United Kingdom) were administered after dissolution in saline (0.9%; Baxter Healthcare Ltd., Berkshire, United Kingdom). All solutions were freshly prepared on the day of study.

Hemodynamic measurements
Blood flow was measured in both forearms by venous occlusion plethysmography using mercury-in-silastic strain gauges as previously described (19–21). Blood pressure was monitored in the noninfused arm at intervals throughout each study with a semiautomated noninvasive oscillometric sphygmomanometer (Takeda UA 751, Takeda Medical Inc., Tokyo, Japan).

Blood sampling and assays
Blood was withdrawn simultaneously from each arm and collected into acidified buffered citrate (Biopool Stabilyte, Ume, Sweden) for t-PA assays and trisodium citrate, ethylene diamine tetraacetic acid, and serum bead tubes (Monovette, Sarstedt, Nümbrecht, Germany) for plasminogen activator inhibitor type 1 (PAI-1), IL-6, and CRP assays, respectively, and kept on ice before being centrifuged at 2,000g for 30 min at 4°C. Platelet-free plasma was decanted and stored at –80°C before assay. Plasma t-PA, PAI-1, IL-6, and CRP concentrations were determined using specific enzyme-linked immunosorbent assays (Coaliza t-PA and Coaliza PAI-1, Chromogenix AB, Mölndal, Sweden; Quantikine human IL-6 immunoassays, R&D Systems, United Kingdom; C-reactive protein enzyme-linked immunosorbent assay, Eurogenetics, Belgium, respectively) and plasma t-PA activity using a photometric method (Coatest t-PA, Chromogenix AB, Mölndal, Sweden). Hematocrit and white cell count were determined using an automated Coulter counter (Beckman-Coulter ACt.8 Coulter Counter, High Wycombe, United Kingdom).

Study design
The S. typhi vaccine or saline placebo were injected into the deltoid muscle of each subject’s dominant arm at 8:30 AM in a randomized, balanced block, double-blind crossover manner at least two weeks apart. Previous reports have indicated that vaccination-induced endothelial dysfunction is transient and resolves within 32 h (22).

Six hours after vaccination and after a 4-h fast, strain gauges and cuffs were applied. The brachial artery of each subject’s nondominant arm was cannulated with a 27-standard wire gauge steel needle (Cooper’s Needle Works Ltd., Birmingham, United Kingdom) under 1% lidocaine (Xylocaine; Astra Pharmaceuticals, Wayne Pennsylvania) local anesthesia and attached to a 16-gauge epidural catheter (Portex Ltd., Hythe, United Kingdom). Patency was maintained by infusion of saline via a MS2000 syringe infusion pump (Graesby Medical, Watford, United Kingdom). Venous 17-gauge cannulae were inserted into large subcutaneous veins of the antecubital fossae of both arms. Forearm blood flow (FBF) was measured every 6 to 10 min. After 30 min of equilibration with saline infusion, intra-arterial bradykinin was administered at 40, 200, and 1,000 pmol/min for 10 min at each dose, acetylcholine at 5, 10, and 20 µg/min, and sodium nitroprusside at 2, 4, and 8 µg/min for 6 min at each dose. The drugs were separated by 20 min of saline infusion and administered in a randomized order that was kept constant for each individual. Venous samples were taken at baseline and during infusion of each bradykinin dose but not during sodium nitroprusside or acetylcholine infusion because they do not affect plasma t-PA or PAI-1 concentrations in this forearm model (19,23). White cell count, hematocrit, IL-6, and CRP were determined 6 h after vaccination and hematocrit was repeated at the end of the forearm study.

Data analysis and statistics
Plethysmographic data were extracted from the chart data files, and FBF was calculated for individual venous occlusion cuff inflations by use of a template spreadsheet (Microsoft Excel 97). Recordings for the first 60 s after wrist cuff inflation were not used because of the variability in blood flow this initial inflation causes. The last five linear plethysmographic recordings in each 3-min measurement period were calculated and averaged for each arm. The estimated net release of t-PA antigen and activity was defined previously (19) as the product of the infused forearm plasma flow (based on the mean hematocrit and the infused FBF) and the concentration difference between the infused ([t-PA]inf) and noninfused ([t-PA]noninf) arms and is shown as follows:


The area under the curve (AUC) was calculated for estimated net t-PA antigen and activity release during bradykinin infusion.

Data were examined, where appropriate, by analysis of variance (ANOVA) with repeated measures and two-tailed paired Student t test using Excel 97 (Microsoft). All results are expressed as mean ± SEM. Statistical significance was assigned at the 5% level.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Inflammatory response.   All subjects remained healthy throughout the study and reported no localized discomfort or systemic side effects after vaccination. Compared with placebo injection, there was a marked elevation in white cell count (11.1 ± 0.5 x 109/l vs. 7.9 ± 0.8 x 109/l; p = 0.004, t test) and plasma IL-6 concentrations (6.9 ± 1.4 pg/ml vs. 1.6 ± 0.4 pg/ml; p = 0.01, t test) 6 h after typhoid vaccination, although serum CRP concentrations (1.8 ± 1.2 µg/ml vs. 1.0 ± 0.6 µg/ml; p = NS, t test) and temperature (p = NS, t-test) (Table 1) were unchanged.


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  		Table 1 Baseline Characteristics

 
Assessment of endothelium-dependent vasomotion
There were no significant effects of vaccination on heart rate, blood pressure, or baseline FBF. There were no significant changes in heart rate, blood pressure, or noninfused FBF during drug infusion on either study day. Forearm blood flow increased in a dose-dependent manner during bradykinin, acetylcholine, and sodium nitroprusside infusions (p < 0.001, ANOVA), but there was no change in the blood flow response after vaccination (p = NS, ANOVA) (Fig. 1).



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  		Figure 1 Infused forearm blood flow during bradykinin (circles), acetylcholine (triangles), and sodium nitroprusside (squares) infusions in subjects who were administered typhoid vaccination (closed symbols) and saline placebo (open symbols). Analysis of variance, p < 0.001 for all (dose-response).

 
Assessment of fibrinolytic activity
After vaccination, there were no changes in baseline plasma t-PA and PAI-1 antigen concentrations nor plasma t-PA activity concentration. Compared with the noninfused arm, bradykinin caused dose-dependent increases in plasma t-PA antigen and activity (p < 0.001 for both, ANOVA) concentrations in the infused arm that were significantly higher after vaccination (p < 0.03, ANOVA) (Table 2). The S. typhi vaccination caused a significant augmentation in the net release of t-PA antigen (45 ± 9 vs. 24 ± 8 ng/100 ml/min at peak dose; p = 0.016, ANOVA) and activity (104 ± 15 vs. 54 ± 12 IU/100 ml/min; p = 0.006, ANOVA) during bradykinin infusion, and a two- to threefold increase in the AUC for net t-PA antigen (37 ± 12 ng/100 ml/min vs. 13 ± 9 ng/100 ml/min; p = 0.14, t test) and activity (70 ± 12 IU/100 ml/min vs. 36 ± 8 IU/100 ml/min; p = 0.037, t test) release compared with placebo (Fig. 2). Plasma PAI-1 concentrations did not change during bradykinin infusion (Table 2).


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  		Table 2 Plasma t-PA and PAI-1 Antigen and t-PA Activity/Concentrations

 


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  		Figure 2 Estimated net release of tissue-type plasminogen activator (t-PA) antigen (solid line) and activity (dotted line) in subjects who were administered typhoid vaccination (closed circles and bars) and saline placebo (open circles and bars). Lower panel represents area under the curve for the response. Analysis of variance, *p < 0.05; {dagger}p = 0.006 (vaccination vs. placebo); t test, {ddagger}p < 0.05 (vaccination vs. placebo).

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
We have demonstrated that an acute mild systemic inflammatory stimulus causes potentiation of bradykinin-induced t-PA release. We conclude that acute systemic inflammation enhances local endothelial t-PA release in men. This may reflect an adaptive mechanism of the vascular endothelium to augment its fibrinolytic response under circumstances of acute inflammation.

Endothelium-dependent vasomotion.   We assessed basal and stimulated FBF after intra-arterial infusions of the endothelium-dependent vasodilators bradykinin and acetylcholine, and the endothelium-independent vasodilator sodium nitroprusside 6 to 8 h after vaccination. Bradykinin and acetylcholine have both been widely used to investigate the function of vascular endothelium. Impaired arterial vasodilatory response to endothelium-dependent agonists has been shown in patients with hypertension (24), diabetes mellitus (25), and hypercholesterolemia (26). Hingorani et al. (22) have previously reported that S. typhi vaccinations generated an inflammatory response that was associated with a temporary suppression of endothelium-dependent vasodilation in the forearm circulation of six healthy volunteers. Although we applied a similar protocol to their study and included overlapping doses of both bradykinin and acetylcholine, we did not replicate their findings of impaired forearm endothelium-dependent vasodilation after vaccination at 6 to 8 h (Fig. 1). This discrepancy may be partly explained by the variability in vasodilatory response with acetylcholine (27) and the higher maximal vasodilator dose used in our studies, although we used a larger sample size and a double-blind, randomized, placebo-controlled, crossover trial.

Endogenous fibrinolysis
Tissue plasminogen activator, the key enzyme in the initiation of fibrinolysis, is synthesized in endothelial cells and stored in small, dense vesicles. It is secreted both basally and in response to thrombin and several vasoactive agents through a calcium-dependent and G protein-coupled pathway (28). The regulated endogenous release of t-PA plays a major role in the defense against intravascular thrombosis, especially in the coronary circulation (18). Bradykinin is a vasoactive peptide and potent stimulant for the acute release of t-PA from the vasculature (23,29–31) and is produced locally through activation of the kallikrein-kinin system on the surface of endothelial cells (32). In the present study, bradykinin-induced t-PA antigen and activity release were augmented two to threefold after typhoid vaccination in the absence of systemic hemodynamic effects (Fig. 2).

The underlying mechanisms for our findings are unknown. Inflammation is recognized to induce a protective response towards tissue injury, and it functions as part of normal host surveillance mechanisms. Various compounds associated with the inflammatory response, including histamine, thrombin and endotoxin, have been shown to increase cellular t-PA transcription and expression (33,34). However, we did not observe an increase in the basal plasma concentrations of either t-PA or PAI-1. The inflammatory stimulus, therefore, appears to augment specifically the storage or acute release of t-PA rather than a generalized upregulation of protein synthesis and basal secretion. This may be mediated by pro-inflammatory cytokines, such as IL-6, that modulate cellular activation, leading to alterations in endothelial function. In particular, molecular and pharmacologic evidence supports the role of bradykinin B2 receptors in the acute phase of inflammation, and upregulation of B2 receptors may account for the potentiation of bradykinin-induced t-PA release.

Clinical implications
The augmentation of acute t-PA release after typhoid vaccination suggests that mild acute inflammation may induce antithrombotic properties in the forearm circulation. This may represent an adaptive response to inhibit intravascular thrombus deposition under circumstances of acute vascular inflammation. This observation is consistent with the increase in endogenous fibrinolysis in systemic inflammation induced by experimental endotoxemia in healthy subjects (35). However, in susceptible individuals, such as those with ischemic heart disease and chronic inflammation, this adaptive and protective acute response may fail or become depleted, leading to thrombus propagation and vessel occlusion. The fibrinolytic response to acute systemic inflammation in patients with ischemic heart disease and the influence of anti-inflammatory therapies, such as aspirin, now needs to be established. Indeed, recent evidence has suggested that preventative treatment with aspirin is able to reverse inflammation-induced endothelial dysfunction (36).

Epidemiologic studies have demonstrated an association between the risk of future cardiovascular events and both plasma inflammatory markers (11–13) and fibrinolytic factors (37). Therefore, the current observations are consistent with the suggestion that elevated plasma t-PA concentrations may provide a marker of vascular inflammation. Irrespective of whether these common associations are partly or wholly explained by inflammation-induced t-PA release, understanding the regulation of both acute and chronic t-PA release will have important clinical implications and may help to develop more effective strategies in the management of atherosclerotic disease.

Study limitations
There are some limitations to our study. We administered the typhoid vaccination in the deltoid muscle of each subject’s dominant arm rather than the gluteus muscle. However, because blood flow was assessed in the forearm and intra-arterial vasodilators were administered in the contralateral nondominant arm, it would be highly unlikely that the site of vaccination would have affected the response in the infused forearm. It would also have been preferable to assess the vascular responses immediately before and 6 to 8 h after vaccination on the same day. However, this would require repeated arterial cannulations within the same day, and we have previously demonstrated that endothelium-dependent vasodilation and t-PA release is reproducible when performed at least one week apart (38,39). The study subjects were healthy and young, and we acknowledge that the response in older subjects may be quite different. Finally, we studied peripheral vascular function; therefore, these findings may not be directly applicable to other vascular beds. However, endothelial dysfunction is often a generalized process, and we have previously shown (21,40) consistent endogenous fibrinolytic responses between the forearm and coronary circulation.

Conclusions
We have demonstrated that mild inflammation generated by typhoid vaccination results in a significant potentiation of bradykinin-induced t-PA release from the vascular endothelium. Additional studies are now required to determine the underlying mechanism and to assess the effects of acute and chronic inflammation on endogenous fibrinolysis in health and disease.


   Acknowledgments
 
The authors thank Pamela Dawson and Kathryn Carruthers for their assistance with this study.


   Footnotes
 
This work was supported by a British Heart Foundation Project Grant (PG/2001068). Dr. Chia is the recipient of a British Heart Foundation Junior Research Fellowship (FS/2001049).


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med. 1999;340:115–125[Free Full Text]
  2. Roivainen M, Viik-Kajander M, Palosuo T, et al. Infections, inflammation, and the risk of coronary heart disease. Circulation. 2000;101:252–257[Abstract/Free Full Text]
  3. Valtonen V, Kuikka A, Syrjanen J. Thrombo-embolic complications in bacteraemic infections. Eur Heart J. 1993;14(Suppl K):20–23
  4. Meier CR, Jick SS, Derby LE, Vasilakis C, Jick H. Acute respiratory-tract infections and risk of first-time acute myocardial infarction. Lancet. 1998;351:1467–1471[CrossRef][Medline]
  5. Quartin AA, Schein RMH, Kett DH, Peduzzi PN. Magnitude and duration of the effect of sepsis on survival. JAMA. 1997;277:1058–1063[Abstract]
  6. Mamode N, Cobbe S, Pollock JG. Infarcts after surgery. Br Med J. 1995;310:1215–1216[Free Full Text]
  7. Liuzzo G, Biasucci L, Gallimore JR, et al. The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med. 1994;331:417–424[Abstract/Free Full Text]
  8. Ridker PM, Rifai N, Pfeffer M, Sacks F, Lepage S, Braunwald E. Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction. Circulation. 2000;101:2149–2153[Abstract/Free Full Text]
  9. Biasucci LM, Vitelli A, Liuzzo G, et al. Elevated levels of interleukin-6 in unstable angina. Circulation. 1996;94:874–877[Abstract/Free Full Text]
  10. Biasucci LM, Liuzzo G, Fantuzzi G, et al. Increasing levels of interleukin (IL)-1Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events. Circulation. 1999;99:2079–2084[Abstract/Free Full Text]
  11. Ridker PM, Cushman P, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973–979[Abstract/Free Full Text]
  12. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836–843[Abstract/Free Full Text]
  13. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 2000;101:1767–1772[Abstract/Free Full Text]
  14. Vane JR, Anggard EE, Botting RM. Regulatory functions of the vascular endothelium. N Engl J Med. 1990;323:27–36[Medline]
  15. van den Eijnden-Schrauwen Y, Kooistra T, de Vries REM, Emeis JJ. Studies on the acute release of tissue-type plasminogen activator from human endothelial cells in vitro and in rats in vivo: evidence for a dynamic storage pool. Blood. 1995;85:3510–3517[Abstract/Free Full Text]
  16. Fox KAA, Robison AK, Knabb RM, Rosamond TL, Sobel BE, Bergmann SR. Prevention of coronary thrombosis with subthrombolytic doses of tissue-type plasminogen activator. Circulation. 1984;72:1346–1354
  17. Brommer EJP. The level of extrinsic plasminogen activator (t-PA) during clotting as a determinant of the rate of fibrinolysis: inefficiency of activators added afterwards. Thromb Res. 1984;34:109–115[CrossRef][Medline]
  18. Rosenberg RD, Aird WC. Vascular-bed-specific hemostasis and hypercoagulable states. N Engl J Med. 1999;340:1555–1564[Free Full Text]
  19. Newby DE, Wright RA, Ludlam CA, Fox KA, Boon NA, Webb DJ. An in vivo model for the assessment of the acute fibrinolytic capacity of the endothelium. Thromb Haemost. 1997;78:1242–1248[Medline]
  20. Newby DE, Wright RA, Dawson P, et al. The L-arginine: nitric oxide pathway contributes to the acute release of tissue plasminogen activator in vivo in man. Cardiovasc Res. 1998;38:485–492[Abstract/Free Full Text]
  21. Newby DE, Wright RA, Labinjoh C, et al. Endothelial dysfunction, impaired endogenous fibrinolysis, and cigarette smoking: a mechanism for arterial thrombosis and myocardial infarction. Circulation. 1999;99:1411–1415[Abstract/Free Full Text]
  22. Hingorani AD, Cross J, Kharbanda RK, et al. Acute systemic inflammation impairs endothelium-dependent dilatation in humans. Circulation. 2000;102:994–999[Abstract/Free Full Text]
  23. Brown NJ, Gainer JV, Stein CM, Vaughan DE. Bradykinin stimulates tissue plasminogen activator release in human vasculature. Hypertension. 1999;33:1431–1435[Abstract/Free Full Text]
  24. Panza JA, Quyyumi AA, Brush JE Jr., Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med. 1990;323:22–27[Abstract]
  25. Calver A, Collier J, Vallance P. Inhibition and stimulation of nitric oxide synthesis in the forearm arterial bed of patients with insulin-dependent diabetes. J Clin Invest. 1992;90:2548–2554[Medline]
  26. Chowienczyk P, Watts G, Cockcroft J, Ritter JM. Impaired endothelium dependent vasodilation of forearm resistance vessels in hypercholesterolaemia. Lancet. 1992;340:1430–1432[CrossRef][Medline]
  27. Chowienczyk P, Cockcroft JR, Ritter JM. Blood flow responses to intra-arterial acetylcholine in man: effects of basal flow and conduit vessel length. Clin Sci. 1994;87:45–51[Medline]
  28. Emeis JJ, van den Eijnden-Schrauwen Y, van den Hoogen CM, de Priester W, Westmuckett A, Lupu F. An endothelial storage granule for tissue-type plasminogen activator. J Cell Biol. 1997;139:245–256[Abstract/Free Full Text]
  29. Brown NJ, Nadeau JH, Vaughan DE. Selective stimulation of tissue plasminogen activator (t-PA) in vivo by infusion of bradykinin. Thromb Haemost. 1997;77:522–525[Medline]
  30. Labinjoh C, Newby DE, Pellegrini MP, Johnston NR, Boon NA, Webb DJ. Potentiation of bradykinin-induced tissue plasminogen activator release by angiotensin-converting enzyme inhibition. J Am Coll Cardiol. 2001;38:1402–1408[Abstract/Free Full Text]
  31. Labinjoh C, Newby DE, Dawson P, et al. Fibrinolytic actions of intra-arterial angiotensin II and bradykinin in vivo in man. Cardiovasc Res. 2000;47:707–714[Abstract/Free Full Text]
  32. Rojkjaer R, Schmaier AH. Activation of the plasma kallikrein/kinin system on endothelial cells. Proc Assoc Am Phys. 1999;111:220–227[CrossRef][Medline]
  33. Dichek D, Quertermous T. Thrombin regulation of mRNA levels of tissue plasminogen activator and plasminogen activator inhibitor-1 in cultured human umbilical vein endothelial cells. Blood. 1989;74:222–228[Abstract/Free Full Text]
  34. Levin EG, Santell L. Stimulation and desensitization of tissue plasminogen activator release from human endothelial cells. J Biol Chem. 1988;263:9360–9365[Abstract/Free Full Text]
  35. van der Poll T, Coyle SM, Levi M, et al. Effect of a recombinant dimeric tumor necrosis factor receptor on inflammatory responses to intravenous endotoxin in normal humans. Blood. 1997;89:3727–3734[Abstract/Free Full Text]
  36. Kharbanda RK, Walton B, Allen M, et al. Prevention of inflammation-induced endothelial dysfunction: a novel vasculo-protective action of aspirin. Circulation. 2002;105:2600–2604[Abstract/Free Full Text]
  37. Hamsten A, Wiman B, de Faire U, Blomback M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med. 1985;313:1557–1563[Abstract]
  38. Newby DE, Sciberras DG, Mendel CM, Gertz BJ, Boon NA, Webb DJ. Intra-arterial substance P mediated vasodilatation in the human forearm: pharmacology, reproducibility and tolerability. Br J Clin Pharmacol. 1997;43:493–499[CrossRef][Medline]
  39. Newby DE, Witherow FN, Wright RA, et al. Hypercholesterolemia and lipid lowering therapy do not affect the acute endogenous fibrinolytic capacity in vivo. Heart. 2002;87:48–53[Abstract/Free Full Text]
  40. Newby DE, MacLeod AL, Uren NG, et al. Impaired coronary tissue plasminogen activator release is associated with coronary atherosclerosis and cigarette smoking: direct link between endothelial dysfunction and atherothrombosis. Circulation. 2001;103:1936–1941[Abstract/Free Full Text]



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