(Hypertension. 1999;33:1431-1435.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Bradykinin Stimulates Tissue Plasminogen Activator Release in Human Vasculature
From the Departments of Medicine and Pharmacology (N.J.B., J.V.G., C.M.S., D.E.V.), Vanderbilt University Medical Center, and Nashville Veterans Administration Medical Center (D.E.V.), Nashville, Tenn.
Correspondence to Nancy J. Brown, MD, 560 MRB-1, Vanderbilt University Medical Center, Nashville, TN 37232-6602. E-mail nancy.brown{at}mcmail.vanderbilt.edu
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Abstract |
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Abstract—Bradykinin stimulates tissue plasminogen activator (tPA) release in isolated perfused animal tissues. The present study tests the hypothesis that bradykinin increases tPA release in humans through local effects on the vasculature. Graded doses of sodium nitroprusside (0.8 to 3.2 µg/min), acetylcholine (ACh) (7.5 to 60 µg/min), and bradykinin (100 to 400 ng/min) were administered intra-arterially in random order in 10 salt-depleted (10 mmol/d of Na) normotensive volunteers. None of the drugs altered mean arterial pressure or heart rate. Forearm blood flow (FBF) was measured by strain-gauge plethysmography. All 3 drugs caused a dose-dependent increase in FBF, although ACh was less potent than either nitroprusside or bradykinin (maximum FBF 7.5±2.4 versus 10.0±1.5 and 11.9±2.1 mL · 100 mL-1 · min-1, respectively). Bradykinin caused a significant, dose-dependent increase in venous (effect of dose F=9.9, P=0.028 by ANOVA), but not arterial (F=0.154, P=0.92) tPA antigen in the infused arm. Thus, net tPA release increased significantly in response to bradykinin (50.6±13.3 at the highest dose versus 0.9±0.4 ng · 100 mL-1 · min -1 at baseline, P=0.014). In contrast, bradykinin did not affect plasminogen activator inhibitor antigen. Neither nitroprusside nor ACh altered plasma levels of tPA or plasminogen activator inhibitor antigen. Bradykinin increased tPA release across the forearm in the absence of systemic effects. This effect could not be attributed to changes in blood flow because doses of equivalent potency of the vasodilator nitroprusside did not increase tPA. These data demonstrate that bradykinin stimulates tPA release in the human vasculature.
Key Words: bradykinin • plasminogen, tissue activator • endothelium • angiotensin-converting enzyme inhibitors
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Introduction |
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Bradykinin is a vasoactive polypeptide that has cardioprotective effects.1 Bradykinin promotes vasodilation by stimulating the production of arachidonic acid metabolites, nitric oxide, and endothelium-derived hyperpolarizing factor in vascular endothelium.2 Bradykinin inhibits thrombin-induced platelet activation.3 In addition, bradykinin is a potent stimulus for release of tissue plasminogen activator(tPA) in endothelial cells4 and perfused tissue preparations, such as the pig ear5 or rat hind limb.6 The effect of bradykinin on tPA release in human vasculature has not been extensively studied. A previous study demonstrated that systemic administration of bradykinin increases venous tPA antigen concentrations in angiotensin-converting enzyme (ACE) inhibitor–pretreated subjects.7 However, because the systemic administration of the vasodilator bradykinin resulted in activation of the sympathetic nervous system, adrenergic stimulation of tPA release, a well-recognized phenomenon,8 could not be excluded. Moreover, changes in venous tPA concentrations in response to systemically administered bradykinin and consequent hemodynamic alterations may have resulted from changes in hepatic blood flow and tPA clearance.9
The purpose of the present study was to test the hypothesis that bradykinin directly stimulates endothelial release of tPA in human vasculature by measuring the effect of direct intra-arterial administration of bradykinin on tPA release across the forearm. This model allows determination of local, vascular tPA release while avoiding confounding systemic effects or changes in hepatic clearance10 and has been used to measure the effect of a number of agonists on endothelial tPA release, including desmopressin,11 methacholine,10 12 and isoproterenol.12 The forearm vasodilator and tPA responses to bradykinin were compared with the responses to acetylcholine (ACh) (another endothelium-dependent vasodilator)13 and nitroprusside (a direct-acting vasodilator).14
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Methods |
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Subjects
The study group was comprised of 10 normotensive subjects. Informed consent was obtained. The protocol was approved by the Vanderbilt University Institutional Review Board, and the study was conducted according to the Declaration of Helsinki. Each subject underwent a history and physical examination, ECG, and routine laboratory analysis. None had any evidence of hypertension, hyperlipidemia, cardiovascular disease, or other systemic condition. All but 1 of the subjects were nonsmokers. A total of 6 men and 4 women were studied. Of the 10 subjects, 5 were black and 5 were white. The mean age was 32.5±2.8 years; mean body mass index was 25.1±1.1 kg/m2. The mean plasma renin activity measured during 10 mmol sodium intake per day and after 1 hour of upright posture was 5.6±2.2 ng Ang I · mL-1 · h-1. All subjects were participating in ongoing studies of the effects of dietary salt intake and race on vasodilator responses.
Experimental Protocol
All studies were performed in the morning in a
temperature-controlled room. Subjects were studied in the supine
position and in the fasting state. An intravenous catheter
was placed in the antecubital vein in both arms. After subdermal
administration of 1% lidocaine, an 18 gauge polyurethane catheter
(Cook, Inc) was inserted into the brachial artery of the
nondominant arm allowing direct intra-arterial
administration of drugs. Before the infusion of vasoactive drugs,
arterial catheter patency was maintained by infusion of 5%
dextrose in water at rate of 1 mL/min. After intravenous
and intra-arterial catheters were placed, subjects were
allowed to rest for 30 minutes before baseline measurements were made.
After measurement of basal forearm blood flow (FBF) and blood sampling,
graded doses of sodium nitroprusside, ACh, and bradykinin were infused
in random order. Sodium nitroprusside was infused at 0.8, 1.6, and 3.2
µg/min; ACh was infused at 7.5, 15, and 30 µg/min in the first 3
subjects and 15, 30, and 60 µg/min in the remaining 7 subjects, and
bradykinin was infused at 100, 200, and 400 ng/min. Each dose was
infused for 5 minutes and FBF was measured during the last 2 minutes of
the infusion. Drug concentrations in the infusate were adjusted to
maintain infusion volumes at 1 mL/min. Before infusion of each drug, a
30-minute rest period was allowed and basal measurements were
repeated.
Forearm Perfusion Measurements
FBF was measured using mercury-in-Silastic strain gauge
plethysmography.15 The wrist was supported in a sling to
raise the level of the forearm to above the level of the atrium, and
the strain gauge was placed in the widest part of the forearm. The
strain gauge was connected to a plethysmograph (model EC-4, D.E.
Hokanson), calibrated to measure the percent change in volume and
connected to a chart recorder to record the flow measurements.
For each measurement, a cuff placed around the upper arm was inflated
to 40 mm Hg with a rapid cuff inflator (model E-10, Hokanson) to
occlude venous outflow from the extremity. The hand was excluded from
the measurement of blood flow by inflation of a pediatric
sphygmomanometer cuff to 200 mm Hg around the wrist before and
during measurement of FBF. Flow measurements were recorded for 
7
of 15 seconds, and the slope was derived from the first 3 to 4
pulses; 7 readings were obtained for each mean value.
Blood Sampling and Biochemical Assays
After FBF was measured, simultaneous venous samples
were obtained from the infused and noninfused arms before drugs were
administered and at the highest dose of each drug. In 6 subjects
(subjects 5 through 10), samples were obtained at each dose of drug and
simultaneous arterial samples were obtained
from the infusion arm to allow calculation of the net release or uptake
rate (see below). Drug infusion was interrupted during
arterial sampling. All samples were obtained after the
first 3 mL of blood were discarded.
Blood samples were collected on ice and centrifuged immediately and plasma was stored at -70°C until the time of assay. Blood for measurement of plasminogen activator inhibitor (PAI-1) and tPA was collected in tubes containing 0.105 mol/L sodium citrate. Antigen levels were determined using a 2-site ELISA (Biopool AB) as previously described.16 Catecholamines were collected in tubes containing reduced glutathione and measured by high-performance liquid chromatography, as previously described.17
Arteriovenous concentration gradients were calculated by subtracting
the plasma level measured in simultaneously collected
venous and arterial blood. Forearm plasma flow was
calculated from the FBF and arterial hematocrit corrected
for 1% trapped plasma. Thus, individual net release or uptake rates at
each time point were calculated with the following formula:
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Statistics
Data are presented as mean±SEM. Comparisons between
drugs were made using ANOVA for repeated measures in which the
within-subject variables were drug and dose increments. Post hoc
comparisons were made using the paired t test or
Wilcoxon signed rank test, as appropriate. A 2-tailed value of
P<0.05 was the criterion for statistical
significance.
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Results |
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Hemodynamics and FBF
There was no significant effect of sodium nitroprusside, ACh, or bradykinin on either mean arterial pressure or heart rate (Table). FBF increased in a dose-dependent fashion in response to nitroprusside (F=8.9, P=0.009 for dose effect by ANOVA), ACh (F=9.8, P=0.007), and bradykinin (F=7.3, P=0.015) (Figure 1). The increase in FBF in response to ACh was significantly less than the increase in FBF in response to either nitroprusside (effect of drug F=14.4, P=0.004) or bradykinin (F=15.7, P=0.003). However, there was not a significant difference between the FBF response to nitroprusside or to bradykinin.
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Fibrinolytic Parameters
No significant effect of either nitroprusside or ACh was
seen on venous tPA antigen concentration in the infused or opposite
arm, arterial tPA antigen, or net tPA release (Table
and Figure 2). In contrast,
bradykinin caused a significant and dose-dependent increase in venous
tPA from the infused arm (effect of dose, F=9.9, P=0.028).
There was no change in arterial tPA concentration. At the
highest bradykinin concentration, the tPA concentration in venous blood
from the noninfused arm was significantly higher than baseline
(4.72±1.01 versus 3.74±0.68 ng/mL, P<0.05) but
significantly lower than venous tPA antigen from the infused arm
(4.72±1.01 versus 9.72±1.90, P<0.05). In the 6 subjects
in whom it was measured, net tPA release increased 60-fold from
baseline to the highest dose of bradykinin (from 0.85±0.43 to
50.6±13.3 ng · min-1 · 100
mL-1; P=0.014). (Figure 2)
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Neither arterial nor venous PAI-1 antigen changed significantly in response to nitroprusside, ACh, or bradykinin. Net extraction of PAI-1 tended to increase with increasing doses of vasodilator but this effect was not significant (eg, for bradykinin, effect of dose F=3.7, P=0.157). There were no differences between the venous PAI-1 antigen concentrations in the infused and noninfused arms during administration of nitroprusside (3.5±0.5 infused versus 3.6±0.6 ng/mL noninfused, P=0.9), ACh (3.1±0.4 infused versus 3.6±0.7 ng/mL, P=0.4), or bradykinin (5.3±1.4 infused versus 3.9±0.6 ng/mL noninfused, P=0.5).
Catecholamines
No effect of nitroprusside, ACh, or bradykinin was found on venous
norepinephrine or epinephrine concentrations
(Table).
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Discussion |
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tPA, the key enzyme in the initiation of fibrinolysis, is synthesized in endothelial cells; stored in small, dense vesicles; and secreted by endothelial cells in response to a number of vasoactive agents.18 Studies of vascular endothelial cells4 18 in isolated perfused tissue preparations,5 6 and in whole rats19 suggest that bradykinin is a potent stimulant of endothelial tPA release. For example, bradykinin was 1000-fold more potent than other agonists, such as histamine, norepinephrine, vasopressin, and ACh in stimulating release of circulating tPA in a rodent model.19 The present study provides evidence that bradykinin is a dose-dependent stimulant of endothelial tPA release in humans.
In an earlier study, systemic administration of bradykinin resulted in increased venous tPA concentrations in the presence of ACE inhibition7 ; however, interpretation of that study was confounded by activation of the sympathetic nervous system and by potential changes in hepatic blood flow resulting from systemic hemodynamic effects of bradykinin. The use of local intra-arterial infusion of bradykinin in the present study allowed us to exclude such confounding factors. Thus, intra-arterial infusion of vasodilators had no systemic effects as measured by mean arterial pressure and heart rate. Although venous tPA increased slightly in the noninfused arm during the highest dose of bradykinin, venous tPA was significantly higher in the infused arm compared with the noninfused arm. This finding and the lack of change in arterial tPA concentrations suggest a local effect of bradykinin on tPA release.
Increased shear has been reported to stimulate tPA release20 ; however, the present study does not support the hypothesis that increased blood flow alone is responsible for the observed effect of bradykinin on tPA release. Administration of nitroprusside, a nitric-oxide synthase-independent vasodilator,14 did not increase tPA release, despite its having a vasodilator effect similar to that of bradykinin. A lack of effect of nitroprusside on tPA release has been observed in several other studies.10 12 21 Furthermore, ACh, a muscarinic agonist, failed to induce an increase in net tPA release in this study. This contrasts with data from Jern et al10 and from a previous study by our group12 that show that methacholine increases net tPA release across the forearm. However, Pedrinelli et al22 have also observed a lack of effect of intra-arterial ACh on tPA concentration across the forearm. One possible explanation for the finding of the present study is that doses of ACh inadequate to stimulate tPA release were administered. The FBF response to ACh was significantly less than the FBF response to either of the other 2 vasodilators administered, despite the fact that the doses of ACh administered (0 to 60 µg/min) were higher than those generally used to assess endothelial vasodilation in humans (0 to 30 µg/min).23 The inclusion of black subjects, who have been shown to have blunted vasodilator responses to muscarinic agonists,24 may have contributed to this effect. Further studies are needed to assess the effect of race on the tPA response to bradykinin and other vasoactive substances. A second explanation for the lack of effect of ACh on tPA release is that ACh and methacholine may differ in their potency for stimulating endothelial tPA release. Previous investigators have shown a 10-fold greater vasodilator potency of methacholine versus ACh and have attributed this to more rapid degradation of ACh by cholinesterases.25 Nevertheless, given the blunted vasodilator response to ACh observed in the present study versus previous studies in healthy volunteers and our previous observation that methacholine increases tPA release,12 we cannot exclude the possibility that ACh would stimulate tPA release under different experimental conditions.
Although this is the first study to delineate the effects of intra-arterial administration of bradykinin on local vascular release of tPA in humans, the subject population studied was heterogeneous with respect to characteristics such as race and gender. Numerous studies have demonstrated that factors such as race,24 smoking,26 lipid level,27 estrogen level,28 hypertension,23 and glucose and insulin levels29 affect endothelial function, as measured by vasodilator responses to intra-arterial agonists or reactive hyperemia. Jern et al30 have also demonstrated that tPA release across the forearm in response to methacholine is attenuated in hypertensive subjects versus normotensive subjects. The extent to which individual subject characteristics influence endothelial function, as measured by the tPA response to bradykinin, remains to be studied.
The mechanism through which bradykinin induces endothelial tPA release is not clear from the present study. Like most substances that have been shown to induce acute tPA release, bradykinin stimulates prostacyclin and nitric oxide synthesis.2 The vasodilator effects of bradykinin are attenuated by bradykinin subtype B2-specific receptor antagonists31 and by the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine,32 but not by cyclo-oxygenase inhibitors33 34 in humans. NG-monomethyl-L-arginine has been shown to attenuate the tPA response to substance P,35 which suggests that nitric oxide plays a role in stimulation of endothelial tPA release. Further studies are needed to delineate the pathways involved in bradykinin-stimulated endothelial tPA release.
Decreased bradykinin degradation appears to contribute to the vasodilator effects of ACE inhibitors in humans. Thus, coadministration of an ACE inhibitor potentiates the effects of intravenous33 34 and intra-arterial bradykinin.34 36 Conversely, bradykinin receptor blockade attenuates the effects of ACE inhibition on endothelium-mediated vasodilation37 and on blood pressure.38 The present finding that bradykinin increases endothelial tPA release suggests that bradykinin may also contribute to a favorable effect of ACE inhibitors on fibrinolytic balance. In this regard, Hornig et al39 recently reported a significant increase in forearm venous tPA antigen during intra-brachial administration of an ACE inhibitor. In addition, during chronic ACE inhibition, plasma tPA antigen concentrations (which reflect both active tPA and inactive tPA complexed with PAI-1) are preserved, despite the fact that PAI-1 antigen concentrations decrease.40 Further studies are needed to determine if coadministration of a bradykinin antagonist will abolish this effect of ACE inhibition on endothelial tPA release.
In summary, the present study demonstrates that intra-arterial administration of bradykinin results in a substantial local release of tPA. This release occurred in a dose-dependent fashion, in the absence of systemic effects, and was independent of changes in FBF. Thus, these data suggest that bradykinin is a flow-independent stimulus for tPA release in the human vasculature.
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Acknowledgments |
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This work was supported by NIH grants HL 51387, HL 60906, HL 56251, HL 56963, and 5 M01 RR 0095; by a Clinical Investigator Award from the Veterans Affairs Research Administration (D.E.V.); and by a Pharmaceutical Research and Manufacturers Association Foundation Career Development Award (C.M.S.).
Received December 3, 1998; first decision January 8, 1999; accepted February 5, 1999.
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V. J. Dzau, E. M. Antman, H. R. Black, D. L. Hayes, J. E. Manson, J. Plutzky, J. J. Popma, and W. Stevenson The Cardiovascular Disease Continuum Validated: Clinical Evidence of Improved Patient Outcomes: Part I: Pathophysiology and Clinical Trial Evidence (Risk Factors Through Stable Coronary Artery Disease) Circulation, December 19, 2006; 114(25): 2850 - 2870. [Full Text] [PDF]
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 L. J. Murphey, H. A. Malave, J. Petro, I. Biaggioni, D. W. Byrne, D. E. Vaughan, J. M. Luther, M. Pretorius, and N. J. Brown Bradykinin and Its Metabolite Bradykinin 1-5 Inhibit Thrombin-Induced Platelet Aggregation in Humans J. Pharmacol. Exp. Ther., September 1, 2006; 318(3): 1287 - 1292. [Abstract] [Full Text] [PDF]
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 A. D. Maslow, G. Stearns, P. Batula, C. S. Schwartz, J. Gough, and A. K. Singh The hemodynamic effects of methylene blue when administered at the onset of cardiopulmonary bypass. Anesth. Analg., July 1, 2006; 103(1): 2 - 8. [Abstract] [Full Text] [PDF]
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 S D Robinson, C A Ludlam, N A Boon, and D E Newby Phosphodiesterase type 5 inhibition does not reverse endothelial dysfunction in patients with coronary heart disease Heart, February 1, 2006; 92(2): 170 - 176. [Abstract] [Full Text] [PDF]
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J. J. Oliver, D. J. Webb, and D. E. Newby Stimulated Tissue Plasminogen Activator Release as a Marker of Endothelial Function in Humans Arterioscler. Thromb. Vasc. Biol., December 1, 2005; 25(12): 2470 - 2479. [Abstract] [Full Text] [PDF]
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M. Pretorius, J. M. Luther, L. J. Murphey, D. E. Vaughan, and N. J. Brown Angiotensin-Converting Enzyme Inhibition Increases Basal Vascular Tissue Plasminogen Activator Release in Women But Not in Men Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2435 - 2440. [Abstract] [Full Text] [PDF]
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 J. P. Tsikouris, J. A. Suarez, G. E. Meyerrose, M. Ziska, D. Fike, and J. Smith Questioning a Class Effect: Does ACE Inhibitor Tissue Penetration Influence the Degree of Fibrinolytic Balance Alteration following an Acute Myocardial Infarction? J. Clin. Pharmacol., February 1, 2004; 44(2): 150 - 157. [Abstract] [Full Text] [PDF]
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M. Pretorius, L. J. Murphey, J. A. McFarlane, D. E. Vaughan, and N. J. Brown Angiotensin-Converting Enzyme Inhibition Alters the Fibrinolytic Response to Cardiopulmonary Bypass Circulation, December 23, 2003; 108(25): 3079 - 3083. [Abstract] [Full Text] [PDF]
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A. H. Schmaier The kallikrein-kinin and the renin-angiotensin systems have a multilayered interaction Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2003; 285(1): R1 - R13. [Abstract] [Full Text] [PDF]
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J.-A. Bjorkman, S. Jern, and C. Jern Cardiac Sympathetic Nerve Stimulation Triggers Coronary t-PA Release Arterioscler. Thromb. Vasc. Biol., June 1, 2003; 23(6): 1091 - 1097. [Abstract] [Full Text] [PDF]
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T. Matsumoto, K. Minai, H. Horie, N. Ohira, H. Takashima, Y. Tarutani, Y. o Yasuda, T. Ozawa, S. Matsuo, M. Kinoshita, et al. Angiotensin-converting enzyme inhibition but not angiotensin II type 1 receptor antagonism augments coronary release of tissue plasminogen activator in hypertensive patients J. Am. Coll. Cardiol., April 16, 2003; 41(8): 1373 - 1379. [Abstract] [Full Text] [PDF]
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S. Chia, M. Qadan, R. Newton, C. A. Ludlam, K. A.A. Fox, and D. E. Newby Intra-Arterial Tumor Necrosis Factor-{alpha} Impairs Endothelium-Dependent Vasodilatation and Stimulates Local Tissue Plasminogen Activator Release in Humans Arterioscler. Thromb. Vasc. Biol., April 1, 2003; 23(4): 695 - 701. [Abstract] [Full Text] [PDF]
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S. Chia, C. A. Ludlam, K. A. A. Fox, and D. E. Newby Acute systemic inflammation enhances endothelium-dependent tissue plasminogen activator release in men J. Am. Coll. Cardiol., January 15, 2003; 41(2): 333 - 339. [Abstract] [Full Text] [PDF]
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 D. T Smith, G. L Hoetzer, J. J Greiner, B. L Stauffer, and C. A DeSouza Effects of ageing and regular aerobic exercise on endothelial fibrinolytic capacity in humans J. Physiol., January 1, 2003; 546(1): 289 - 298. [Abstract] [Full Text] [PDF]
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 G. L. Hoetzer, B. L. Stauffer, J. J. Greiner, Y. Casas, D. T. Smith, and C. A. DeSouza Influence of oral contraceptive use on endothelial t-PA release in healthy premenopausal women Am J Physiol Endocrinol Metab, January 1, 2003; 284(1): E90 - E95. [Abstract] [Full Text] [PDF]
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J. A. S. Muldowney III and D. E. Vaughan Tissue-type plasminogen activator release: New frontiers in endothelial function J. Am. Coll. Cardiol., September 4, 2002; 40(5): 967 - 969. [Full Text] [PDF]
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 D. Huber, E. M. Cramer, J. E. Kaufmann, P. Meda, J.-M. Masse, E. K. O. Kruithof, and U. M. Vischer Tissue-type plasminogen activator (t-PA) is stored in Weibel-Palade bodies in human endothelial cells both in vitro and in vivo Blood, May 15, 2002; 99(10): 3637 - 3645. [Abstract] [Full Text] [PDF]
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 Z. Shariat-Madar, F. Mahdi, and A. H. Schmaier Identification and Characterization of Prolylcarboxypeptidase as an Endothelial Cell Prekallikrein Activator J. Biol. Chem., May 10, 2002; 277(20): 17962 - 17969. [Abstract] [Full Text] [PDF]
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M. Pretorius, D. A. Rosenbaum, J. Lefebvre, D. E. Vaughan, and N. J. Brown Smoking Impairs Bradykinin-Stimulated t-PA Release Hypertension, March 1, 2002; 39(3): 767 - 771. [Abstract] [Full Text] [PDF]
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 V. R. Conti and C. McQuitty Vasodilation and Cardiopulmonary Bypass : The Role of Bradykinin and the Pulmonary Vascular Endothelium Chest, December 1, 2001; 120(6): 1759 - 1761. [Full Text] [PDF]
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C. Labinjoh, D. E. Newby, M. P. Pellegrini, N. R. Johnston, N. A. Boon, and D. J. Webb Potentiation of bradykinin-induced tissue plasminogen activator release by angiotensin-converting enzyme inhibition J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1402 - 1408. [Abstract] [Full Text] [PDF]
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 W. C. Wolf, D. M. Evans, L. Chao, and J. Chao A Synthetic Tissue Kallikrein Inhibitor Suppresses Cancer Cell Invasiveness Am. J. Pathol., November 1, 2001; 159(5): 1797 - 1805. [Abstract] [Full Text] [PDF]
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 M.P. Pellegrini, D. E Newby, S. Maxwell, and D. J Webb Short-term effects of transdermal nicotine on acute tissue plasminogen activator release in vivo in man Cardiovasc Res, November 1, 2001; 52(2): 321 - 327. [Abstract] [Full Text] [PDF]
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K. Minai, T. Matsumoto, H. Horie, N. Ohira, H. Takashima, H. Yokohama, and M. Kinoshita Bradykinin stimulates the release of tissue plasminogen activator in human coronary circulation: effects of angiotensin-converting enzyme inhibitors J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1565 - 1570. [Abstract] [Full Text] [PDF]
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T. Wilsdorf, J. V. Gainer, L. J. Murphey, D. E. Vaughan, and N. J. Brown Angiotensin-(1-7) Does Not Affect Vasodilator or TPA Responses to Bradykinin in Human Forearm Hypertension, April 1, 2001; 37(4): 1136 - 1140. [Abstract] [Full Text] [PDF]
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 C. F. Mojcik and J. H. Levy Aprotinin and the systemic inflammatory response after cardiopulmonary bypass Ann. Thorac. Surg., February 1, 2001; 71(2): 745 - 754. [Abstract] [Full Text] [PDF]
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J. V. Gainer, C. M. Stein, T. Neal, D. E. Vaughan, and N. J. Brown Interactive Effect of Ethnicity and ACE Insertion/Deletion Polymorphism on Vascular Reactivity Hypertension, January 1, 2001; 37(1): 46 - 51. [Abstract] [Full Text] [PDF]
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N. J. Brown, J. V. Gainer, L. J. Murphey, and D. E. Vaughan Bradykinin Stimulates Tissue Plasminogen Activator Release From Human Forearm Vasculature Through B2 Receptor-Dependent, NO Synthase-Independent, and Cyclooxygenase-Independent Pathway Circulation, October 31, 2000; 102(18): 2190 - 2196. [Abstract] [Full Text] [PDF]
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C. Labinjoh, D. E. Newby, P. Dawson, N. R. Johnston, C. A. Ludlam, N. A. Boon, and D. J. Webb Fibrinolytic actions of intra-arterial angiotensin II and bradykinin in vivo in man Cardiovasc Res, September 1, 2000; 47(4): 707 - 714. [Abstract] [Full Text] [PDF]
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L. J. Murphey, J. V. Gainer, D. E. Vaughan, and N. J. Brown Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism Modulates the Human In Vivo Metabolism of Bradykinin Circulation, August 22, 2000; 102(8): 829 - 832. [Abstract] [Full Text] [PDF]
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L. J. Murphey, D. L. Hachey, J. A. Oates, J. D. Morrow, and N. J. Brown Metabolism of Bradykinin In Vivo in Humans: Identification of BK1-5 as a Stable Plasma Peptide Metabolite J. Pharmacol. Exp. Ther., July 1, 2000; 294(1): 263 - 269. [Abstract] [Full Text]
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N. J. Brown, M. Agirbasli, and D. E. Vaughan Comparative Effect of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Antagonism on Plasma Fibrinolytic Balance in Humans Hypertension, August 1, 1999; 34(2): 285 - 290. [Abstract] [Full Text] [PDF]
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