© 1997 American Heart Association, Inc.
Articles |
Evidence Against an Effect of Endothelin-1 on Blood Coagulation, Fibrinolysis, and Endothelial Cell Integrity in Healthy Men
From the Department of Clinical Pharmacology (S.K., B.J., T.S., E.D., H.-G.E.) and the Clinical Institute of Medical and Chemical Laboratory Diagnostics (S.K., O.W., W.S.), University of Vienna, Vienna, Austria.
Correspondence to Wolfgang Speiser, MD, c/o Department of Clinical Pharmacology, General Hospital Vienna, Währinger Gürtel 18-20, A-1090 Wien, Austria. E-mail stylianos.kapiotis{at}univie.ac.at
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Abstract |
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Abstract On the basis of an array of preclinical experimental results, it has been widely assumed that endothelin-1 (ET-1) may affect blood coagulation, fibrinolysis, and endothelial cell function, thereby playing a pathophysiological role in various cardiovascular diseases in humans. However, confirmation of this assumption is still lacking. ET-1 or placebo was administered intravenously to 12 healthy volunteers in a prospective, randomized, double-blind, crossover trial. Pathophysiologically relevant concentrations of ET-1 (an approximate threefold increase of normal blood levels) causing hemodynamic effects were reached by continuous intravenous infusion for 6 hours. Components of the coagulation (thrombin-antithrombin complexes, prothrombin fragment F1+2, activated factor VII, and factor VII antigen) and fibrinolytic (fibrin split product D-dimer, plasmin–plasmin inhibitor complex, tissue-type plasminogen activator, urokinase-type plasminogen activator, and plasminogen activator inhibitor-1) systems and markers of endothelial cell perturbation/dysfunction (von Willebrand factor and thrombomodulin) were measured before the start of infusion and after 2, 6, 12, and 24 hours. Comparing changes in the plasma concentrations of these parameters during and after infusion of ET-1 and placebo, we found no specific effects of ET-1. In contrast to previous reports from preclinical experiments, ET-1 does not appear to affect coagulation or fibrinolysis, nor does this peptide induce relevant endothelial cell perturbations in humans.
Key Words: endothelin • coagulation • fibrinolysis • von Willebrand factor • endothelium
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Introduction |
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Endothelin-1 is a member of a family of 21–amino acid peptides that are the most potent vasoconstrictor substances yet discovered.1 Synthesis and release of ET-1 were first demonstrated in cultured human ECs.2 3 ET-1 is also produced by several other cell types, including kidney4 and epithelial5 cells, leukocytes,6 and macrophages.7 Owing to its vasoconstricting and mitogenic properties, ET-1 is thought to be involved in the pathogenesis of arterial vessel wall tension dysregulation and the development of atherosclerosis. Although ET-1 is primarily released abluminally8 from its main source, the vascular endothelium, elevated plasma levels of ET-1 are found in various disease states in humans. Enhanced plasma ET-1 levels probably result from a "spillover" from the interface of ECs, releasing increased amounts of ET-1, and subendothelial structures. Elevated ET-1 levels are found in hypertension,9 10 advanced atherosclerosis,11 acute myocardial infarction,12 13 cardiogenic shock,14 chronic heart failure,15 disseminated intravascular coagulation,16 17 and preeclampsia.18 Perturbation of ECs and hypercoagulability are characteristic features of most of these diseases.
ECs not only are a source of ET-1 but also are reactive to this peptide via specific receptor interaction, which can lead to the induction of increased release of prostanoids19 or endothelium-derived relaxing factor.20 There is evidence from ex vivo and animal studies that ET-1 exerts procoagulant effects, eg, increased release of vWF from ECs,21 upregulation of immunoreactive vWF in the endothelia of intact umbilical cords,22 and systemic activation of coagulation in pigs and rats.22 23 24 Furthermore, ET-1 has been shown to affect EC integrity, as Stanimirovic et al25 have demonstrated in an ET-1–induced increase of 51Cr release from the cerebromicrovascular endothelium in vitro. However, conflicting data exist on the effect of ET-1 on the fibrinolytic system. TPA release from vascular ECs has been found to be increased,21 26 27 unchanged,28 or decreased29 by ET-1.
It has been proposed that the prohemostatic properties of ET-1 may contribute to the increased activation of coagulation that is seen along with increased plasma ET-1 levels.24 30 However, confirmation of this assumption from in vivo studies in humans is lacking. It was therefore the aim of the present study to investigate the effect of ET-1 infusion, yielding pathophysiologically relevant plasma concentrations, on the activity of blood coagulation and fibrinolysis and EC integrity in healthy volunteers.
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Methods |
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Study Design
The study was designed as a double-blind, randomized, placebo-controlled, two-way crossover study of 12 healthy, young, male volunteers. The study was approved by the Ethics Committee on Human Subjects in Medical Research, University of Vienna. Written informed consent was obtained from all volunteers prior to inclusion in the study.
Subjects
The 12 study volunteers were nonsmokers, were aged 19 to 35
years, and had a body mass index between the 15th and 85th percentiles.
Each subject passed a screening examination that included a medical
history; physical examination; 12-lead ECG; blood pressure measurement;
complete blood cell count with differential; clinical chemistry, liver,
and kidney function test (including creatinine clearance);
coagulation screening (prothrombin time, activated partial
thromboplastin time, and fibrinogen); serological tests for hepatitis
viruses and HIV; urinalysis; and urine drug screening. Subjects were
requested to maintain their usual diet and exercise habits and were
instructed not to take any OTCs throughout the study. Subjects were
excluded if they had taken any prescription medication within the last
3 months or any OTC within the last 3 weeks, had donated blood within
the last 3 months prior to the first study day, were abusing alcoholic
beverages, or were smoking. Subjects were also excluded if they had any
clinically relevant illness in the 3 weeks before the first study day,
or if any abnormality was found as part of the screening examination
that the investigators considered to be clinically relevant.
Study Protocol and Blood Samples
Pilot Study
To ascertain that the planned infusion rates of 0.4 pmol
· kg-1 · min-1 would in
fact give rise to the desired
pathophysiologically relevant plasma
concentration of 2 to 4 pmol/L31 and to verify the
safety of the desired dose for the volunteers, a pilot study with 4
healthy volunteers who received an intravenous infusion of
0.4 pmol · kg-1 ·
min-1 ET-1 for 6 hours was conducted. Fasting healthy
subjects arrived at the Department of Clinical Pharmacology at 7:45
AM on the first study day after they had consumed 3 g
NaCl/d on the 3 preceding days. Subjects were kept fasting
throughout the observation period of this study day. After a 30-minute
rest in the supine position with the chest tilted up, three 19-gauge
intravenous cannulas were inserted into forearm veins. An
infusion of 5% glucose (Glucose 5% "Leopold" Infusionsflasche,
Leopold Pharma; 200 mL/h) and 0.9% NaCl (Physiologische
Kochsalzlösung "Leopold" Infusionsflasche, Leopold Pharma;
250 mL/h) was started and continued for 10 hours, and measurements of
blood pressure (at 3-minute intervals), heart rate, and continuous ECG
recording were started. ET-1 (Clinalfa) infusion was then
started immediately (0 hours) and was continued for 6 hours. For a
rough estimate of renal plasma flow, PAH (aminohippurate sodium, MSD)
clearance was determined as described.32
Glomerular filtration rate was determined by the clearance
of inulin (Inutest, Laevosan Linz) as described.32 Renal
plasma flow and glomerular filtration rate were measured
every 30 minutes during the ET-1 infusion until 10 hours after the
infusion had ceased.
Main Study
Fasting subjects arrived at the Department of Clinical
Pharmacology at 7:45 AM on the first study day after they
had consumed 3 g NaCl/d on the 3 preceding days. Subjects
were kept fasting throughout the observation period of this study day.
After a 30-minute rest in the supine position with the chest tilted up,
two 19-gauge intravenous cannulas were inserted into
forearm veins. An infusion of 5% glucose and 0.9% NaCl (flow rates of
200 and 250 mL/h, respectively) was started and continued for 10 hours
to guarantee constant urinary output and constant blood glucose levels.
Measurements of blood pressure (at 3-minute intervals), heart rate, and
continuous ECG began. ET-1 at 0.4 pmol ·
kg-1 · min-1
(Clinalfa) or placebo (gelatin, Haemaccel, Behring) infusion at a flow
rate of 8 mL/h each was then started immediately (t=0) and continued
for 6 hours. Subjects remained fasting in our research ward, were
monitored until the 12-hour blood samples were drawn, and were then
discharged. They returned at 8 AM on the following day to
our department for drawing of the 24-hour blood samples and were
discharged thereafter. Crossover to the other treatment occurred after
a minimum washout period of 6 days.
Blood Sampling
Blood for PAH and inulin determinations (pilot study) was drawn
into siliconized glass tubes (Vacutainer, Becton Dickinson) without
additives from the intravenous cannulas before
administration of PAH/inulin (two baseline values) and at 30-minute
intervals for 10 hours thereafter. Blood samples for the determination
of erythrocytes, ET-1 plasma levels, coagulation,
fibrinolysis, and EC parameters were drawn
by separate venipuncture with 213/4-gauge
needles before the start of infusions (two samples with an interval of
20 minutes). Additional blood was drawn at 2, 6, 12, 24, and 24.25
hours. Blood for the determination of erythrocytes was drawn into
EDTA-containing tubes (Vacutainer). Citrated (final concentration,
0.013 mol/L sodium citrate) blood for determination of
coagulation, fibrinolysis, and EC-viability
parameters was drawn into siliconized glass tubes
(Vacutainer). Blood for ET-1 determination was drawn into polypropylene
tubes containing 100 µL of saturated potassium EDTA and immediately
placed on ice. Platelet-poor plasma was prepared from citrated
blood by centrifugation at 3000g for 20
minutes at 4°C within 15 minutes of collection. Plasma samples were
kept frozen at -70°C for <8 weeks before assessment.
Assay Systems
Plasma ET-1 levels were determined using the
ET-1,2[125I] assay system from Amersham International.
Erythrocyte determinations were made immediately on an automated Sysmex
NE 8000 hematology analyzer (TOA Sysmex). PAH and inulin serum
levels were determined as described.32 vWF antigen was
determined by enzyme immunoassay from Boehringer Mannheim. The
enzyme immunoassay for circulating thrombomodulin was from
Diagnostica Stago. TAT complexes, prothrombin fragment
F1+2, and plasmin–plasmin inhibitor complexes
were determined by enzyme immunoassays from Behring; the fibrin split
product D-dimer was measured with an enzyme immunoassay from
Boehringer Mannheim. The enzyme immunoassay kit for UPA was
from Biopool. Active PAI-1 antigen was measured with an enzyme
immunoassay from Technoclone; the TPA antigen was measured with an
enzyme immunoassay test kit from Chromogenix. Activated factor
VII was measured by the Staclot VII-rTF assay from
Diagnostica Stago with an automatic coagulometer, also from
Diagnostica Stago. The enzyme immunoassay kit for factor
VII was also from Stago.
Data Analysis
Baseline and 24-hour values were calculated as the arithmetic
means from the two pretreatment and the two 24-hour values,
respectively. Because the data were not normally distributed, the
Friedman ANOVA was used for analysis, and post hoc comparisons
were made by the Wilcoxon signed-rank test. The level of
significance was set at P<.05. An a priori sample size
calculation33 had indicated that 12 subjects were adequate
to detect a difference of 1.4 SDs (
=.05, ß=.02) in the end points
to be measured.
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Results |
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Changes in ET-1 Plasma Levels
After 6 hours of ET-1 infusion, plasma levels of this compound were increased twofold to ninefold in the pilot study and by a mean of 333% in the main study. Mean baseline values in the pilot study were 1.7 pmol/L (CI, 0.9 to 2.5) in the placebo (gelatin) group and 1.7 pmol/L (CI, 1.1 to 2.3) in the ET-1 group. Values measured at the end of ET-1 infusion were 1.9 pmol/L (CI, 1.0 to 3.1) in the placebo group and 4.6 pmol/L (CI, 3.3 to 6.0) in the ET-1 group (P<.05 between groups). At the 24-hour time point, all ET-1 values had returned to baseline.
Hematological Changes
A slight hemodilution occurred during the first 12 hours, which
peaked at 6 hours. The mean hemoglobin values were found to be
decreased, from a baseline level of 14.2 g/dL (CI, 13.8 to 14.6)
in the ET-1 group and 13.8 g/dL (CI, 13.3 to 14.4) in the
placebo group to 13.3 g/dL (CI, 12.9 to 13.8) and 13.0
g/dL (CI, 12.5 to 13.5) in the ET-1 and placebo groups,
respectively. This corresponds to a change of -7% (CI, -9% to
-5%) during ET-1 infusion and of -6% (CI, -8% to -5%) during
placebo infusion. At 24 hours, hemoglobin values had returned to
baseline. Plasma levels of all measured parameters were
corrected with respect to the decreases in hemoglobin values.
Hemodynamic Changes
In the pilot study, a decrease in renal plasma flow was observed
during ET-1 infusion, which was maximal after 6 hours (a mean decrease
of -43%; CI, -35% to -51%; P<.001 at 6 hours; Fig 1
). Because the glomerular
filtration rate was unaffected by ET-1 infusion (P>.05 at 6
hours), the filtration fraction increased by 80% (CI, 20% to 110%;
P<.001 at 6 hours; also see Fig 1). The mean heart rate
decreased from 66.4 to 60.6 beats/min (ie, -10%; CI, -4% to -15%)
at 6 hours after ET-1 infusion in the main study (P=.012
between groups), whereas placebo had no effect on heart rate. No
significant changes in blood pressure were observed in either
group.
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, P<.001 after 6 hours), glomerular
filtration rate (GFR) was unchanged (
, P>.05 after 6
hours), and filtration fraction increased (
Effect of ET-1 on Coagulation Parameters
At 2, 6, and 12 hours after the start of infusion, significantly
lower levels of factor VIIa were measured in the ET-1 group
(P=.034, .002, and .002, respectively) and in the control
group (P=.05, .002, and .004, respectively) with respect to
the pretreatment values. Factor VIIa levels returned to baseline at 24
hours. There were no significant changes in factor VIIa antigen,
prothrombin fragment F1+2, or TAT complex with respect to
baseline values at any time. No significant differences between the
ET-1 and placebo (gelatin) groups with respect to the three
aforementioned coagulation parameters were detected (Fig 2A and 2B).
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Effect of ET-1 on Fibrinolysis Parameters
The known diurnal variation34 was seen in tissue-type
plasminogen activator and PAI-1 levels. Compared with
baseline values, plasma TPA levels were found to be significantly
decreased at 12 and 24 hours in the ET-1 group (P=.005 and
.013, respectively) as well as in the placebo group (P=.018
and .012, respectively). Plasminogen activator
inhibitor-1 levels also decrease between 8 and 20 hours and
remained low until the next morning. Values measured at 6, 12, and 24
hours were significantly lower than baseline values in the ET-1 group
(P=.005, .005, and .005, respectively) as well as in the
placebo group (P=.04, .007, and .008, respectively).
Moreover, a diurnal variation, with the lowest levels in the morning
and the highest in the evening, was also observed for plasmin–plasmin
inhibitor complex. The levels of this complex measured at 6
and 12 hours were significantly higher than those at baseline in the
ET-1 group (P=.018 and .003, respectively) as well as in the
placebo group (P=.05 and .003, respectively). There were no
significant changes in UPA or D-dimer levels with respect to baseline
at any time. No significant differences between the ET-1 group and the
placebo group with respect to TPA, UPA, D-dimer, or plasmin–plasmin
inhibitor complex were detected (see Fig 3A and 3B).
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Effect of ET-1 on EC Markers
There was no significant change in vWF and thrombomodulin plasma
levels compared with baseline at any time. No significant difference
between ET-1 and placebo (gelatin) groups with respect to vWF or
thrombomodulin levels were detected (Fig 4).
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Discussion |
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ET-1, an endothelium-derived vasoconstrictor peptide, acts on several components of the vascular wall. Owing to its mitogenic potency on vascular smooth muscle cells,35 its chemoattractant effect on circulating monocytes,36 and its activating influence on macrophages,37 ET-1 fulfills the criteria for an atherogenic peptide. Zeiher et al38 reported increased ET-1 immunostaining in active coronary atherosclerotic lesions. Increased plasma levels of ET-1 are frequently found in diseases characterized by EC injury or dysfunction and by increased activity in blood coagulation, eg, in advanced atherosclerosis,11 acute myocardial infarction,12 13 disseminated intravascular coagulation,16 17 and preeclampsia.18 There is experimental evidence that ET-1 affects EC release of several mediators involved in the regulation of platelet function/blood coagulation (prostanoids19 and vWF21 22 ) and fibrinolysis (TPA21 26 27 28 29 ). ET-1 has also been shown to induce thrombosis and disseminated intravascular coagulation in animal models.22 23 24 Yasuda et al13 found a statistically significant correlation between the plasma levels of the blood coagulation activation marker TAT and those of ET-1 in patients with acute myocardial infarction. It is unclear, though, whether this correlation reflects a cause/effect relationship or merely an epiphenomenon secondary to defects in the vascular wall.
To investigate the effect of ET-1 on blood coagulation and fibrinolysis in vivo in humans, we infused ET-1 into healthy volunteers at a dosage of 0.4 pmol · kg-1 · min-1, resulting in approximately threefold higher than normal concentrations, levels that are commonly seen in such diseases as heart failure, hypertension, or advanced atherosclerosis.31 39 Molecular markers of blood coagulation and fibrinolysis activation were determined during 6 hours of infusion and for as long as 24 hours after the start of ET-1 or gelatin (placebo control) infusion. Measuring TAT and prothrombin fragment F1+2 levels, we found no evidence of coagulation activation by ET-1. Obviously, ET-1 infusion neither induces activation of blood coagulation via a direct "short-term" irritating effect on the vessel wall, which could lead to contact between subendothelial structures and the blood with subsequent activation of coagulation, nor does it favor "long-term" prohemostatic endothelial activities, such as de novo synthesis of tissue factor40 or reduction of endothelial surface thrombomodulin activity,41 phenomena that are characteristic of endothelial activation by various mediators. We also determined two forms of coagulation factor VII, a component of the main coagulation activator, tissue factor–factor VII complex42 : ET-1 infusion had no effect on factor VII antigen levels or on levels of circulating factor VIIa, the active portion of circulating factor VII molecules.43 Interestingly, circulating factor VIIa levels showed a decrease during the study day, suggesting a diurnal variation of this parameter; this phenomenon has not yet been described. Similar to the known diurnal variation of the fibrinolysis inhibitor PAI-1,34 44 the higher levels of factor VIIa observed in the morning may be discussed in connection with the increased incidence of coronary events at this time of day.45
Lidbury et al26 and Pruis and Emeis21 reported an ET-1 induced increased release of TPA from ECs in a canine and rat hindleg model, respectively. On the other hand, TPA release has also been found to be unchanged28 and decreased29 by others. We could not confirm any profibrinolytic or antifibrinolytic effects of ET-1 in humans, as no significant difference in TPA plasma levels was found between ET-1 and gelatin infusion periods. This was also true for UPA, PAI-1, and the fibrinolysis activation markers plasmin–plasmin inhibitor complex and the fibrin split product D-dimer. These data indicate that fibrinolysis was neither directly activated by a release from activators from endogenous sources nor indirectly activated by ET-1–induced fibrinolysis, eg, through increased deposition of fibrin within the vasculature. During an observation period of 24 hours, we observed the known diurnal variation in plasma fibrinolysis activity, ie, significant decreases in TPA and the main inhibitor of fibrinolysis activation, PAI-1, with high levels in the morning and low levels in the evening.34 The decrease in PAI-1 obviously caused stimulation of basal blood fibrinolytic capacity, as plasmin–plasmin inhibitor complex plasma levels increased correspondingly. Most likely due to the low amount of fibrin deposition on the vascular walls of these healthy individuals, the increase in plasma fibrinolytic activity was not accompanied by an increase in D-dimer levels. PAI-1 and TPA levels at 24 hours were significantly lower than those measured before the infusion. This unexpected phenomenon may be explained by fluid loading on the study day or an unknown placebo effect on PAI-1 and TPA levels.
The discrepancy between our present data and those in published preclinical reports may in part be due to the high doses used in in vitro and animal studies: 10 to 100 nmol/L in in vitro experiments21 25 27 28 29 and plasma levels of 96 pmol/L in animals24 (the mean peak value in the present study was 4.6 pmol/L). The differences may also be due to different susceptibilities of ET-1 in other species with respect to coagulation and fibrinolysis. Our results are unlikely false-negative due to underdosing with ET-1 because (1) the identical ET-1 dose infusion regimen used in the pilot trial led to a 43% decrease in renal blood flow, which exceeded values from previously reported short-term ET-1 infusion studies46 47 48 ; higher doses would have been ethically unacceptable and (2) furthermore, the ET-1 levels reached in this study were clearly in the upper range of levels found in patients with cardiovascular diseases.11 13
Our data suggest that ET-1, at plasma levels found in various disease states, does not affect the coagulation system in humans. The thrombotic phenomena observed along with increased ET-1 plasma levels in humans are most likely due to other prothrombotic stimuli on the hemostatic system. In contrast to cell culture and ex vivo experiments, ET-1 does not affect the release of fibrinolytic components into the blood and therefore does not exert a specific effect on blood fibrinolysis in vivo in humans. Because ET-1 was given for the relatively short period of 6 hours to healthy volunteers, our data resemble the biological effects of short-time elevations of this mediator. From the phenomena observed, however, one cannot draw conclusions on the effects of long-term elevations of ET-1 on coagulation and fibrinolysis.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by the Medizinisch-Wissenschaftlicher Fonds des Bürgermeisters der Bundeshauptstadt Wien to S.K. (No. 1432).
Received March 18, 1997; accepted July 8, 1997.
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