From the Department of Nephrology and Hypertension (M.C.V., H.A.K.,
T.J.R.), University Hospital Utrecht, The Netherlands, and the Department of
Medicine (F.E.S., D.E.N., N.L.C., D.J.W.), University of Edinburgh, Western
General Hospital, Edinburgh, EH4 2XU, Scotland.
Correspondence to Dr Marianne Verhaar, Department of Nephrology and Hypertension, Room F 03.226, Heidelberglaan 100, 3584 CX Utrecht, University Hospital Utrecht, The Netherlands. E-mail t.rabelink{at}digd.azu.nl
Methods and Results—Two studies were performed, each in groups of
eight healthy subjects. Brachial artery infusion of BQ-123 caused
significant forearm vasodilatation in both studies. This vasodilatation
was reduced by 95% (P=.006) with inhibition of the
endogenous generation of nitric oxide and by 38%
(P<.001) with coinfusion of the ETB
receptor antagonist BQ-788. In contrast, inhibition of
prostanoid generation did not affect the response to BQ-123. Infusion
of BQ-788 alone produced a 20% reduction in forearm blood flow
(P<.001).
Conclusions—Selective ETA receptor antagonism causes
vasodilatation of human forearm resistance vessels in vivo. This
response appears to result in major part from an increase in nitric
oxide generation. ETB receptor antagonism either alone or
on a background of ETA antagonism causes local
vasoconstriction, indicating that ETB receptors in blood
vessels respond to ET-1 predominantly by causing vasodilatation.
Initially, it was thought that ETB receptors were
present only on endothelial cells, where they cause
vasodilatation through release of endothelium-derived
vasodilators, including nitric oxide (NO) and
prostacyclin.6 7 However, it is now recognized
that ETB receptors are also present on the
smooth muscle of human arteries8 and can mediate
vasoconstriction,9 10 11 although their
contribution to ET-1–mediated constriction in humans remains to be
defined.12 Therefore, although
ETA receptor–mediated vasoconstriction is
undisputed, it is unclear whether the balance of the effects of
endogenous ET-1 on the endothelial and
vascular smooth muscle ETB receptors results
predominantly in a vasodilator or constrictor tone.
In addition to mediating vasodilator effects of
endothelial ETB receptor
activation, endothelium-derived dilators can in turn
modulate the production and actions of
ET-1.6 13 14 15 In the short term NO inhibits
production of ET-113 whereas chronic
exposure causes upregulation of ETA
receptors.16 In addition, endothelin receptor
antagonists attenuate the pressor response to NO
inhibition,17 18 suggesting that this response
may not simply be due to loss of basal NO-mediated dilator tone. These
interactions indicate the existence of a complex relationship between
the endothelin and NO systems.
As a consequence of its potent vasoconstrictor19
and growth-promoting properties,20 ET-1 has also
been implicated in the pathophysiology of diseases such as
hypertension, heart failure, and renal failure.21
The recognition of the endothelin system as a new therapeutic target in
the treatment of cardiovascular disease has lead to the
rapid development of pharmacological agents that inhibit either the
production of ET-1 or its actions. Recently, potent
intravenous and orally active endothelin receptor
antagonists with different pharmacological profiles have
become available for clinical studies.21 22 We
are now in a position where it would be valuable to explore the
contribution of the ETB receptor to the vascular
effects of ET-1.
The present study, in human forearm resistance vessels in vivo, was
designed to further investigate the physiological
role of ETA and ETB
receptor subtypes and their possible interactions in mediating the
vasodilator response to selective ETA receptor
antagonism. The first part of the study aimed to investigate whether
increased release of the endothelium-dependent relaxant
factors NO and prostacyclin contributes to the vasodilator response to
selective ETA receptor antagonism. We therefore
compared the response to the selective ETA
receptor antagonist BQ-123 during local inhibition of NO
synthase and during systemic inhibition of prostanoid generation with
the response to BQ-123 alone. In the second part of the study, to
investigate the role of the ETB receptor in
BQ-123–induced vasodilatation, we examined the effects of
simultaneous ETA and
ETB receptor blockade compared with
ETA or ETB receptor
blockade alone.
Drug Administration
Drugs
The endogenous NO system in the forearm was inhibited by
use of an "NO clamp," as described
previously.26 The NO synthase
inhibitor
L-NG-monomethyl-arginine
(L-NMMA; Institut fur Pharmazie, Universitat Leipzig) was continuously
infused at a rate of 200 µg/100 mL forearm volume per minute to
achieve maximal inhibition of local NO
synthase.27 28 29 Sodium nitroprusside (SNP), an
exogenous NO donor (Merck) was then coinfused at titrated doses (12 to
30 ng/min). After 8 minutes of L-NMMA infusion, when steady state
forearm blood flow was obtained, SNP was coinfused in incremental
doses and titrated until baseline forearm blood flow had been
restored. L-NMMA and SNP were then coinfused, at these rates, for the
remainder of the study. This allowed simulation of normal basal NO
activity during continuous inhibition of endogenous NO
synthesis.
Aspirin (600 mg calcium acetylsalicylic acid;
Carbasalatum Calcium, Dagra Pharma BV) was administered orally 30
minutes before measurements in one phase of study 1. Aspirin
irreversibly inhibits cyclooxygenase (EC
1.14.99.1), which is responsible for the production of
prostaglandins and thromboxanes. When given at
a dose of 600 mg, aspirin inhibits bradykinin-stimulated
endothelial production of prostacylin by at
least 85% with recovery occurring over the next 6
hours.30
Measurements
Blood Pressure
General Study Design
Study 1: Inhibition of NO Synthase and Prostanoid Generation With
ETA Receptor Blockade
Study 2: Separate and Combined Blockade of ETA and
ETB Receptors
Analysis
Study 1
BQ-123 caused progressive vasodilatation during coinfusion of saline
and after inhibition of prostanoid generation (P<.01 for
both). The response appeared to plateau at 60 minutes, and no
differences were observed in these responses (38±9% versus 42±7% at
90 minutes; P=.5). The vasodilator response to BQ-123 was
markedly reduced during NO-clamping (2±5% at 90 minutes,
P=.006 versus saline coinfusion) (Fig 1
Study 2
In the present study, to exclude the influence of the
endogenous NO system in mediation or modulation of the
effects of ET-1, L-NMMA was infused to inhibit endogenous
local generation of NO. SNP was coinfused with L-NMMA to restore
baseline blood flow26 because local inhibition of
NO would otherwise result in vasoconstriction. In this situation,
endogenous NO is replaced with exogenous NO, in effect
applying a clamp to the local endogenous NO system. Using
this technique we have shown, for the first time in humans in vivo,
that the vasodilatation to BQ-123 is in large part related to NO
generation. Inhibition of endogenous prostanoid generation
by oral administration of aspirin has no effect on basal forearm blood
flow or systemic hemodynamics and, more importantly,
had no effect on the response to BQ-123, indicating that the dilator
prostanoids do not provide an important contribution to the vasodilator
response to BQ-123. Almost all of the response to BQ-123 appeared to be
blocked by NO clamping. However, on the basis of vasodilatation to the
ECE inhibitor
phosphoramidon34 in previous
studies,3 we think it is likely that at least
part of the response to BQ-123 is directly due to withdrawal of
endogenous ETA-mediated
vasoconstriction.
Selective ETA antagonism inhibits the actions of
ET-1 at the ETA receptor while allowing its
actions at the ETB receptor to be unopposed. ET-1
can stimulate both the endothelial
ETB receptor to cause dilatation and the vascular
smooth muscle ETB receptor to cause
vasoconstriction. Therefore, the overall effect depends on a balance
between these two actions. Unfortunately, there are no available
pharmacological tools that have been shown clearly to distinguish
between the endothelial and vascular smooth muscle
ETB receptors. We have shown that coinfusion of
the ETB receptor antagonist BQ-788
reduces the vasodilator response to BQ-123, suggesting that the balance
of effects of ET-1 favors vasodilatation via the
endothelial ETB receptor. This is
further supported by the vasoconstriction in these vessels to BQ-788
alone and by the lesser degree of vasodilatation to the combined
ETA/ETB endothelin receptor
antagonist TAK-0444 than to the
ETA-selective agent
BQ-123.3 It is possible that the predominant
effects of intra-luminal infusion of BQ-788 selectively affect the
endothelial ETB receptor because
the drug has better access to the endothelial than to
the smooth muscle receptors. However, we believe this is unlikely
because ET-1 and BQ-123 find ready access to the smooth muscle. The
response to BQ-788 may indicate either displacement of ET-1 from, or
failure of clearance of ET-1 by, ETB
receptors.35 However, our present results
cannot distinguish between these effects.
The observation that selective ETA receptor
blockade not only antagonizes direct ETA
receptor–mediated constriction but also preserves beneficial
ETB receptor–mediated vasodilator tone and
enhances endogenous NO generation may have important
implications in the use of endothelin antagonists as
treatments in cardiovascular disease. For example, the
increased NO generation caused by ETA receptor
antagonists is potentially beneficial in ischemic
heart disease. However, the clinical relevance of our findings in
various pathophysiological conditions cannot be
fully determined from the present study because endothelin
receptors may be modified under these circumstances. Indeed, in
ischemic heart disease, there appears to be upregulation of
human coronary ETB
receptors,36 and this is associated, in heart
failure, with enhanced vasoconstrictor responses to sarafotoxin S6c in
both the forearm37 and coronary
circulation,38 whereas the response to BQ-788
appeared similar to that of controls.39 Clearly,
at some stage, it will be necessary to examine the integrated
physiology of systemic ETA and
ETB blockade in physiological
and pathophysiological conditions to fully
understand the relative importance of the receptor subtypes.
In summary, we have demonstrated that the local vasodilator response to
selective ETA receptor antagonism in human
forearm resistance vessels is derived in large part from increased
NO-mediated vasodilatation, most probably mediated by the
endothelial ETB receptor.
Although our observations were made in the forearm resistance vessels,
these vessels are generally representative of other
vascular beds30 40 and, importantly, reflect the
interaction of these systems in vivo. Our results may indicate new
therapeutic uses for ETA receptor
antagonists because increased NO synthesis may be a
desirable effect in, for example, ischemic heart disease. One
could also postulate that enhanced endogenous NO generation
may be responsible for the headaches that are a recognized side effect
of ET receptor antagonists.
Received July 15, 1997;
revision received October 13, 1997;
accepted October 16, 1997.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Endothelin-A Receptor Antagonist–Mediated Vasodilatation Is Attenuated by Inhibition of Nitric Oxide Synthesis and by Endothelin-B Receptor Blockade
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—The role of endothelin
(ET)-1 in maintenance of basal vascular tone has been
demonstrated by local and systemic vasodilatation to endothelin
receptor antagonists in humans. Although the constrictor
effects mediated by the vascular smooth muscle ETA
receptors are clear, the contribution from endothelial
and vascular smooth muscle ETB receptors remains to be
defined. The present study, in human forearm resistance vessels in
vivo, was designed to further investigate the
physiological function of ETA and
ETB receptor subtypes in human blood vessels and determine
the mechanism underlying the vasodilatation to the
ETA-selective receptor antagonist BQ-123.
Key Words: endothelin • nitric oxide • flow • receptors • prostaglandins
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
The endothelin (ET)
family of peptides (ET-1, ET-2, ET-3) are generated in a variety of
tissues and act primarily as paracrine and autocrine factors. The major
isoform in the cardiovascular system, ET-1, is
generated in the endothelium from a precursor, big
ET-1, through cleavage by a specific endothelin-converting enzyme
(ECE). Its actions are mediated by two receptors, the
ETA and the ETB receptor,
which have been characterized and cloned1 2 and
are pharmacologically distinct. The ETA receptor
has a higher affinity for ET-1 (ET-1
ET-3), whereas the
ETB receptor is nonisopeptide selective
(ET-1=ET-3). ETA receptors are expressed on
vascular smooth muscle cells, and their activation by ET-1 leads to
vasoconstriction. The physiological importance of
endogenous ET-1 in the maintenance of basal
vascular tone and blood pressure in humans has been demonstrated by
local3 4 and systemic4
vasodilatation in response to inhibitors of the endothelin
system. An important role for the ETA receptor in
mediating this response is suggested by the substantial forearm
vasodilatation to local administration of the selective
ETA receptor antagonist
BQ-1235 in healthy subjects.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Subjects
Twenty-two healthy subjects (1 woman) ranging in age from 20 to
43 years participated in two studies that were performed in the
University Hospital Utrecht (study 1) and the University
Department of Medicine, Western General Hospital, Edinburgh (study 2),
with the approval of the local research ethics committees of each
hospital and the written informed consent of each subject. The
investigations conformed with the principles outlined in the
Declaration of Helsinki. No subjects had received vasoactive medication
or nonsteroidal anti-inflammatory drugs within the week before each
phase of a study, and all subjects abstained from alcohol for 24 hours
and from food, caffeine-containing drinks, and tobacco for at least 4
hours before any measurements were made. All studies were performed in
a quiet room maintained at a controlled temperature between 22°C
and 24.5°C.
The brachial artery of the nondominant arm was cannulated with a
22 (study 1) or 27 SWG cannula (study 2) under lidocaine local
anesthesia (lidocaine 2%; Astra Pharmaceuticals Ltd).
Drugs, with the exception of aspirin, were dissolved in
physiological saline (0.9%; Baxter Healthcare Ltd)
and infused intra-arterially at locally active doses. The
infusion rate was kept constant at 80 mL/h (study 1) or 60 mL/h (study
2). All solutions were prepared aseptically from sterile stock
solutions or ampules on the day of the study.
BQ-123 (100 nmol/min, study 1; 10 nmol/min, study 2), was
used as a selective ETA receptor
antagonist (study 1: American Peptide Co; study 2: Clinalfa
AG). We have demonstrated previously local forearm vasodilatation to
intra-arterial infusion of BQ-123 (100
nmol/min).3 In study 2, we used a 10-fold lower
dose of BQ-123 (10 nmol/min) because more recent studies have shown
that this causes vasodilatation of equal magnitude to that seen with
the higher dose.23 BQ-788 (1 nmol/min) was used
as a selective ETB receptor
antagonist24 (American Peptide Co).
This dose has been shown to completely inhibit venoconstriction to the
selective ETB receptor agonist sarafotoxin
S6c.25
Forearm Blood Flow
Forearm blood flow was measured simultaneously in
both arms by venous occlusion plethysmography using calibrated
mercury-in-Silastic strain-gauges applied to the widest part of the
forearm.3 27 31 The hands were excluded from the
circulation during each measurement period by inflation of a wrist cuff
to 220 mm Hg. Upper arm cuffs were intermittently inflated to
40 mm Hg for 10 seconds every 15 seconds to temporarily prevent
venous outflow from the forearm and thus obtain plethysmographic
recordings. Recordings of forearm blood flow were made
over 2.5-minute periods at 5-minute intervals (study 1) and over
3-minute periods at 10-minute intervals (study 2). Venous occlusion
plethysmography was performed using a dual-channel strain-gauge
plethysmograph (Hokanson), and calibration was achieved using the
internal standard of the Hokanson plethysmography unit. In study 1, a
microcomputer-based R-wave–triggered system for online semicontinuous
monitoring was used,32 whereas in study 2,
voltage output was transferred to a Macintosh personal computer
(Classic II; Apple Computer) using a MacLab analog-digital converter
and Chart software (version 3.2.8; both from AD Instruments).
Blood pressure was monitored during each study using either
continuous intra-arterial measurements in the infused arm
(study 1) or a semiautomated noninvasive oscillometric method in the
noninfused arm (study 2).33 Blood pressure in
study 2 was measured immediately after each forearm blood flow
measurement, thereby avoiding any effect of venous congestion caused by
this procedure on blood flow.
Subjects rested recumbent throughout each study with both
forearms resting slightly above the level of the heart. Strain gauges
and arm cuffs were applied, and the left brachial artery cannula was
sited. Before the administration of drugs, saline was infused for at
least 30 minutes, during which baseline measurements of forearm blood
flow were made.
Eight subjects were studied on three separate occasions, each
separated by at least 1 week. After baseline infusion of saline, BQ-123
was infused for 90 minutes: on one occasion, during saline coinfusion;
on another, after stabilization of the NO-clamp; and on another, after
systemic inhibition of prostanoid generation. The effects of the
NO-clamp on forearm blood flow were studied during a 2-hour period in 3
subjects (time control NO-clamp).
On 2 separate study days, in 8 subjects, the
ETA receptor antagonist BQ-123 was
infused for 120 minutes alone or during coinfusion of BQ-788, also for
120 minutes. On a separate occasion, BQ-788 was infused alone for 120
minutes in 8 subjects (2 of whom also participated in the earlier parts
of study 2).
Blood flow in both forearms was obtained from the mean of the
last five consecutive recordings of each measurement period.
Because wrist cuff inflation results in a transient forearm
vasoconstriction, recordings made in the first 60 seconds after
wrist cuff inflation were not used for analysis. The ratio of
flows in the infused and noninfused arms was calculated for each time
point and expressed as percentage change from baseline or, in the
NO-clamp experiments, as percentage change from the average of the last
four recordings during NO-clamping, before the administration
of BQ-123. In both studies, plethysmographic data listings were
extracted from data files, and forearm blood flows were calculated for
individual venous occlusion cuff inflations using a template
spreadsheet (Excel 5.0; Microsoft). All results are expressed as
mean±SEM. Data were examined by repeated measures ANOVA (study 1,
SigmaStat; Jandel Corp; study 2, Excel 5.0; Microsoft). Statistical
significance was taken at the 5% level.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
There were no significant changes in baseline
hemodynamics between phases of each study
(Table
) and no change in blood pressure or blood flow in the
noninfused forearm during the course of the studies.
View this table:
[in a new window]
Table 1. Baseline Hemodynamic Values During Saline
Infusion Before Infusion of Drugs
Baseline forearm blood flow was restored during the NO-clamp
(basal infused forearm blood flow; 3.7±0.3: during basal NO clamp;
3.4±0.2; P=.15) and kept stable for at least 40 minutes
before BQ-123 infusion was started. Blood flow in the infused forearm
in the time control NO clamp protocol varied by <5% between baseline
(pre–NO clamp) and with 120 minutes of NO clamping in 3 subjects. ).
View larger version (18K):
[in a new window]
Figure 1. Eight subjects received brachial artery infusion
of BQ-123 (100 nmol/min) during coinfusion of saline ( 
), BQ-123 (100
nmol/min) during inhibition of prostanoid generation (
), or BQ-123
(100 nmol/min) during inhibition of NO generation (
). Slow-onset
vasodilatation occurred in response to BQ-123; this response was
attenuated during NO clamp but not during inhibition of prostanoid
generation.
Both BQ-123 alone and coadministration of BQ-123 and BQ-788 caused
progressive vasodilatation (P<.001) that appeared to
plateau at 60 minutes (Fig 2). The
vasodilatation to BQ-123 alone was significantly greater than that
during coinfusion with BQ-788 (76±13% versus 47±14% at 120 minutes,
P<.001). BQ-788 alone caused a small but consistent
reduction in forearm blood flow (20±3% at 120 minutes,
P<.001) (Fig 2).
View larger version (14K):
[in a new window]
Figure 2. Eight subjects received brachial artery infusion
of BQ-123 (10 nmol/min) alone ( ), BQ-788 (1 nmol/min) alone (
),
or BQ-123 (10 nmol/min) coinfused with BQ-788 (1 nmol/min) (
).
Slow-onset vasodilatation occurred in response to BQ-123; this response
was attenuated during coinfusion of BQ-788. BQ-788 infusion alone
caused a small but significant vasoconstriction.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
In two centers, we have demonstrated slow-onset forearm
vasodilatation in response to local arterial infusion of
the selective ETA receptor antagonist
BQ-123, confirming the importance of endogenous ET-1 in the
mediation of vascular tone. From these data, it appears that this
vasodilator response is caused in large part by increased generation of
NO, which could be mediated by stimulation of the
endothelial ETB receptor. Indeed,
our observation that the vasodilator response to combined
ETA and ETB receptor
antagonism was significantly less than that to selective
ETA receptor antagonism alone probably reflects
the presence of an endogenous
ETB-mediated vasodilator tone. This is further
supported by the local vasoconstrictor effect of
ETB receptor antagonism in the forearm resistance
vessels.
Acknowledgments
This work was supported by grants from The Dutch Heart
Foundation, The Wellcome Trust, and The British Heart Foundation. Dr
Rabelink was supported by a fellowship of the Royal Dutch Academy of
Sciences (KNAW), Dr Newby was supported by a British Heart Foundation
Junior Research Fellowship (FS/95009), and F. Strachan was supported by
a Wellcome Trust project grant (PG-048560).
Footnotes
Guest editor for this article was Jeffrey M. Isner, MD, St Elizabeth Medical Center, Boston, Mass.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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J. Goddard, N. R. Johnston, M. F. Hand, A. D. Cumming, T. J. Rabelink, A. J. Rankin, and D. J. Webb Endothelin-A Receptor Antagonism Reduces Blood Pressure and Increases Renal Blood Flow in Hypertensive Patients With Chronic Renal Failure: A Comparison of Selective and Combined Endothelin Receptor Blockade Circulation, March 9, 2004; 109(9): 1186 - 1193. [Abstract] [Full Text] [PDF]
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 C. M. McEniery, A. Qasem, M. Schmitt, A. P. Avolio, J. R. Cockcroft, and I. B. Wilkinson Endothelin-1 regulates arterial pulse wave velocity in vivo J. Am. Coll. Cardiol., December 3, 2003; 42(11): 1975 - 1981. [Abstract] [Full Text] [PDF]
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R B Vaughan, P W Angus, and J P F Chin-Dusting Evidence for altered vascular responses to exogenous endothelin-1 in patients with advanced cirrhosis with restoration of the normal vasoconstrictor response following successful liver transplantation Gut, October 1, 2003; 52(10): 1505 - 1510. [Abstract] [Full Text] [PDF]
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E. Mildenberger, B. Biesel, G. Siegel, and H. T. Versmold Nitric oxide and endothelin in oxygen-dependent regulation of vascular tone of human umbilical vein Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1730 - H1737. [Abstract] [Full Text] [PDF]
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T. Noguchi, Z. Chen, S. P. Bell, L. Nyland, and M. M. LeWinter Endothelin receptor blockade has an oxygen-saving effect in Dahl salt-sensitive rats with heart failure Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1428 - H1434. [Abstract] [Full Text] [PDF]
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D. Merkus, B. Houweling, A. Mirza, F. Boomsma, A. H van den Meiracker, and D. J Duncker Contribution of endothelin and its receptors to the regulation of vascular tone during exercise is different in the systemic, coronary and pulmonary circulation Cardiovasc Res, September 1, 2003; 59(3): 745 - 754. [Abstract] [Full Text] [PDF]
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