(Circulation. 1997;96:3641-3646.)
© 1997 American Heart Association, Inc.
Articles |
Differential Effects of Endothelin Receptor Activation on Cyclic Flow Variations in Rat Mesenteric Arteries
From the Division of Molecular Medicine/Cardiology (K.F., E.T.H.Y.), Department of Internal Medicine and Research Center for Cardiovascular Diseases, Institute for Molecular Medicine for the Prevention of Human Diseases; Department of Ophthalmology (A.C.); Department of Internal Medicine, University of Texas–Houston Health Science Center and Texas Heart Institute (E.T.H.Y., J.T.W.); and Texas Biotechnology Corporation (L.S., P.B., T.A.B.), Houston, Tex.
Correspondence to Kenichi Fujise, MD, Division of Molecular Medicine/Cardiology, University of Texas Health Science Center at Houston, 6431 Fannin, Suite 4.200, Houston, TX 77030. E-mail kfujise{at}heart.med.uth.tmc.edu
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Abstract |
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Background Cyclic flow variations (CFVs) represent repetitive cycles of platelet adherence–aggregation and vasoconstriction, followed by dislodgment of platelet thrombi and restoration of blood flow at the site of vascular injury. Although activation of endothelin A (ETA) and endothelin B (ETB) receptors leads to vasoconstriction and nitric oxide release, respectively, the roles of endogenous endothelin-1 (ET-1) and its receptors in CFVs are unknown.
Methods and Results A side branch of a mesenteric artery of
male Wistar rats was cannulated and a short segment of the artery was
mechanically injured to induce CFVs. After 20 minutes of saline
infusion, either saline (negative control), BQ-123 (ETA receptor
antagonist, 10 µg/min), BQ-788 (ETB receptor
antagonist, 10 µg/min), or sarafotoxin S6c (ETB receptor
agonist, 10 ng/min) was infused for 20 minutes from the side branch
into the injured arterial segment. Percent (%) luminal
stenosis as well as proximal and distal vessel diameters were
observed and quantitatively measured every minute using intravital
video microscopy and a micrometer-calibrated video screen.
Both BQ-123 and sarafotoxin S6c significantly reduced CFVs
represented by the mean luminal stenosis
(BQ-123=29±13% and sarafotoxin S6c=27±11% reduction, respectively;
P<.05 for both, compared with saline). In contrast, BQ-788
significantly increased CFVs (33±6% increase, P<.05
compared with saline). Moreover, the inhibitory effect of
sarafotoxin S6c on CFVs was completely abolished in the presence of
N
-nitro-L-arginine methyl ester
(L-NAME) (a nitric oxide synthase inhibitor,
10-5 mol/L) in superfusate over the arteries
(16.1±5% increase, P=NS compared with saline in the
presence of L-NAME). In addition, BQ-123 caused a significant increase
in the diameter of the vessel distal to the injured segment (12±4%
increase, P<.05 compared with saline).
Conclusions Endogenous ET-1 release from sites of vascular injury contributes to CFVs and vasomotor tone in the rat mesenteric artery CFV model. ETA and ETB receptors have differential roles in CFVs: ETA receptor antagonism and ETB receptor stimulation reduce CFVs, the latter at least partially through increased nitric oxide formation.
Key Words: endothelin • nitric oxide • arteries • receptors
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Introduction |
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Intravascular thrombosis is a multicellular event in which cell-to-cell interactions among platelets, neutrophils, and endothelium, along with various humoral factors, regulate the growth of the thrombus. ET-1, a potent 21-residue endothelium-derived vasoconstrictor peptide,1 has diverse effects on both cellular and humoral components of thrombosis. First, ET-1 activates neutrophils. ET-1 increases the intracellular superoxide concentration2 and stimulates neutrophil migration,3 aggregation,4 and adhesion5 to endothelial cells. Second, ET-1 directly inhibits serotonin-induced platelet aggregation in vitro6 and indirectly reduces platelet aggregation by stimulating prostacyclin release from endothelial cells in vivo.7 Finally, ET-1 exerts multiple actions on vascular endothelial cells. ET-1 stimulates the endothelial expression of P-selectin8 and the release of vasoactive substances, such as prostacyclin,9 prostaglandin E2,10 and NO.11 ET-1 also decreases tissue plasminogen activator release from endothelial cells.12 However, the role of endogenous ET-1 in the intravascular thrombotic process in vivo remains unclear.
CFVs are cyclical blood flow patterns in vivo, characterized by progressive declines in blood flow, interrupted by sudden spontaneous restorations of blood flow at sites of vascular damage and stenosis.13 The reduction in blood flow corresponds histologically13 and ultrastructurally14 to the accumulation of numerous platelets and some neutrophils at the site of vascular injury. It has been demonstrated that platelet activation,15 platelet interaction with endothelial cells,16 coagulation cascades,17 and vasoactive18 and chemotactic19 substances released from platelets and endothelial cells all play critical roles in the initiation and maintenance of CFVs.
Given the evidence that ET-1 modulates platelet, neutrophil, and endothelial function, we hypothesized that endogenous ET-1 has a pathophysiological role in the intravascular thrombotic process. We further hypothesized that there is a significant difference between the action of the two endothelin receptors, namely, ETA and ETB. This hypothesis was tested using a rat mesenteric artery model20 21 22 to generate CFVs. The effects on CFVs of BQ-123 and BQ-788, selective inhibitors of ETA and ETB, respectively, along with sarafotoxin S6c, a selective ETB receptor agonist, were tested in this model. Additionally, L-NAME, an NO synthase inhibitor, was used to investigate a possible role of NO synthesis in ET-1 receptor stimulation and changes in CFVs.
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Methods |
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Materials
BQ-123, c(DTrp-DAsp-Pro-DVal-Leu) (American Peptide Company Inc), is a selective ETA receptor antagonist (800-fold ETA receptor selectivity).23 24 BQ-788, N-cis-2,6-dimethylpiperidino carbonyl-L-
-Me-Leu-D-Trp(COOCH3)-D-Nle
(Peptide International Inc), is a selective ETB receptor
antagonist25 (1000-fold ETB receptor
selectivity).26 Sarafotoxin S6c (American Peptide Company
Inc), a structural homologue to ET-1, is a selective ETB receptor
agonist.26 Endotoxin-free saline was used as a vehicle and
to dilute test compounds (Sigma Chemical Co). All compounds were
dissolved into saline, pH adjusted, filtered through a 0.2-µm pore
syringe filter, aliquoted, and stored at -20°C until use. L-NAME
(Sigma) is a selective inhibitor of the constitutive NO
synthase.27 It was dissolved in PBS
(10-5 mol/L).
Animal Preparation
The original method to induce mesenteric artery
thrombosis20 21 22 was modified as described
elsewhere.28 Briefly, male Wistar rats (Inbred, Munich
substrain, Harlan Co, Houston, Tex) weighing 250 to 274 g were
anesthetized with an intramuscular injection of sodium
pentobarbital. After a small mid-abdominal incision, a segment of large
intestine was pulled out and spread over a transparent glass stage. A
first-order branch of the mesenteric artery that bifurcated into
branches of approximately 300 µm in diameter was identified. Fat
and connective tissues surrounding the mesenteric artery were removed
with a cotton applicator under a dissecting microscope. A
stretch-pulled polyethylene catheter (Intramedic, PE-10, Clay Adams Co)
was inserted into the second branch of the mesenteric artery so that
its tip was located just distal to the bifurcation (Fig 1A
). A small amount of saline was
injected to confirm the intravascular location of the catheter. The
preparation was mounted on the stage of a triocular microscope (BIOMAX,
BX40, Olympus), which was attached to a color CCD camera (CCD-IRIS,
Sony) and a 15-inch high-resolution video monitor (Sony). This system
enabled us to magnify the experimental field of less than 5 mm by
5 mm to the full 15-inch high-resolution monitor screen. A stage
micrometer was used to calibrate the monitor screen for
real-time measurement of the vessel diameter and luminal
stenosis. The core temperature of the animal was maintained at
35.5°C using a rectal probe connected to an infrared light warming
system. The surface of the mesentery was continuously superfused with
warm PBS or L-NAME solution. The experimental system was stabilized
after the surgery for at least 20 minutes.
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). After adequate injury to a
vascular segment, a thrombus formed at the site of injury, gradually
increased in size (B), and eventually occluded the lumen completely
(C). During the complete occlusion, the distal vessel was constricted,
whereas the diameter of the proximal vessel remained the same. Thrombi
then dissolved spontaneously as they embolized and flowed
downstream. SMA indicates superior mesenteric artery; INT, large
intestine; and Injury, site of the vascular injury.After the preparation had been stabilized, baseline proximal and distal vessel diameters were measured. To induce CFVs, a short segment (approximately 300 µm) of the other branch of the cannulated artery was compressed 10 to 20 times by a metal rod attached to a micromanipulator. This mode of vascular injury has been shown to cause a loss of endothelial cells and a disruption of the internal elastic lamina.21 After the CFVs were established and found stable for at least two complete cycles, video recording was initiated and the experiment started.
The luminal stenosis (percent), the proximal and distal vessel diameters (microns), and the incidence of embolization were monitored every minute. The luminal stenosis was graded into 0, 25, 50, 75, 90, and 100% stenoses, aided by calipers and calibration lines drawn on the monitor screen. The incidence of thrombi embolization was easily visualized on the screen. The entire process was recorded on videotape for further analysis.
During the first 20 minutes of the experiment, saline was infused at a rate of 1 µL/min (baseline phase) using a syringe pump (Harvard Apparatus). This phase was followed by infusion of the test compound at the same rate (intervention phase) for 20 minutes. Doses of BQ-123, BQ-788, and sarafotoxin S6c were 10 µg/min (16.4 nmol/min), 10 µg/min (15.6 nmol/min), and 10 ng/min (4.0 pmol/min), respectively. Finally, saline was infused for 20 minutes at the same rate (recovery phase). In pilot experiments, dye infused at a rate of 3 µL/min from the catheter showed no spillover to other branches of the mesenteric artery (data not shown).
The number of animals in each experiment group was: 7 for saline control, 10 for BQ-123, and 6 each for BQ-788 and sarafotoxin S6c. In a separate experiment, L-NAME (instead of PBS) was superfused over the mesenteric arteries of 12 animals that were infused with either sarafotoxin S6c (n=6) or saline (n=6).
Statistical Analysis
CFVs were assessed by calculating percent change of the mean
luminal stenosis as follows: (%Change of Mean
Luminal Stenosis)={[(Mean Luminal Stenosis of Intervention
Phase)-(Mean Luminal Stenosis of Baseline Phase)]/(Mean Luminal
Stenosis of Baseline Phase)}x100
Positive values indicate increased mean luminal stenosis during the interventional phase compared with the baseline phase, while negative values represent decreased mean luminal stenosis during the interventional phase compared with the baseline phase.
Percent change of vessel diameters was calculated to assess the effect of ETA and ETB receptors on proximal and distal vessel diameter. To take into account the passive vessel diameter changes over time, the following method was used to calculate percent change of vessel diameter: (%Change of Vessel Diameter)={[(Mean Diameter of Intervention Phase)-(Mean Diameter of Control Phase)]/(Mean Diameter of Control Phase)}x100
where mean diameter of control phase was the average of the vessel diameters of baseline and recovery phases.
Data are presented as mean±SEM. StatView (Abacus Concepts Inc) supplemented by SAS (SAS Institute) was used to perform statistical analyses. A nonparametric analysis (Mann-Whitney test) was used in most analyses. An ANOVA with repeated measurements (SAS PROC MIXED) was used to analyze the baseline characteristics of CFVs. A value of P<.05 was considered significant.
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Results |
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Initiation of CFVs and Baseline Characteristics
CFVs were successfully initiated in 87% of rats. Typically, following vascular injury, thrombus formation occurred over the next 3 to 5 minutes (Fig 1B
) and eventually occluded the lumen completely (Fig 1C). This event was associated with vasospasm of the distal vessel (Fig 1C). Subsequently, the vasospasm disappeared, the thrombus dissipated
and embolized, and blood flow restarted within 1 to 2 minutes
(Fig 2A). Once started, CFVs remained
stable for at least 1 hour (Fig 2A), during which time mean luminal
stenosis remained essentially constant (67±4.0%, 73±5.2%,
and 69±9.8% for the first, second, and last 20 minutes, respectively,
P=.65) (Table). The average
proximal and distal diameters of the vessels before intervention were
301±14.1 and 230±15.6 µm, respectively (Table). Without
pharmacological intervention, these values did not change over the
course of the experiment (proximal diameter: 301±14.1, 301±14.4, and
300±14.0 µm, P=.19; distal diameter: 230±15.6,
225±18.9, 222±20.0 µm, P=.76 for the first, second,
and third 20-minute periods, respectively) (Table and Fig 2A). There
was an average of 4±0.4 emboli noted over each 20-minute segment; the
frequency of the embolization did not change over the course of the
experiment (4±0.4, 5±1.5, 4±1.4 for the first, second, and third
20-minute periods, respectively, P=.36) (Table and Fig 2A).
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Changes in CFVs by BQ-123, BQ-788, and Sarafotoxin S6c
Changes in CFVs were assessed by comparing changes in the mean
luminal stenosis. When compared with saline, infusion of BQ-123
decreased the mean luminal stenosis by 29±13.4%, a
statistically significant change (P<.05) when compared with
increase in the mean luminal stenosis for saline infusion
(9±6.7%) (Fig 3). In contrast, BQ-788
increased the mean luminal stenosis by 33±5.8%
(P<.05, compared with saline) (Fig 3). Selective
stimulation of ETB receptors using sarafotoxin S6c decreased the mean
luminal stenosis by 27±10.8% (P<.05 compared with
saline) (Fig 2B and Fig 3). Actual mean luminal stenoses are
shown in the Table.
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Changes in Vessel Diameters by BQ-123, BQ-788, and Sarafotoxin
S6c
The proximal vessel diameter did not change significantly with or
without intervention (Table and Fig 4A).
When compared with saline, BQ-123 increased the distal vessel diameter
significantly (percent change in vessel diameter: -1.0±3.0% and
12±4.4%, saline versus BQ-123, respectively; P<.05) (Fig 4B). Neither BQ-788 (4±4.4%; P=.13 compared with saline)
nor sarafotoxin S6c (-.3±5.6%; P=.81 compared with
saline) changed the distal vessel diameter significantly (Fig 4B).
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CFVs in the Presence of L-NAME
To investigate the mechanism(s) linking ETB receptor stimulation
to a decrease in CFVs, sarafotoxin S6c was infused in the presence of
L-NAME, an inhibitor of NO synthase. This was compared with
animals in whom saline was infused in the presence of L-NAME. The
presence of L-NAME alone in the superfusate did not change the
mean luminal stenosis (8.6±6.7% versus -0.1±5.4%, saline
alone versus saline plus L-NAME) (Fig 5)
or vessel diameters (P>.05 for all variables).
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As illustrated in Fig 5, the effect of sarafotoxin S6c in reducing the
mean luminal stenosis was completely abolished in the presence
of L-NAME. In addition, there was a tendency to increase the mean
luminal stenosis (change of percent mean luminal
stenosis; 16.1±5.4% versus 0.1±5.4%, sarafotoxin S6c plus
L-NAME versus saline plus L-NAME, P=.06). However,
this trend did not reach statistical significance.
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Discussion |
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In the present study, we have demonstrated that ETA receptor antagonism (BQ-123) decreases CFVs and increases distal vessel luminal diameter after mechanical injury of the rat mesenteric artery. ETB receptor antagonism (BQ-788) has the opposite effect: It increases CFVs and mildly decreases distal vessel diameter. Furthermore, ETB receptor stimulation (sarafotoxin S6c) in the absence of L-NAME decreases CFVs. The presence of L-NAME in the superfusate, however, abolishes the effect of the ETB receptor agonist (sarafotoxin S6c) on CFVs. The rat mesenteric artery CFV model20 21 22 used in this study is unique in that it enables one to see the events occurring inside the vessel in "real time" under an intra-vital microscope-video system. Unlike other larger-animal models, the luminal stenosis and vessel diameter can be directly and quantitatively estimated using a calibrated video screen and readily correlated with thrombotic occlusion of the lumen. Use of endothelin receptor antagonist and agonist, instead of infusion of ET-1, was important to delineate the role of endogenous ET-1 in CFVs.
Differential Effects of ETA and ETB Receptor Antagonism on
CFVs
Because of the wide range of effects of ET-1 on neutrophils,
platelets, and vascular endothelial cells, it is
not surprising that manipulation of ET-1 receptors influences the in
vivo thrombus formation and CFVs in particular. Leadley et
al29 have previously demonstrated that infusion of
sarafotoxin S6b, a nonselective ETA and ETB receptor
agonist, reduced CFVs in canine coronary arteries. The
present study, using a selective ETA antagonist, ETB
agonist, and ETB antagonist, not only confirms a
pathophysiological role of endogenous
ET-1 in CFVs but also provides evidence that ETA and ETB receptor
stimulation has differential and opposite effects on CFVs. To our
knowledge, this concept has not been previously reported in the
literature.
It is interesting that the effect of ETB receptor stimulation is abolished in the presence of L-NAME (NO synthase inhibitor) and demonstrates that the reduction of CFVs by ETB receptor stimulation is mediated by the NO release from vascular endothelial cells. There are several possibilities as to how NO can reduce CFVs: NO may have an anti-adhesive effect on endothelial cell surface,27 reduce P-selectin expression,5 8 or inhibit signal transduction by ET-1 receptors.30
In the current study, L-NAME, an NO synthase inhibitor, did
not have a significant effect on CFVs (Fig 5) by itself, while BQ-788,
a selective ETB receptor blocker, promoted CFVs (Fig 3). One may ask
why L-NAME did not increase CFVs if the effect of BQ-788 is mediated by
NO synthesis. We speculate that this can be explained by the presence
of multiple, not a single, subcellular events linked to ETB receptor
activation. Some of these events may be "anti-" CFVs as is the case
of NO production, while others may be "pro-" CFVs. The
blockage of NO synthesis by L-NAME may still leave other "anti-"
and "pro-" CFV pathways, which are in balance, causing no change in
CFVs as a whole. The blockage of the ETB receptor with BQ-788, however,
may cause an unbalance among these pathways in such a way that the net
effect is the increase in CFVs. Further investigation is necessary to
clearly show the presence of such pathways and their roles in CFVs.
The antithrombotic effects of ETA receptor antagonism in vivo have not been previously reported. Elferink et al3 recently demonstrated in vitro that the ET-1–induced neutrophil activation and migration are blocked by BQ-123, an ETA antagonist. Activated neutrophils promote thrombus formation.31 Additionally, ET-1 is known to increase the intracellular pH of platelets (pHi), an indicator of platelet activation, which is abolished by ETA receptor antagonists.32 Thus, an ETA antagonist may reduce neutrophil and/or platelet activation in vivo and thereby retard the intravascular thrombotic process and the generation of CFVs.
Vasomotor Tone and ETA and ETB Receptor Antagonism
The vasoconstrictor effects of ETA receptor
stimulation33 and vasodilator effects of ETB receptor
stimulation have been well documented in the absence of thrombi. We
have demonstrated in the present study that ETA receptor antagonism
increased and ETB receptor antagonism somewhat reduced the distal
vessel diameter in the presence of CFVs and intravascular thrombi.
Using a system similar to the one used in this study, Araki et
al21 showed that nonthrombotic mechanical obstructions of
the arteries resulted in no significant reduction in the distal vessel
diameters. Moreover, topical application of acetylcholine dilated the
downstream vascular bed, which had been constricted after the
thrombotic occlusion.21 Therefore, diameter reductions
after thrombotic occlusion may not be caused by passive collapse due to
decreased intravascular pressure but by active constriction of the
artery. Collectively, these observations provide evidence that local
ET-1 release after vascular injury plays an important role in
regulating vasomotor tone of the distal vessel in the presence of an
intravascular thrombus.
Clinical Implications
Although further investigation is necessary before our
findings can be generalized to other vascular beds and species, it is
possible that ET-1 may exert similar actions on human coronary
arteries during unstable angina, presumably a clinical counterpart of
CFVs. Although not tested, differential ET receptor activation, that
is, simultaneous ETA receptor antagonism and ETB receptor
stimulation, might reduce CFVs and vasoconstriction more significantly
than a single agent does. This may then serve as a rationale for
identifying compounds with ETA inhibitory and ETB
stimulatory characteristics for evaluation in the treatment of selected
coronary heart disease syndromes, especially unstable angina
and acute myocardial infarction. More extensive CFVs in research
animals have been associated with higher degrees of intimal
proliferation at the site of vascular injury in some experimental
models.34 In the same study, the blockage of platelet
products, such as serotonin and thromboxane
A2 receptors, reduced but did not completely prevent
neointimal proliferation. In another study, administration
of ET-1 augmented and administration of a nonselective
ET-antagonist reduced up to 50% the neointimal
formation in a rat carotid artery balloon injury model,
respectively.35 These studies suggest that ET-1 may play a
role in stimulating neointimal proliferation. Thus,
reduction of CFVs by either ETA receptor antagonism and/or ETB receptor
stimulation may be protective against the rapid progression of luminal
stenosis in other experimental and clinical settings; these
possibilities need to be examined.
Conclusions
Endogenous ET-1 has a
pathophysiological role in the intravascular
thrombotic process, CFVs in particular. ETA and ETB receptors appear to
have differential effects on both CFVs and vasomotor tone in a rat
mesenteric CFV model: ETA receptor antagonism and ETB receptor
stimulation result in reduction of CFVs. ETA receptor antagonism
increases the vessel diameter distal to the injury site in the presence
of thrombi. The inhibitory effect of an ETB receptor
agonist on CFVs is at least partially mediated by NO synthesis.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Dr James T. Willerson is supported by grants (RO-HL 50179-01 and RO-HL 54839) from the National Institutes of Health. We thank Cherie Chalk for excellent editorial assistance.
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Footnotes |
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Guest editor for this article was Dana R. Abendschein, MD, Washington University, St. Louis, Mo.
Received July 17, 1996; revision received July 8, 1997; accepted July 12, 1997.
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