(Circulation. 2001;103:1899.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Effects of L-749,329, an ETA/ETB Endothelin Receptor Antagonist, in a Porcine Coronary Artery Injury Model of Vascular Restenosis
From the Departments of Pharmacology (W.R.H., R.C.M., R.G.J.), Laboratory Animal Resources (M.D.D., W.R.A., M.P.), Biometrics (D.J.H.), and Exploratory Chemistry (T.F.W., W.J.G.), Merck Research Labs, West Point, Pa, and Division of Cardiovascular Diseases (R.S.S.), Department of Medicine, Mayo Clinic and Foundation, Rochester, Minn.
Correspondence to Dr William R. Huckle, Department of Biomedical Sciences & Pathobiology (0442), Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061. E-mail wrhuckle{at}vt.edu
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Abstract |
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Background—Previous studies in animal models of angioplasty have suggested a role in neointimal hyperplasia for endothelins (ETs), potent vasoconstricting peptides that also exert growth-promoting effects. The present studies were undertaken to test the hypothesis that endothelin receptor blockade can reduce neointimal thickening in injured porcine coronary arteries.
Methods and Results—An
ETA/ETB antagonist,
L-749,329, was evaluated as an inhibitor of intimal thickening in a
porcine balloon/stent model of coronary artery injury. L-749,329
competitively inhibited [125I]ET-1 binding
to porcine ETA (IC50
0.3 nmol/L) or ETB
(IC50 20 nmol/L) receptors and inhibited
ET-1–stimulated signaling in cell culture. In anesthetized pigs, big
ET-1–stimulated increases in systemic blood pressure were totally
inhibited after intravenous infusion of L-749,329 (
0.2 mg ·
kg-1 ·
h-1). In vascular injury studies, pigs
were treated with vehicle or L-749,329 (1 mg ·
kg-1 · h-1)
beginning 2 days before and continuing 28 days after experimental
angioplasty. Left anterior descending, left circumflex, and/or right
coronary arteries were injured by inflation of an angioplasty balloon
wrapped with a coiled metallic stent. After 28 days, mean neointimal
thickness in the L-749,329–treated group was reduced by 9.0% compared
with vehicle-treated controls, but this effect was not statistically
significant
(P=0.13).
Conclusions—Blockade of endothelin receptors for 28 days with only a mixed ETA/ETB receptor antagonist is insufficient to substantially inhibit intimal hyperplasia after balloon/stent coronary artery injury in the pig, in contrast to results with a selective ETA antagonist. The effects of selective or mixed ETA/ETB antagonists in diseased vessels remain to be determined in this model.
Key Words: restenosis • endothelin • coronary disease • angioplasty
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Introduction |
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The endothelins constitute a family of endothelium-derived polypeptides that are among the most potent vasoconstrictors known.1 2 The major endothelin receptor subtypes (ETA and ETB) are expressed in vascular smooth muscle, where they mediate vasoconstriction,3 whereas the ETB subtype on endothelial cells is believed to mediate vasorelaxation.4 These receptors have become targets for the development of agents to treat hypertension, myocardial ischemia, and congestive heart failure.5
In addition to their acute effects on vascular tone, endothelins are recognized to exert growth-promoting effects,6 a response associated with activation of the ETA receptor.7 Endothelin receptors are elevated in atherosclerotic coronary arteries.8 Elevated plasma levels of immunoreactive ET-1 or its immediate precursor, big ET-1, have been detected in patients with angina pectoris9 and acute myocardial infarction.10 In addition, elevated endothelins have been observed acutely after cardiac catheterization11 or PTCA.12 The clinical results, together with in vitro data,13 have suggested that endothelins may be involved in atherosclerosis, vascular hypertrophy, and restenosis after angioplasty.14
Balloon denudation of rabbit carotid arteries was associated with prolonged elevation in immunoreactive ET-1 and induction of ETB binding activity localized to the neointima.15 16 In rat carotid arteries, mRNAs for endothelin precursors, endothelin-converting enzyme-1, and both ETA and ETB receptors were induced by balloon injury.17 Moreover, infusion of ET-1 was found to potentiate carotid neointimal formation provoked by balloon angioplasty in rats.18 19 In inhibitor studies, long-term administration of antagonists with activity toward both ETA and ETB receptors markedly reduced neointimal formation in balloon-injured rat carotid arteries.20 21 The ETA-selective antagonist BQ-123 was ineffective in rat20 and rabbit15 carotid artery studies, suggesting a predominant role for the ETB receptor in lesion development. In contrast to these findings, several ETA-selective agents have been reported to inhibit neointimal thickening in rat and porcine vascular injury studies.22 23 24 25 Thus, results reported to date do not clearly indicate whether the ETA or ETB receptor subtype is of principal importance in the response to injury. In the present studies, we evaluated a potent, mixed ETA/ETB endothelin receptor antagonist for its ability to inhibit intimal thickening in a porcine coronary artery model of vascular restenosis.26
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Endothelin Receptor Ligands
Porcine sequence ET-1 and big ET-1 (Peptide Institute), BQ-123 (Bachem), and sarafotoxin S6C (Peninsula) were prepared as recommended by their respective vendors. For PTCA studies, L-749,329 (racemic L-754,14227 ) was prepared at 50 mg/mL in 0.9% saline. All agents were filter sterilized before administration.
Receptor Binding Assays
Levels of L-749,329 in pig plasma were estimated by
radioreceptor assays with rat aortic smooth muscle cell (SMC)
cultures28 in which only the
ETA receptor subtype is detectable. Confluent
cultures in 24-well culture dishes were washed with 0.5 mL of
Waymouth’s medium containing 0.1% bovine serum albumin (BSA), 20
mmol/L
N-[2-hydroxyethyl]piperazine-N'-[2-ethanesulfonic
acid], pH 7.3 (WBH). Binding incubations (0.3 mL of WBH plus 10 U/mL
heparin) contained 50 pmol/L [125I]ET-1
(DuPont-NEN) plus 10% (vol/vol) test plasma or 10% control plasma
spiked with known concentrations of L-749,329. Incubation, washing,
harvesting of bound [125I]ET-1, and data
analysis were performed as described
previously.28 A similar
procedure was used for assays of endothelin receptor antagonist potency
in pig SMC and LLC-PK1
cells,29 except that binding
incubations contained 0.01% BSA and no plasma or heparin. Specific
binding was defined as total binding minus binding occurring in the
presence of 1 µmol/L ET-1.
Measurement of Inositol Phosphate
Production
Confluent cultures of pig coronary artery SMCs in
24-well dishes were labeled for 48 hours at 37° with 3 µCi of
[3H]myoinositol
(Amersham; 18.3 Ci/mmol) in inositol-free DMEM (Irvine), 0.5% fetal
bovine serum. Cells were washed with DMEM containing 1 mg/mL
myoinositol, 10 mmol/L LiCl,
and 0.1% BSA and stimulated with ET-1 in the presence or absence of
L-749,329 for 60 minutes at 37°C.
[3H]Inositol phosphates were measured as
described
previously.30
Instrumentation
All animal studies were performed according to
procedures approved by the Merck-West Point Institutional Animal Care
and Use Committee. Juvenile male or female Yorkshire pigs
(weight 30 kg) were catheterized for compound infusion and blood
sampling as described
previously.28 When required
for blood pressure monitoring, a vascular access port was placed in the
common carotid artery and secured subcutaneously in the right lateral
cervical area. Arterial pressure in animals under isoflurane anesthesia
was measured by DTX pressure transducer systems with ECG monitoring.
Animals were allowed to recover in their home cages and were observed
until stable.
Angioplasty Studies
Animals were premedicated with 650 mg of aspirin (24
hours before angioplasty), 30 mg of nifedipine (2 hours before), and
10 000 U of heparin (immediately before). After 2 days of pretreatment
with vehicle (0.9% saline) or L-749,329 (50 mg/mL; 1 mg ·
kg-1 ·
h-1), animals were reanesthetized and
subjected to angioplasty of the left anterior descending, left
circumflex, and/or right coronary arteries under fluoroscopic
imaging.28 The balloon was
inflated to 8 atm for 15 seconds to deploy the coiled, tantalum wire
stent, resulting in a 1.2- to 1.4-fold ratio of balloon diameter to
initial vessel diameter. After intravenous administration of 1 g
of cefoxitin, animals were allowed to recover in their home cages and
were maintained for 28 days after angioplasty with constant intravenous
infusion of vehicle or test compound. Jugular catheters were flushed
aseptically with saline 3 times per week and locked with 50%
glucose/heparin. Blood samples were drawn weekly for measurement of
plasma drug levels. Ampicillin (500 mg PO) was given
daily.
Analysis of Neointimal Thickening
Animals were euthanatized with pentobarbital (60
mg/kg IV) on day 28 after angioplasty. Formalin-fixed coronary arterial
segments containing the expanded stent were excised and processed for
5-µm cross-sectioning and hematoxylin/eosin and elastin-van Gieson
staining as described
previously.26 28
Sections from each vessel were scored for degree of injury and
neointimal thickness using the section showing the most severe injury.
The measurements for each vessel were averaged to produce a single data
point. Luminal areas and areas circumscribed by internal and external
elastic laminae also were measured at the site of injury.
Preangioplasty lumen size was estimated by measuring the uninvolved
luminal area 5 mm distal to the site of balloon/stent
deployment.
All values reported are estimates of the mean±SE. For neointimal thickness, injury score, and luminal areas, estimates were calculated by maximum likelihood methodology and a linear mixed-effects model with a random effect for each pig. Separate analyses were performed on data from the L-749,329–treated and control pigs. Neointimal thickness was fit on the logarithmic scale; all other variables were fit with the scale on which they were measured. Comparisons of injury score and external elastic lamina areas for the 2 treatment groups were made by a maximum likelihood ratio test; probability values for these comparisons were 2-sided. Comparisons of the treatment means that were adjusted for injury score (neointimal thickness and luminal areas) were made with linear regression and the jackknife procedure28 to estimate standard errors. Specifically, after we checked for parallelism, log(neointimal thickness) or log(luminal area) was regressed on injury score for the injured vessels of antagonist-treated and control pigs. Regression lines with equal slopes were fit for the treated and control pigs, allowing the difference between treatment and control to be measured by the difference in intercepts. By this method, the comparisons were on a "per pig" basis. Probability values reported for these comparisons are 1-sided.
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Results |
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Potency of L-749,329 Toward Porcine ET-1 Receptors
L-749,329 is the racemic form of the nonpeptide endothelin receptor antagonist L-754,142, which exhibits potent activity toward both the ETA (Ki=0.062 nmol/L for the cloned human receptor) and ETB (Ki=2.25 nmol/L) subtypes.27 The ability of L-749,329 to interact with porcine endothelin receptors was confirmed in binding studies with porcine coronary artery SMCs and LLC-PK1 porcine kidney epithelial cells (Figure 1
). In the presence of 50 pmol/L
[125I]ET-1 radioligand, L-749,329 blocked
ET-1 binding with an IC50 of 0.3 nmol/L.
[125I]ET-1 binding to porcine SMCs was
totally inhibited by the ETA-selective
antagonist BQ-123 (IC50 1 nmol/L) but not
appreciably by the ETB-selective ligand
sarafotoxin 6-C, indicating that the ETA
receptor subtype is expressed predominantly in these cells
(Figure 1A). In cultures of LLC-PK1 cells, which principally
express the ETB
subtype,29 L-749,329
inhibited [125I]ET-1 binding with an
IC50 of 20 nmol/L
(Figure 1B). The predominance of ETB
sites on these cells is confirmed by the high competitive potency of
sarafotoxin 6-C (IC50 1 nmol/L) and the
relatively low potency of BQ-123. Thus, relative potencies of L-749,329
toward porcine ETA and
ETB receptors in intact-cell binding assays
(ETB/ETA
IC50 ratio 65) are comparable to that for
L-754,142 toward the human receptor forms
(Ki
ratio 35).27
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, BQ-123; 
, sarafotoxin 6C (S6C).
Inhibition of ET-1 Signaling by
L-749,329
Pig coronary artery SMCs prelabeled with
[3H]myoinositol
were stimulated with ET-1 in the presence or absence of L-749,329, and
total cellular [3H]inositol phosphates
were measured. In these experiments, ET-1 stimulated
[3H]inositol phosphate production by 2.5-
to 3-fold, with an EC50 of 0.18 nmol/L
(Figure 2). In the presence of 100 nmol/L L-749,329, the ET-1
dose-response curve was shifted rightward by 2.4 log units without a
reduction in the maximal response to ET-1, consistent with a
competitive inhibition of the ETA
receptor.
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) or challenged with ET-1 in the absence (
) or presence (•) of 100 nmol/L L-749,329. L-749,329 treatment alone had no detectable effect on inositol phosphate (InsP) accumulation. Data shown (mean±SD) are representative of 3 separate experiments.
Dose-Finding Experiments
Pressor responses to ET-1 or its biosynthetic
precursor, big ET-1, were measured in anesthetized animals before and
after a series of intravenous infusions of L-749,329. ET-1 (0.25 to 0.5
nmol/kg) produced rapid and prolonged increases in mean arterial
pressure (MAP); at lower doses of ET-1 (0.1 to 0.2 nmol/kg), a
transient depressor phase of response was noted 1 to 3 minutes after
ET-1 administration (not shown). Depressor responses to ET-1 have been
linked to ETB-mediated vasodilation in other
species.4 Bolus doses of
L-749,329 (1 to 10 mg/kg) were associated with decreases in both the
magnitude and duration of MAP increases stimulated by ET-1. In separate
studies, doses of ET-1 (0.25 nmol/kg) and big ET-1 (0.5 nmol/kg) that
yielded similar maximum 
MAP responses in the pig (30 to 40 mm Hg)
were determined empirically
(Figure 3, "Control"). Consistent with previous
reports,31 big ET-1 produced
an increase in MAP that was slower in onset and relatively prolonged
compared with that stimulated by ET-1. In the experiment shown,
constant intravenous infusion of L-749,329 at 1.0 mg ·
kg-1 · h-1
for 24 hours produced 78% inhibition of the pressor response to ET-1
and total inhibition of the response to big ET-1
(Figure 3). This degree of inhibition of the response to ET-1
was not exceeded even when L-749,329 infusion was increased to 5 mg ·
kg-1 · h-1,
whereas rates lower than 0.2 mg · kg-1
· h-1 were associated with diminished
inhibition of both the ET-1 and big ET-1 responses. The rates of
infusion associated with maximal inhibition of ET-1 and big ET-1
pressor responses gave rise to plasma levels of L-749,329340 nmol/L.
On the basis of these results, a dose of 1 mg ·
kg-1 · h-1
was chosen for the PTCA studies, with a target plasma L-749,329
concentration of 400 nmol/L.
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Angioplasty Studies
Seven pigs each were assigned to receive vehicle or
L-749,329 infusion beginning 2 days before PTCA. Balloon/stent
angioplasty was performed on a total of 21 vessels in the vehicle group
and 20 vessels in the L-749,329–treated group. In the
antagonist-treated animals, mean plasma levels of L-749,329 were
1300±540 nmol/L on the day of angioplasty and were maintained between
1210 and 1670 nmol/L throughout the 28-day study period. These levels
are well above those determined independently to be associated with
maximal blockade of pressor responses to endothelins.
At day 28 after angioplasty, animals were euthanatized, and
hearts were removed for histomorphometric analysis. Elastin-van
Gieson–stained sections from each injured vessel were examined by
light microscopy for determination of injury score and neointimal
thickness
(Figure 4). Mean injury scores did not differ between the 2
groups (P=0.76;
Table).
Treatment with L-749,329 was associated with a 9.0% decrease in mean
neointimal thickness when adjusted for injury score, but this effect
was not statistically significant
(P=0.13)
(Figure 5). Mean vessel luminal area at the site of
angioplasty (adjusted for injury score) was increased by 18% in the
L-749,329–treated animals compared with the vehicle group; again, this
effect was not statistically significant
(P=0.06). When the net change
in luminal area was calculated for each vessel (luminal area at the
site of injury minus the preinjury luminal area approximated as the
uninvolved luminal area measured 5 mm distal to the site of
angioplasty), the increase associated with L-749,329 treatment dropped
to 7.0% (P=0.36). Thus, the
small reduction in neointimal thickness (9.0%) associated with
L-749,329 treatment was accompanied by a small increase in luminal area
(7.0%). The mean areas circumscribed by the internal elastic laminae
in the 2 treatment groups were very similar
(Table),
consistent with the approximately reciprocating changes in luminal area
and neointimal thickness noted above. Mean areas circumscribed by the
external elastic lamina in the 2 groups also were
similar.
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) or L-749,329 (•). Regression lines determined by jackknife analysis are shown for vehicle (solid curve) and L-749,329-treated (broken curve) groups. B, Mean natural logarithms of neointimal thicknesses and injury scores averaged within each pig are shown. |
Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Endothelin receptor antagonists have been used to probe the involvement of endothelins in postangioplasty neointimal hyperplasia. Studies in animal models of vascular injury have suggested a role for endothelins in neointimal formation but have produced conflicting results with respect to the endothelin receptor subtype(s) involved. In the present studies, we evaluated a mixed ETA/ETB endothelin receptor antagonist, L-749,329, for its ability to inhibit intimal thickening in a porcine balloon/stent injury model. L-749,329 competitively inhibited [125I]ET-1 binding to ETA (IC50
0.3
nmol/L) or ETB (IC50
20 nmol/L) receptors on cultured porcine cells. L-749,329
competitively inhibited ETA-mediated signaling
in vitro, as measured by ET-1-stimulated phosphoinositide metabolism in
pig coronary artery SMCs. In anesthetized pigs, increases in systemic
blood pressure in response to big ET-1 were totally abolished after
intravenous infusion of L-749,329 (0.2 mg ·
kg-1 ·
h-1). In conscious pigs, chronic L-749,329
treatment (1 mg · kg-1 ·
h-1) was associated with a median decrease
in MAP of 22.1 mm Hg and an increase in heart rate of 15 bpm (W.R.H.,
R.G.J., unpublished data, 1998). In angioplasty studies, L-749,329 was
administered by chronic intravenous infusion beginning 2 days before
balloon/stent injury and continuing until animals were killed (day 28
after angioplasty). Plasma levels of the antagonist in
L-749,329–treated animals were considerably in excess of levels
associated with maximal pressor blockade, as well as the
IC50 values determined in vitro. Mean neointimal
thickness in the L-749,329–treated group was reduced by 9.0% compared
with vehicle-treated controls, but this effect was not statistically
significant
(P=0.13). Our results using a mixed ETA/ETB endothelin receptor antagonist differ from previous findings obtained with an ETA-selective agent in the same model system.24 Several factors may contribute to this difference. Although the present results suggest that blockade of both ETA and ETB receptors is not an effective means of reducing neointimal thickening in pig coronary artery, the value of ETA versus ETB selectivity remains unresolved.20 22 It is possible, for example, that preservation of vasodilatation mediated by ETB might be protective after vascular injury in the pig, such that ETB blockade might exacerbate luminal loss. Another difference between the 2 studies is route of administration (intravenous and oral), which may have produced a distribution of inhibitor that favored efficacy in the prior studies. In addition, different methods of statistical analysis were applied in the 2 studies. Finally, the mean injury scores in the present study (2.07 and 2.13 for the vehicle and L-749,329–treated groups, respectively) were uniformly higher than those measured in the previous study (ranging from 1.73 to 1.9424 ); measurements for both studies were made by the same core investigators at the Mayo Clinic. Thus, the absence of significant efficacy in the present study may stem from our relatively higher degree of vessel injury. This idea is supported by the observation in the previous study that the intermediate dose of ETA-selective agent was ineffective against a mean injury score of 1.94, whereas a lower dose was effective against a lower mean injury score of 1.73. Similarly, the ETA-selective antagonist LU 135252 recently was reported to significantly reduce the neointimal:medial ratio in a porcine balloon-only injury model32 ; balloon expansion alone typically imparts an injury no more severe than medial dissection (ie, equivalent to injury score 2), whereas stent deployment can rupture the external elastic lamina as well (injury score 3). The mean injury scores >2 in the present study reflect the greater incidence of external elastic lamina disruption.
Several limitations to the present studies should be noted. The animals used likely were normolipidemic, and the vessels targeted were not previously injured. Consequently, we cannot infer the effects of L-749,329 in atherosclerotic vessels. However, all of the prior studies mentioned above likewise were conducted in nondiseased arteries, and effects of endothelin antagonists still were manifest. Second, treatment with endothelin receptor antagonists is recognized to increase endothelin receptor levels in culture33 and increase circulating endothelin levels in vivo.34 Because we did not measure endothelin levels or monitor pressor inhibition throughout the 30-day study, it might be argued that compensatory changes in endothelin or receptor expression rendered L-749,329 less effective. This argument is countered by the observation that mean L-749,329 plasma levels were maintained at >1000 nmol/L, ie, >50-fold excess over the IC50s for ET-1 binding. Third, we cannot exclude the possibility that adequate concentrations of L-749,329 did not reach sites critical for reducing neointimal hyperplasia, although the inhibitor clearly had access to sites involved in endothelin pressor responses.
A variety of studies have documented the activities of endothelins and their receptors in normal and injured porcine coronary arteries. Endothelin-stimulated contraction of isolated strips of pig coronary arteries is composed of both ETA antagonist-sensitive and -insensitive components, suggesting that both ETA and ETB receptors can mediate constriction of these vessels.35 36 In addition, ETB receptors may be heterogeneous in pig coronary artery.37 Net release of ET-1 from pig coronary arteries has been detected after short-term vessel occlusion38 and in thrombosis/thrombolysis models.39 ET immunoreactivity and increased densities of presumptive ETA and ETB receptors have been detected at sites of experimental angioplasty in pigs.24 32 40 The consequences of endothelin receptor blockade at injury sites may be determined by the balance between the benefit of inhibiting ETA/ETB-mediated growth promotion or vasoconstriction and the penalty of inhibiting vasorelaxation. The relative influence of these factors and therefore the utility of endothelin antagonists for controlling neointimal hyperplasia may vary with species, vessel types, and the nature and severity of injury imparted. Further studies using subtype-selective agents in coronary injury models with atherosclerotic subjects, as well as results from clinical studies, will help resolve these issues.
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Footnotes |
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Guest Editor for this article was Carl J. Pepine, MD, University of Florida, Gainesville, Fla.
Received May 14, 1998; revision received October 31, 2000; accepted November 1, 2000.
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