(Circulation. 1999;99:1069-1076.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Inhibition of Nitric Oxide but Not Prostacyclin Prevents Poststenotic Dilatation in Rabbit Femoral Artery
From the Bioengineering Laboratory, Department of Chemical Engineering (W.J.C.), and the Department of Physiology and Biophysics, School of Medicine (G.H., J.A.R.), State University of New York at Buffalo, and the Institute for Medicine and Engineering, Department of Chemical Engineering, University of Pennsylvania, Philadelphia, Pa (S.L.D.).
Correspondence to Scott L. Diamond, Institute for Medicine and Engineering, Department of Chemical Engineering, 394 Towne Bldg, University of Pennsylvania, Philadelphia, PA 19104. E-mail sld{at}eniac.seas.upenn.edu
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Abstract |
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Background—Poststenotic dilatation (PSD) occurs in a low-pressure region where recirculation eddies oscillate in size during the cardiac cycle. NO may be an important mediator of PSD.
Methods and Results—Femoral arteries of 7 adult male New Zealand White rabbits were stenosed bilaterally to achieve a diameter reduction of 70.9±6.7% (n=14). At the time of stenosis, the adventitia of one of the arteries was coated with 1 mmol/L of NG-nitro-L-arginine methyl ester (L-NAME) in 22% (wt/vol) Pluronic gel, while the contralateral vessel was coated with gel without L-NAME. In stenosed femoral arteries that were treated with gel without L-NAME, a maximum PSD of 30.99±7.92% (n=7) was observed in polymer casts at 3 days relative to the mean proximal diameter of 1.57±0.25 mm at a position 12 mm upstream of each stenosis. In contrast, the vessels treated with L-NAME exhibited a maximum PSD of only 7.16±8.81% (n=7) relative to the mean proximal diameter of 1.55±0.16 mm. L-NAME caused a 76.9% reduction (P<0.001, n=7) of PSD. Similarly, NG-monomethyl-L-arginine 1 mmol/L and NG-nitro-L-arginine 10 µmol/L attenuated PSD by 57.5% (P<0.001, n=6) and 63.9% (P<0.05, n=6), respectively. Indomethacin 10 µmol/L caused no reduction in PSD. Arterial rings obtained from the poststenotic region were more sensitive and responsive to acetylcholine than those obtained proximal to the stenosis.
Conclusions—NO, but not prostacyclin, is a major mediator of PSD.
Key Words: endothelium • hemodynamics • stenosis
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The pronounced dilatation of vessels distal to a stenosis is a dramatic response of vessel and vascular cell function to hemodynamic forces. The earliest descriptions of poststenotic dilatation (PSD) date back to 18421 and 1845 (as cited in References 2 and 32 3 ), but the mechanisms and mediators of the process are still unknown. As reviewed by Roach,4 aneurysms associated with PSD can occur in humans in regions distal to the coarctation of the aorta, abdominal aorta, and pulmonary arteries. Atherosclerotic plaques of the renal, carotid, and femoral arteries can cause PSD, as can compression of arteries by abnormal anatomy of bones, muscle, or ligaments. PSD can be generated experimentally in rabbit carotid and thoracic arteries5 6 and canine femoral and carotid arteries4 and is reversible after removal of the stenosis.7 Fenestration and fragmentation of the internal elastic lamina increase distal to a stenosis8 9 within 10 days of vessel stenosis. Degenerative changes during PSD include a decrease in smooth muscle cell number density and elastin content and an increase in collagen6 and collagenase activity.10
The studies by Roach4 and others in the 1960s can be viewed in the context of the well-established endothelial response to hemodynamic forces (for review, see References 11 and 1211 12 ). Fluid shear stress enhances, within seconds, endothelial production of NO and prostacyclin,13 14 15 both of which are relatively short-lived species that act locally. Exposure to arterial shear stresses elevates endothelial NO synthase (eNOS) mRNA and protein16 17 within a few hours and suppresses endothelin gene expression in cultured endothelium.18 19 The NO production and eNOS mRNA levels are elevated during the stretching of endothelial cells,20 as is endothelin production.21 Yet, these studies do not fully explain the occurrence of PSD, because the region distal to the stenosis is a site of low pressure and complex hemodynamics where recirculation eddies oscillate in size as the flow reattachment point moves back and forth during the cardiac cycle.22 23 24
Turbulence-induced vibration had been hypothesized to cause PSD, because isolated human iliac arteries dilate when vibrated via a loudspeaker.2 However, Gow et al25 showed that mechanical vibration of rabbit thoracic aorta in vivo does not cause vasodilation. In addition, Ojha and Langille26 conducted extensive flow visualization of model stenosed rabbit carotids and found that PSD can occur with stenoses from 50% to 60% diameter reduction in the carotid arteries, whereas no transition to turbulence is observed in corresponding flow models. In flow models of more severe carotid stenoses of 70% diameter reduction, a very localized transition to turbulence was identified (6 to 8 tube diameters downstream) during the early deceleration phase of the cardiac cycle.26 However, this position of helical flow and vortex shedding (a transition to turbulence) did not correlate with the position of maximal PSD. These studies indicate that turbulence is not strictly required for the development of PSD.
Locally elevated capacity of the vessel wall to produce and/or respond to NO may be the cause of PSD and represents a response to the complex hemodynamics within the poststenotic recirculating vortex. Our study investigated pharmacological antagonism of NO production at the site of a stenosis to modulate the progression of PSD. The stenoses of 70% reduction in diameter used in this study are not associated with turbulence and create a modest reduction in flow associated with vasoconstriction proximal to the stenosis.27
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Methods |
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Animal Surgery
Male New Zealand White rabbits (2.1±0.3 kg) were anesthetized with ketamine (30 to 40 mg/kg IM) and xylazine (5 to 8 mg/kg IM). The femoral arteries were exposed distal to the hip joint and carefully isolated from the femoral vein and sciatic nerve. A well-defined stenosis was produced on the left and right arteries according to the methods of Langille et al28 by use of a 4-0 Tevdek (polyester fiber, nonabsorbable) suture tied snugly around the vessel and the shaft of a 25-gauge hypodermic needle (OD, 0.51 mm). The needle shaft was then removed. The L-arginine analogue NG-nitro-L-arginine methyl ester (L-NAME) (Research Biochemicals International) was added after stenosis by coating the adventitia of one of the exposed femoral arteries with 1 mL of a sterile suspension of 1.0 mmol/L L-NAME in 22.5% (wt/vol) of F-127 Pluronic gel (Molecular Probes, Inc) diluted in sterile PBS. The contralateral femoral artery was treated with 1 mL of a sterile suspension of 22.5% (wt/vol) of F-127 Pluronic gel alone. In some experiments, NG-monomethyl-L-arginine (L-NMMA) 1 mmol/L, NG-nitro-L-arginine (L-NNA) 10 µmol/L, or indomethacin 10 µmol/L was in the gel. In experiments using unilateral stenosis without Pluronic gel, we observed that the gel was not required for the development of PSD. Placement of a sterile 2-mm transit-time ultrasonic probe (Transonics Systems, Inc) before and after the placement of the stenosis allowed measurement of volumetric flow rate (mL/min) through the femoral vessels. Time-averaged flows through rabbit femoral artery were
10 mL/min
before stenosis. After placement of the suture, the
stenoses caused an 30% reduction in mean flow (Figure 1
). Rabbits were given Crystiben (sterile
penicillin G benzathine and penicillin G procaine in aqueous
suspension; 300 000 IU/mL) on the day of surgery (1 mL) and every 48
hours afterward. All surgeries were performed in the School of
Medicine, Laboratory Animal Facility, at SUNY–Buffalo under approval
by the Internal Review Board.
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Polymer Casting and Diameter Analysis
At 3 days after surgery, the rabbits were anesthetized
by injection of 30 mg/kg sodium pentobarbital IV through the marginal
ear vein. The midabdominal aorta was catheterized and perfused with a
warm saline solution (37°C) followed by a methyl methacrylate casting
compound (Batson's No. 17 corrosion casting compound, Polysciences
Inc) under a constant pressure of 100 mm Hg, according to the
methods of Langille27 28 and Levesque.29
After the compound had set for 24 hours, the abdominal aorta and the
femoral branches were dissected as a unit. The remaining tissue was
removed by immersion of the cast into 25% NaOH at 50°C for 12 hours.
Diameters along the vessel cast were measured by calibrated light
microscopy with NIH Image 1.54 software (pixel resolution of
±0.01 mm). Recent studies by Moore et al30
demonstrated excellent geometric fidelity of the above casting
technique compared with in vivo determination by MRI of the geometry of
the aortoiliac bifurcation in New Zealand White rabbits. Diameter data
from vessel casts obtained from n=5 to 7 animals were then averaged by
aligning the position of the stenosis. The percent
stenosis was calculated as the diameter of the stenosis
(Dstenosis) relative to
Dprox at 12.0 mm proximal to the
stenosis by Equation 1:
 | (1) |
:
 | (2) |
) does not necessarily correspond to the % PSD
observed in averaged aligned cast diameter data sets because the exact
position of maximal PSD of each cast varied slightly.
Computational Fluid Dynamics
The velocity field and mean wall shear stress for cast
geometries were obtained by Galerkin finite-element method (FIDAP 7.0,
Fluid Dynamics International) solution of the Navier-Stokes equation
for steady, laminar flow of a Newtonian fluid equivalent to blood
(viscosity, 0.035 poise) through the 2-dimensional axisymmetric cast
geometry as described by Strony et al.31 Assuming blood to
behave as a Newtonian fluid results in wall shear stresses that have
been shown to be accurate to 10% compared with a more complex
constitutive equation for shear thinning behavior.31
Meshes were refined to >14 500 quadrilateral elements, with increased
mesh resolution at the stenosis and near the wall to eliminate
spurious numerical oscillations in the velocity field.
Fully developed parabolic flow was used as the inlet condition,
corresponding to a mean volumetric flow of 7 mL/min (as observed
experimentally in Figure 1, bottom), and the no-slip boundary
condition was applied at the wall.
Vascular Ring Studies
For ring studies, the femoral arteries were dissected from
anesthetized rabbits that had 3-day unilateral
stenosis. The arteries were placed in room-temperature
Krebs-Ringer solution (in mmol/L: NaCl 118, KCl 4.7,
CaCl2 2.5,
KH2PO4 1.2,
MgSO4 1.2, NaHCO3 25.5,
glucose 5.6). Dissected arteries were cut into rings 2 to 3 mm
wide (3 to 4 mg each), mounted on stainless steel hooks, and placed in
water-jacketed organ baths maintained at 37°C as previously
described.32 Arteries were bathed in 6 mL of Krebs-Ringer
solution aerated with a mixture of 94% O2 and
6% CO2 to obtain a pH of 7.4, a
PCO2 of 38 mm Hg, and a
PO2 >500 mm Hg. Continuous
isometric force readings were obtained with a force-displacement
transducer (Statham UC 2). All rings were allowed to equilibrate for 15
minutes in the Krebs-Ringer solution. Rings were then placed at their
optimal length by repeated stretching in small increments over the next
20 minutes until resting tone remained stable at 0.8 g. This
procedure places each vessel at its optimal length.33
Rings were precontracted with an EC50
concentration of the 
1-adrenergic receptor
agonist phenylephrine. When the contraction had reached a
plateau, acetylcholine 10-8 to
3x10-5 mol/L was added to the bathing solution
in a cumulative manner to induce endothelium-dependent
vascular relaxation by activating NOS in the
endothelium. Before exposure to
phenylephrine, all tissues were incubated with
10-6 mol/L propranolol for 5 minutes
to prevent any potential stimulation of ß-adrenergic receptors and
with 10-5 mol/L indomethacin to
block production of prostaglandins. Data were
expressed as mean±SEM. Statistical comparisons for the vascular
reactivity studies were performed on the concentration-response curves
by use of ANOVA with Student-Newman-Keuls test for post hoc testing of
multiple comparisons. The 50% inhibitory concentrations
(IC50) for acetylcholine inhibition of
constriction were obtained from the concentration-response curves in a
similar manner. Significance was accepted at a value of
P<0.05.
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Results |
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After 3 days, the stenosis of the femoral artery without L-NAME caused a pronounced dilatation at positions distal to the stenosis, as seen in the polymer cast, which was blocked by adventitial application of L-NAME (Figure 2
). In this experiment, oxygen delivery
due to an arterial flow was quite large, and any putative
hypoxic dilatation would be much less than the observed
PSD.34 Furthermore, in large arteries, L-NAME would not be
expected to completely antagonize dilatation due to
hypoxia,35 because intrinsic mechanisms during
hypoxia would predominate.36 Histology of the
vessel wall after 3 days of stenosis is consistent with
proximal vasoconstriction (Figure 3A) and
PSD (Figure 3B).
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The average diameters for aligned casts of stenosed femoral arteries in
the absence or presence of L-NAME after 3 days of bilateral
stenosis are shown in Figure 4A.
In gel-treated femoral arteries (no L-NAME), the position of maximal
PSD was 6.1±2.8 mm (n=7) distal to the stenosis,
corresponding to 4 vessel diameters downstream of the
stenosis. In each of the 7 rabbits, L-NAME treatment of one of
the stenosed femoral arteries attenuated the development of a large PSD
compared with the contralateral stenosed vessels
(Table). The average percent
stenosis for the 14 stenoses was 70.9±6.7%
(Table). In gel-treated femoral arteries (no L-NAME), the max %
PSD ranged from 17.9% to 39.7% (mean, 30.99±7.92% max % PSD, n=7)
after 3 days for 71.7±7.01% stenosis (diameter reduction) of
rabbit femoral artery. In contrast, L-NAME–treated femoral arteries
displayed significantly less PSD, ranging from 0% to 25.0% max % PSD
(mean, 7.16±8.81% max % PSD, n=7). Thus, 1 mmol/L of L-NAME
caused a 76.9% reduction (P<0.001) in PSD. The mean
diameter at a position of 12 mm proximal to the stenosis
was 1.57±0.25 mm for gel-treated vessels, compared with
1.55±0.16 mm for L-NAME–treated vessels. Consistent with
the observations in the rabbit and canine carotid artery during chronic
decreased flow,27 37 we have observed proximal
vasoconstriction (n=8) in formalin-fixed or polymer-casted rabbit
femoral arteries that had a stenosis relative to unstenosed
contralateral sham-operated controls (data not shown).
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) or presence (
) of adventitial
administration of L-NAME 1 mmol/L (A). Vessel geometries were used
for 2-dimensional computational fluid dynamic calculation of
time-averaged wall shear stress (dynes/cm2) for mean blood
flow rate of 7 mL/min (B). Mean positions of flow reattachment points
are indicated (arrows) for vessels stenosed in absence (B) or presence
(C) of adventitial L-NAME. Flow was from left to right.
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Computational fluid dynamic analysis of the average vessel
geometries shown in Figure 4A was conducted at a mean steady
flow rate of 7.0 mL/min (see Figure 1) through each geometry.
The wall shear stress reached peak values of 600 to 700
dynes/cm2 in the throat of the stenosis,
as expected for converging flows.31 A prominent
poststenotic vortex was observed in the simulations. The
time-averaged position of flow reattachment was predicted to occur at
7 mm and 5 mm distal to the stenosis for gel-treated
and L-NAME–treated vessel geometries, respectively (Figure 4B and 4C). This predicted position of reattachment corresponded well with
the position of max % PSD of 6.1±2.8 mm observed in the casts of
the no–L-NAME group. The spatial wall shear stress gradient as
determined by computational fluid dynamic analysis at the
position of flow reattachment
[(
w/x)|w=0]
was +29.7±0.3 and +50.4±0.5 dynes ·
cm-2 · cm-1 in
gel-treated and L-NAME–treated vessel geometries, respectively,
suggesting that the PSD response caused a >40% reduction
(P<0.001) of the time-averaged shear stress gradient at the
site of flow reattachment. In both gel- and L-NAME–treated stenosed
vessels, the mean wall shear stress at positions between the
stenosis and the reattachment point were elevated to 15 to 25
dynes/cm2 relative to the far upstream shear
stress of 13 to 15 dynes/cm2.
For 6 rabbits with bilateral stenosis with one of the stenosed
femoral arteries treated with L-NMMA, the L-NMMA caused a 57.5%
reduction (P<0.001, n=6) in PSD, from 27.3±5.6% to
11.6±3.1% average max % PSD (Figure 5A). For 6 rabbits with bilateral
stenosis with one of the stenosed femoral arteries treated with
L-NNA, the L-NNA caused a 63.9% reduction (n=6, P<0.05) in
PSD, from 24.7±17.2% to 8.93±10.1% average max % PSD (Figure 5B).
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A possibility exists that L-NAME may attenuate
endothelial production of prostacyclin in the
presence of flow38 39 40 or antagonize muscarinic
receptors.41 We used adventitial delivery of 10
µmol/L indomethacin in Pluronic gel to inhibit
cyclooxygenase activity in a stenosed vessel
(Figure 6A). Indomethacin
had no effect on the development of PSD. The average max % PSD for
indomethacin-treated stenoses was
26.4±11.5% (n=5), compared with 23.6±9.5% (n=5) for contralateral
stenoses without indomethacin treatment. When
both L-NAME and indomethacin were applied adventitially
to a stenosed femoral artery (Figure 6B), an 11.8±8.15% (n=5)
average max % PSD occurred, whereas the contralateral stenosed vessel
treated only with indomethacin displayed a 29.4±8.75%
(n=5) average max % PSD. Thus, L-NAME caused a 59.9% reduction in the
formation of PSD when both vessels were simultaneously
treated with indomethacin.
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Over all experiments, stenosis of rabbit femoral artery
produced 26.9±10.6% max % PSD (n=24) that was dramatically and
significantly reduced in the 19 stenosed vessels treated with
L-arginine analogues (L-NAME, L-NMMA, or L-NNA) and
additionally in the 5 vessels treated with L-NAME plus
indomethacin but was not reduced in any of the 10
vessels treated with indomethacin alone (Figure 7).
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In control vessel rings and rings taken proximal (2 to 12
mm) and distal (2 to 12 mm) to the stenosis, acetylcholine
at concentrations from 10-8 to
3x10-6 mol/L caused relaxation (Figure 8) and at higher concentrations of
>10-5 mol/L caused mild contraction, by
stimulating the muscarinic receptors on vascular smooth muscle cells.
In rings distal to the stenosis, 10-6
mol/L acetylcholine was sufficient to produce nearly 90% of maximal
vasorelaxation (n=8), which significantly exceeded (P<0.01)
the 35% and 45% relaxations achieved in proximal rings (n=9) and
control rings (n=6), respectively. The 50% inhibitory
concentration (IC50) from the acetylcholine
dose-response curves in Figure 8 was left-shifted
(P<0.05) for PSD segments
(IC50=87±19 nmol/L, n=8) compared with proximal
rings (IC50=256±60 nmol/L, n=9) or control rings
(IC50=324±96 nmol/L, n=6). In addition, the
poststenotic segments displayed relaxations of greater
magnitude (at all doses of acetylcholine) than proximal or control
rings, consistent with elevated capacity to produce and/or
respond to NO in the poststenotic region. Control and proximal
vessel rings precontracted to their EC50 with
phenylephrine achieved similar tensions of 1015±262 g/g
tissue (n=6) and 1480±204 g/g tissue (n=9), respectively
(P<0.001). However, distal vessel rings exhibited a greater
EC50 tension of 1625±159 g/g tissue
(P<0.05).
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; n=9) or from contralateral
sham-operated control femoral arteries (
; n=6). |
Discussion |
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We have shown that inhibition of NO production by L-arginine analogues significantly attenuated the development of PSD. To the best of our knowledge, this is the first report of pharmacological antagonism of PSD. Furthermore, the enhanced vascular reactivity of vessel rings to acetylcholine in the poststenotic region is consistent with an important role for endothelium-produced NO as a mediator of PSD. In the present study, large-scale turbulence throughout the flow field is not expected, because the upstream, time-averaged Reynolds numbers were <100, based on the mean velocity. Turbulence would be expected to occur in this geometry at a Reynolds number of 300 to 400.42 In light of several reports12 13 14 16 17 of steady unidirectional laminar shear stress inducing NO production and elevating eNOS gene expression levels in cultured endothelial cells, elevated wall shear stress or rapid changes in direction and magnitude of wall shear stress are the likely initiators of PSD. This linkage was suggested in earlier experimental studies by Ojha et al.43
Placement of a long stenosis (>4 mm) in conjunction with a thrombogenic stimulus (thrombin, endothelial denudation, or electric current) has been a model for thrombosis.44 The short length (<1 mm) of the stenosis in the present study was not sufficient for shear-induced platelet activation or arterial thrombosis.31 We have not observed thrombosis at the site of the stenosis or proximal or distal to the stenosis even out to 14 days. The vascular casts also provided no indication of thrombosis, because filling defects were never observed. Langille et al28 observed extremely low endothelial replication rates downstream of the stenosis during the first week after placement of the stenosis. Furthermore, they observed (by scanning electron microscopy) no indication of injury or denudation of the endothelium at or near the coarctation. Importantly, removal of endothelium is generally associated with vasoconstriction,45 not vasodilation, through the loss of basal endothelial NO production as well as platelet adhesion and consequent release of serotonin and thromboxane A2.46
In an earlier study to address the role of NO in PSD,26 the placement of L-NAME 0.1 g/L in the drinking water of rabbits did cause a blockade of acetylcholine-induced vasodilation, as measured by carotid resistance, but had no effect on the development of PSD. As the authors noted, however, L-NAME has been shown to be an antagonist of the cholinergic pathway.41 It is possible that in these earlier experiments, the systemic blockade of NO production was not sufficient at the site of the stenosis to block hemodynamically released NO. A higher level of 0.5 g/L L-NAME in drinking water has been shown to attenuate vascular remodeling in rabbit carotid aorta in response to elevated flows created by an arteriovenous fistula.47 With adventitial delivery or oral delivery of an L-arginine analogue, the exact level of the free agent within the target endothelium is not known. However, any nonlocal downstream effects of L-NAME diluted in the arterial flow (a concentration that we estimate by a steady-state wall diffusion/boundary layer flow model to be quite low) would be expected to be minimal, because systemic dosing with low-level L-NAME is insufficient to block PSD.26
The experiments with indomethacin suggest that the attenuation of PSD by L-NAME or the other NO inhibitors was not due to a nonspecific inhibition of prostacyclin production.38 Our observation that L-NNA (which does not inhibit the muscarinic receptor41 ) significantly attenuated the development of PSD supports the role of NO as the mediator of PSD.
The induction of smooth muscle cell inducible NOS (iNOS) and release of NO (or peroxynitrite) by the altered mechanics of the stenosed vessel remain important avenues of investigation. Interestingly, the proximal region is exposed to greater distending forces due to pulsatile pressure and wave reflection, whereas the distal region experiences damped pulsatility due to the stenosis. In preliminary experiments, we have not detected elevated levels of iNOS antigen in the media of the vessel. Also, we observed that the distal PSD segments develop increased tone in response to phenylephrine and increased dilatory response to acetylcholine. In contrast, when iNOS is induced,48 49 rabbit vessels display decreased response to both phenylephrine and acetylcholine.
In addition, the persistent lack of smooth muscle cell contraction in the poststenotic region may make the noncellular structural elements of the vessel wall more susceptible to distension and circumferential stresses. It may be possible that excess NO (potentially via peroxynitrite) has a role in preaneurysmal processes such as the breakdown of the internal elastic lamina.
The results presented in this study also suggest that the 3-day stenosis model resulted in a functional change of vessel reactivity. An increased responsiveness of the PSD region to a receptor-mediated release of endothelial NO was observed. Similar findings have been observed in vessels exposed to chronic increases in blood flow and shear stress.50 This is consistent with our calculations of increased shear stresses in the distal segment of the vessel. Miller and Burnett50 found that both tonic and receptor-stimulated production of NO was enhanced in arterial blood vessels of the arteriovenous fistula canine model.
Although the hemodynamic origin of PSD is generally undisputed, the precise mechanisms have been controversial and the mediators unknown. The present study indicates that the major molecular mediator of PSD is NO, not prostacyclin. Further experimental and computational studies will help evaluate the hemodynamic regulation of NO and NO-derived species during the development of PSD.
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Acknowledgments |
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This study was supported by NIH FIRST awards HL-47486 (Dr Diamond) and HL-49405 (Dr Hajduczok) and American Heart Association grant 92-310G (Dr Hajduczok). Dr Diamond is a recipient of the NSF National Young Investigator Award.
Received June 22, 1998; revision received September 30, 1998; accepted October 5, 1998.
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