Circulation. 1999;100:II-322-II-327
(Circulation. 1999;100:II-322.)
© 1999 American Heart Association, Inc.
Myocardial Protection and Vascular Biology |
Enhanced Nitric Oxide–Mediated Vascular Relaxation in Radial Artery Compared With Internal Mammary Artery or Saphenous Vein
Oz M. Shapira, MD;
Aiming Xu, MD;
Gabriel S. Aldea, MD;
Joseph A. Vita, MD;
Richard J. Shemin, MD;
John F. Keaney, Jr, MD
From the Department of Cardiothoracic Surgery and Evans Department of
Medicine (A.X., J.A.V., J.F.K), Boston University School of Medicine, Boston,
Mass.
 |
Abstract
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Background—The superior
long-term patency of internal
mammary artery coronary bypass
grafts compared with venous grafts
has been attributed in part to
increased endothelium-derived
nitric oxide (·NO)
production. Interest in the radial
artery as an alternative
bypass conduit has recently been revived;
however, its biological
characteristics remain incompletely
defined. The purpose of this study
was to compare the ·NO-mediated
vasomotor properties of the radial
artery to those of the internal
mammary artery and saphenous
vein.
Methods and Results—Matched segments of radial artery, internal
mammary artery, and saphenous vein (n=24 patients) were examined by use
of organ-chamber methodology. Endothelium-dependent and
-independent vasomotor responses were assessed by dose-response curves
to acetylcholine,
NG-nitro-L-arginine methyl ester
(L-NAME), 8-bromo-cyclic 3',5'-guanosine monophosphate (8-bromo-cGMP),
and nitroglycerin. Maximum ·NO-mediated radial artery
relaxation in response to acetylcholine (86±10%) was significantly
greater than internal mammary artery (56±9%) or saphenous vein
(11±5%, both P<0.0001). Similarly,
acetylcholine-stimulated cGMP accumulation in radial artery (9.1±1.7
pmol/mg protein) was also greater than internal mammary artery
(6.2±0.3 pmol/mg protein) or saphenous vein (1.4±0.2 pmol/mg protein,
both P<0.05). Estimated basal
endothelial ·NO production, assayed as the
percent maximum contraction in response to L-NAME, was greater in
radial artery (39±5%) than internal mammary artery (23±6%) or
saphenous vein (5±2%, both P<0.05). Maximum
relaxation of all vessels to nitroglycerin was similar,
although the sensitivity of radial artery to
nitroglycerin was greater (EC50=33±7
nmol/L) than the internal mammary artery (203±32 nmol/L) or saphenous
vein (97±12 nmol/L, both P<0.05). Vascular cGMP in
response to 0.1 µmol/L nitroglycerin was
significantly higher in the radial artery (8.3±1.4 pmol/mg protein)
compared with the internal mammary artery (3.5±1.3 pmol/mg protein) or
saphenous vein (1.4±0.3 pmol/mg protein, both
P<0.0001). Relaxation to 8-bromo-cGMP was identical for
all 3 conduits.
Conclusions—These data indicate that ·NO-dependent relaxation
of radial artery is greater than that of internal mammary artery or
saphenous vein. This difference is related to
endothelial production of ·NO and/or vessel
sensitivity to ·NO. Such favorable physiological
characteristics of radial artery could conceivably contribute to
improved long-term patency of this conduit compared with saphenous
vein.
Key Words: arteries • veins • nitric oxide • endothelium • vessels
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Introduction
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Arterial conduits are increasingly preferred for
CABG because
of their improved long-term patency rates compared
with venous
conduits.
1 This difference in patency between
arterial and
venous the conduits persists even when these
grafts supply the
same coronary bed.
2 This
observation suggests that specific
biological properties of the grafts
themselves may account for
the difference in long-term patency between
arterial and venous
conduits.
3 4 One inherent
difference between arterial and venous
conduits is
endothelial production of nitric oxide
(·NO).
The importance of ·NO in vascular homeostasis has become
increasingly apparent.5 ·NO contributes to resting
vascular tone,6 impairs platelet
activation,7 8 prevents leukocyte adhesion to the
endothelium,9 and inhibits the
migration10 and proliferation11 of vascular
smooth muscle cells. These effects of ·NO on the vessel wall are
thought to afford protection against thrombosis and
atherosclerosis.5 Using
endothelium-dependent relaxation as an index of ·NO
production, several investigators have found that
endothelium-derived ·NO production in the
internal mammary artery is more pronounced than that of the saphenous
vein.3 4 One proposed consequence of increased
endothelial ·NO production is superior short-
and long-term patency rates of the internal mammary artery grafts
compared with saphenous vein grafts.3 4
The radial artery has recently been rejuvenated as a bypass conduit
with encouraging early and intermediate-term results. Some of this
success has been attributed to improved harvesting techniques and
prolonged administration of antispasmodic
agents,12 13 14 in keeping with the tendency of the
radial artery for vasospasm.15 16 However, ·NO-mediated
relaxation of the radial artery compared with internal mammary artery
and saphenous vein is not yet defined. Therefore, the purpose of this
study was to evaluate ·NO-mediated relaxation of the radial artery in
relation to that of the internal mammary artery and saphenous vein.
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Methods
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Patients
Matched segments of the radial artery, internal mammary artery,
and
saphenous vein that would otherwise have been discarded were
obtained
from patients (n=24) undergoing CABG at Boston Medical Center.
Subjects
were included in this study only if segments of all 3 conduits
could
be obtained. The study was approved by the Boston Medical Center
Institutional
Review Board. There were 21 men and 3 women with a mean
age
of 58±7 years (range, 39 to 73 years). The clinical profile
of
these patients is depicted in Table 1
. All patients were
being treated
with aspirin.
Materials
Physiological salt solution (PSS) contained
(in mmol/L) NaCl 118.3, KCl 4.7, CaCl2 2.5,
MgSO4 1.2,
KH2PO4 1.2,
NaHCO3 25, glucose 11.1, and
Na2EDTA 0.026. Nitroglycerin was
obtained from Baxter Healthcare Inc. Acetylcholine, U46619,
NG-nitro-L-arginine
methyl ester (L-NAME), 3-isobutyl-1-methylxanthine (IBMX), and
8-bromo-3',5'-cGMP (8-bromo cGMP) were purchased from Sigma Chemical
Co. Kits for cGMP determination by ELISA were obtained from
Cayman.
Organ-Chamber Methodology
Vessels were harvested with the accompanying fat pedicle,
immediately placed in ice-cold PSS, and prepared for studies of
vascular function. The vessels were carefully dissected from their
surrounding fat tissue and cut into 2 to 3 segments measuring 4 mm
in length. Vessel segments were placed in organ chambers (37°C)
containing 20 mL PSS, suspended between 2 tungsten stirrups for
measurement of isometric tension as described,17 18 19 and
constantly aerated with 95% O2/5%
CO2. Each vessel was then progressively stretched
in 1-g increments to its optimal resting tension that produced a
maximal response to 80 mmol/L KCl. Vessels were then allowed to
equilibrate for 1 hour before the introduction of vasoactive drugs as
described.17 Relaxation studies were performed after
vessels were contracted with 0.1 to 1 µmol/L of U46619 so that
contraction was 50% to 60% of the maximal KCl-induced contraction.
All experiments were done in the presence of 10 µmol/L
indomethacin to inhibit prostanoid synthesis. Responses
to acetylcholine were evaluated in vessels with and without
endothelium. In addition, vessel response to
acetylcholine was assessed in the presence (300 µmol/L) or
absence of the NO synthase (NOS) inhibitor
L-NAME.20 21 The dose-response curves to
nitroglycerin were obtained in vessels in which the
endothelium was removed. For estimation of basal
endothelial ·NO production, the contractile
response to L-NAME was assessed. Briefly, vessel segments were
contracted with 1 to 10 nmol/L of U46619 to 20% of the maximal
KCl-induced contraction and exposed to increasing doses of L-NAME. The
contractile response was recorded as the percent of maximum
contraction produced by 80 mmol/L KCl. Because vascular relaxation
in response to nitrovasodilators is due in part to increased smooth
muscle cGMP content,22 we examined cGMP-dependent vascular
relaxation in all 3 conduits with the cell-permeable cGMP analog
8-bromo-cGMP.
Tissue cGMP
Segments of the radial artery, mammary artery, and saphenous
vein with or without endothelium were incubated in
organ chambers for 90 minutes as described above without tension. To
inhibit phosphodiesterase activity, 0.1 mmol/L IBMX was added 20
minutes before 1 µmol/L acetylcholine, 0.1 µmol/L
nitroglycerin, or vehicle. Three minutes after the
agents were added, vessels were immediately snap-frozen in liquid
nitrogen. Rings were homogenized in 1 mL of 6%
trichloroacetic acid at 4°C, and cGMP levels were measured as
described.23
Histology and Scanning Electron Microscopy
To assess vascular morphology and endothelial
integrity in our experiments, we subjected samples of the radial
artery, internal mammary artery, and saphenous vein obtained from 7
randomly selected patients to histological examination
and scanning electron microscopy. Segments were fixed with a solution
of 10% formalin in PBS, pH 7.4, for 20 minutes. Segments were then
cleaned, washed in cacodylate-sucrose buffer (10.26 g sucrose in 150 mL
of 0.1-mol/L cacodylate) for 5 minutes, and further fixed in
glutaraldehyde-cacodylate solution (3%
glutaraldehyde, 0.1 mol/L cacodylate) for 24 hours.
Samples prepared in this manner were sectioned (0.2 mm),
dehydrated, and embedded in paraffin as described.24
Sections were stained with resorcin fuchsin (for elastin) and subjected
to morphometric analysis of intimal and medial areas with an
automated videomicroscopy system (Image Technology Corp). Fixed tissues
were also prepared for scanning electron microscopy by postfixation in
1% osmium tetroxide and dehydration with graded ethanol exposure.
Sections were dried in hexamethyldisilazane, coated with gold and
palladium, and observed in an AMR 100-nm scanning electron
microscope (AMRAY).
Statistical Analysis
Unless otherwise specified, all data are expressed as mean±SEM.
Vessel relaxation is expressed as percent reduction in tension induced
by U46619. EC50 represents the drug
concentration producing 50% of maximum relaxation determined by
sigmoidal curve fitting with the use of commercially available software
(Origin, Microcal Inc). Dose-response curves for acetylcholine,
nitroglycerin, and L-NAME were compared among groups by
use of 2-way ANOVA for repeated measures. Comparisons of cGMP and
tension were performed with a 1-way ANOVA and appropriate post hoc test
(Neuman-Keuls’ or Dunnet’s as appropriate).
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Results
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Vascular Contraction and Endothelial Morphology
The contractile responses of the radial artery, internal mammary
artery,
and saphenous vein are given in Table 2
. Raw contractions of
the radial artery
and saphenous vein to 80 mmol/L KCl were comparable,
and both were
greater than the internal mammary artery. In contrast,
contractions of
all conduits to 80 mmol/L KCl were similar if
corrected for wall
thickness (Table 2
.) Representative scanning
electron
micrographs of harvested vessels for this study are given in
Figure
1
. As shown, we observed an intact
endothelial cell layer with
the harvesting technique
used in this study.
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Figure 1. Representative scanning electron
micrographs of endothelium in human radial artery (A),
internal mammary artery (B), and saphenous vein (C) segments harvested
for organ-chamber studies. Random samples of vessel segments from 7
patients were subjected to scanning electron microscopy as described in
Methods.
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Endothelium-Dependent Vascular Relaxation
We observed dose-dependent relaxation of radial artery, saphenous
vein, and internal mammary artery in response to acetylcholine, a known
stimulus for endothelial ·NO production
(Figure 2). Maximum relaxation of the radial
artery to acetylcholine (86±10%) was significantly greater than that
of either the internal mammary artery (56±9%, P<0.0001)
or saphenous vein (11±5%, P<0.0001). This difference
between the radial artery and other conduits was evident throughout the
dose-response curve to acetylcholine (Figure 2). In 6
experiments, we found that saphenous vein relaxation to acetylcholine
was inhibited 92±4% in the presence of 300 µmol/L L-NAME (data
not shown). The corresponding values for the radial and internal
mammary arteries were 96±6% and 95±4%, respectively. In the absence
of endothelium, no conduit demonstrated any relaxation
to acetylcholine (data not shown).
Estimated Basal Endothelial ·NO
Production
We observed dose-dependent contraction of all conduits in response
to the NOS inhibitor L-NAME (Figure 3). Maximum contraction of the radial artery
(30±5%) was significantly greater than either the saphenous vein
(5±2%, P<0.05) or internal mammary artery (23±6%,
P<0.05), suggesting a greater basal ·NO
production in radial artery endothelium than
other vessels. We observed no contraction to L-NAME in conduits devoid
of endothelium (data not shown).
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Figure 3. Effect of L-NAME on contraction of human radial
artery (RA), internal mammary artery (IMA), and saphenous vein (SV).
Matched segments of radial artery, internal mammary artery, and
saphenous vein were contracted to 20% of maximum with 1 to 10 nmol/L
U46619. Additional contraction force was assessed in response to
indicated doses of L-NAME. Data represent percent of maximum
(80 mmol/L KCl) contraction produced by each dose of L-NAME and
represent mean±SEM derived from 6 patients.
*P<0.05 vs saphenous vein;  P<0.05 vs
internal mammary artery for dose response to L-NAME by 2-way
repeated-measures ANOVA with post hoc Neuman-Keuls comparison.
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Endothelium-Independent Vascular
Relaxation
In vessels devoid of endothelium, the response to
nitroglycerin is as shown in Figure 4. Maximum relaxation to 1 µmol/L
nitroglycerin was similar for the radial artery
(108±4%), internal mammary artery (96±3%), and saphenous vein
(100±4%, all P=NS). In contrast, we found that the radial
artery was significantly more sensitive to
nitroglycerin (EC50=33±7 nmol/L)
than either the saphenous vein (97±12 nmol/L, P<0.05) or
internal mammary artery (203±32 nmol/L, P<0.05). To assess
cGMP-mediated vascular relaxation, we examined dose-dependent
relaxation to 8-bromo-cGMP; these data are given in Figure 5. We found no differences in dose responses
of all 3 conduits to 8-bromo-cGMP over a concentration range of 0.1 to
100 µmol/L.
Vessel cGMP levels
As shown in Figure 6A, baseline vascular
cGMP was greater in radial artery (1.8±0.4 pmol/mg protein) and
internal mammary artery (1.6±0.7 pmol/mg protein) than saphenous vein
(0.3±0.3 pmol/mg protein, P<0.05 versus both by 1-way
ANOVA). Similarly, cGMP in response to 1 µmol/L acetylcholine
was also greater in the radial artery (9.1±1.7 pmol/mg protein) than
either the internal mammary artery (6.2±0.3 pmol/mg protein) or
saphenous vein (1.4±0.2 pmol/mg protein, P<0.05 versus
both by 1-way ANOVA). Vascular tissue levels of cGMP after exposure to
0.1 µmol/L nitroglycerin are depicted in Figure 6B. The radial artery produced significantly more cGMP (8.3±1.4
pmol/mg protein) than either the internal mammary artery (3.5±1.3
pmol/mg protein, P<0.001 by 1-way ANOVA) or saphenous vein
(1.4±0.3 pmol/mg protein, P<0.001 by 1-way ANOVA) in
response to nitroglycerin.
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Figure 6. Tissue levels of cGMP in human radial artery (RA),
internal mammary artery (IMA), and saphenous vein (SV). A, Matched
segments of radial artery, internal mammary artery, and saphenous vein
were incubated in organ chambers and treated for 20 minutes with
0.1 mmol/L IBMX before treatment with 1 µmol/L
acetylcholine (ACH) or vehicle (CTL) for 3 minutes. Vessels were then
snap-frozen in liquid nitrogen and cGMP determined by ELISA. B, Matched
segments of denuded vessels were otherwise treated as in A except for
0.1 µmol/L nitroglycerin. Data represent
mean±SEM derived from 6 patients. *P<0.05 vs
corresponding saphenous vein sample; P<0.05 vs
internal mammary artery or saphenous vein, both by 1-way
repeated-measures ANOVA with post hoc Neuman-Keuls comparison.
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Discussion
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The superior patency rate of the internal mammary artery compared
with
saphenous vein is well documented and has triggered interest
in
the use of other arterial conduits.
1 Luscher
and colleagues
3 were the first to link the superior
internal mammary artery
graft function to enhanced in vitro
production of ·NO.
They found that both receptor-mediated
(acetylcholine-induced)
and receptor-independent (calcium
ionophore–induced) endothelium-dependent
relaxation of
the internal mammary artery was significantly
greater than the
saphenous vein.
3 These responses could be
prevented
through mechanical removal of the endothelium, guanylyl
cyclase
inhibition, or ·NO scavenging with oxyhemoglobin. Pearson
and
coworkers
4 confirmed these observations and demonstrated
that
internal mammary artery relaxation to acetylcholine was attenuated
by
the NOS inhibitor L-NMMA. These in vitro properties of
the internal
mammary artery appear operative in vivo. Nishioka and
colleagues
25 have demonstrated greater
acetylcholine-induced ·NO
production (as nitrite
accumulation) in internal mammary artery
grafts compared with saphenous
vein grafts in post-CABG patients.
The concept that enhanced graft
endothelium-derived ·NO
production may
translate into superior long-term patency has
prompted speculation that
transfection of saphenous vein with
the endothelial NOS
gene may enhance vein graft patency.
26
Our study extends these observations to another arterial
conduit, the radial artery. We observed that
endothelium-dependent relaxation in the radial artery
was superior to other conduits. We believe that these observations
indicate that acetylcholine-stimulated ·NO production in
radial artery is enhanced compared with the internal mammary artery or
saphenous vein. The role of ·NO is supported by previous
data,4 our own observations that acetylcholine-mediated
conduit relaxation was inhibited >90% by the NOS
inhibitor L-NAME, and the fact that no relaxation was
observed in the absence of endothelium. Moreover, we
also observed a greater degree of cGMP accumulation in response to
acetylcholine in the radial artery compared with other conduits, again
pointing to ·NO as the species responsible for our observations.
Because our vascular relaxation studies were performed in the presence
of indomethacin, there is also no evidence for
involvement of prostacyclin in the data presented here.
Our studies also support the idea that basal ·NO production
from radial artery endothelium is enhanced compared
with the saphenous vein and comparable to the internal mammary artery.
We observed that dose-dependent NOS inhibition with L-NAME produced a
greater degree of contraction in the radial artery than either the
internal mammary artery or saphenous vein (Figure 3
). This
indirect assessment of basal ·NO production has been used
successfully in other studies27 but is limited because we
cannot exclude the possibility that some contribution of the
contractile response is due to U46619. However, we also observed
increased basal levels of cGMP in the radial and internal mammary
arteries compared with the saphenous vein (Figure 6),
consistent with greater basal
endothelium-derived ·NO production in these
arterial conduits. Thus, our data support relatively
greater endothelial NOS activity in both the basal and
stimulated states in the radial and internal mammary arteries compared
with the saphenous vein.
Our observations of enhanced endothelium-dependent
relaxation of the radial artery are in contrast to prior studies
reporting comparable responses of the radial and internal mammary
arteries.15 16 Several factors may account for these
differences among studies. In the present study, both the internal
mammary and radial arteries were harvested with the accompanying fat
and veins with a minimum of mechanical manipulation. Grafts were not
flushed with any solution (avoiding chemical injury), and hydrostatic
or mechanical dilation of the vessel was strictly avoided. These
precautions were designed to minimize endothelial
trauma. Consequently, we observed an intact endothelial
cell layer in all vessels by electron microscopy (Figure 1) and
a uniform response (100%) of the vessels to acetylcholine in the organ
chamber. In contrast, Chardigny and colleagues15 observed
endothelium-dependent relaxation in only 62% and 40%
of radial and internal mammary artery segments, respectively. In the
study of He and Yang,16
endothelium-dependent relaxation was not observed in
all radial and internal mammary artery segments. There were also
considerable differences in the stimuli for
endothelium-derived ·NO in these studies. For
example, we stimulated endothelium-derived ·NO with a
dose response to acetylcholine. In contrast, He and Yang16
used substance P and calcium ionophore to induce
endothelium-dependent relaxation. Although Chardigny
and colleagues15 used acetylcholine, they assessed
relaxation by response to a single dose only.
An unexpected and new finding in our study was the greater sensitivity
of the radial artery to nitroglycerin (Figure 4). This enhanced sensitivity to nitrovasodilators was also
associated with greater tissue levels of cGMP in response to
nitroglycerin in the radial artery compared with the
internal mammary artery or saphenous vein (Figure 6). These
findings suggest that smooth muscle cells in the radial artery may
contain more guanylyl cyclase (or a greater specific enzymatic
activity) than the smooth muscle in either the internal mammary artery
or saphenous vein. To date, there is limited information on the ·NO
sensitivity of vascular beds with respect to cGMP production.
Papapetropoulos and colleagues28 investigated the response
of human and animal vascular tissues to sodium nitroprusside. They
found that vascular endothelium and smooth muscle cells
obtained from different vascular beds had distinct cGMP responses to
sodium nitroprusside.28 One explanation offered by those
investigators was a difference in guanylyl cyclase gene expression
based on the vascular bed. Our study results are consistent
with this contention. Alternatively, we cannot exclude the possibility
that our observations reflect some difference in
nitroglycerin metabolism among the 3
conduits. The exact mechanisms underlying this phenomenon and its
clinical significance warrant investigation.
The long-term patency rate of the radial artery is presently
unknown. However, excellent clinical and angiographic results with a
follow-up of up to 5 years have recently been
reported.12 13 14 In this study, we documented enhanced
endothelium-dependent, ·NO-mediated vascular
relaxation and greater sensitivity to nitroglycerin in
the radial artery compared with the internal mammary artery or
saphenous vein. From the known bioactivity of ·NO as a vasodilator
and antiatherogen, one might expect that these properties of the radial
artery protect against vasoconstriction and graft
atherosclerosis and thus translate into improved
long-term patency of this conduit.
|
Acknowledgments
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This work was supported by grants from the American Heart
Association,
National Center (Dr Keaney) and the National Institutes of
Health
(HL-53398 to Dr Vita and HL-59346 and HL-55854 to Dr Keaney).
Dr
Vita is an established investigator of the American Heart
Association,
and Dr Keaney is the recipient of a Clinical Investigator
Development
Award (HL-03195) from the National Institutes of
Health.
|
Footnotes
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Reprint requests to Oz M. Shapira, MD, Department of Cardiothoracic
Surgery, Boston Medical Center, 88 E Newton St, Boston, MA 02118.
|
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Abstract
Introduction
), and saphenous vein (
) were suspended in organ
chambers as described in Methods and contracted with 0.1 to 1
µmol/L U46619. Relaxation was assessed in response to indicated
acetylcholine doses. Data represent percent reduction in
contraction and represent mean±SEM derived from 11 patients.
*P<0.001 for dose response vs internal mammary artery
or saphenous vein.
), internal mammary artery (
), and
saphenous vein (
) were denuded of endothelium,
suspended in organ chambers, and contracted with U46619. Relaxation was
recorded in response to indicated 8-bromo-cGMP doses. Data
represent percent reduction in U46619-induced contraction and
are expressed as mean±SEM derived from 6 patients.