(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
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.
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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.
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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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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).
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), 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.
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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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.
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.
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), 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.
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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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 colleagues3 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 coworkers4 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 colleagues25 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.
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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.
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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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