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2 levels in rabbit carotid
artery
1 Vascular Biology Unit, Boston Medical Center, Boston, Massachusetts 02118; and 2 Department of Clinical Chemistry, Umeå University Hospital, Umeå, Sweden
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Endogenous superoxide anion
(O
2) interferes with the bioactivity
of nitric oxide (NO) in endothelium-dependent arterial relaxation
(EDR). Using the lucigenin chemiluminescence assay, we measured
O2 in the thoracic and abdominal aortas and the carotid artery of rabbits to determine whether ambient
O2 varies among the three arteries and differentially diminishes the effect of NO. Basal levels of
O2 were significantly higher in
carotid arteries than in the thoracic aorta [23 ± 6.1 vs. 3.9 ± 1.4 chemiluminescence units (CU);
P < 0.05], whereas EDR in
response to ACh
(108-105
M) was not significantly different on ANOVA. After treatment with the
superoxide dismutase (SOD) inhibitor diethyldithiocarbamate (DDC; 10 mM), O2 levels were significantly
elevated, becoming greater in the carotid artery and abdominal aorta
than in the thoracic aorta (185 ± 31.2 and 202 ± 40.3 vs. 89 ± 18 CU; P < 0.05). DDC
significantly reversed EDR in the thoracic aorta but not in the carotid
artery; at 106 M ACh, the
decrease seen with DDC was 48 ± 6.2 vs. 6.8 ± 8.0% of maximal
relaxation in the thoracic aorta and carotid artery, respectively. In
the thoracic aorta, exogenous SOD reversed the inhibition of EDR caused
by DDC. Moreover, DDC/O2-resistant EDR
in the carotid artery was ablated by the addition of
nitro-L-arginine methyl ester (300 µM;
P < 0.05), an NO synthase inhibitor,
consistent with peroxynitrite or an
O2-resistant NO donor being involved
in carotid relaxation. Indeed, exogenous peroxynitrite caused similar
relaxation of the carotid artery and thoracic aorta, which was
unaffected by DDC. Our studies show a greater production of nitrite and
O2 per unit area by the carotid artery, suggesting a greater amount of their product peroxynitrite. These findings support the hypothesis that peroxynitrite is the relaxing agent that resists high O2 in
the carotid artery.
aorta; reactive oxygen species; superoxide anion
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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BECAUSE THE diffusion-limited reaction between
superoxide anion (O2) and nitric oxide
(NO) has generally been considered to render NO inactive (4), there has
been a great deal of interest in oxidative stress as a mechanism by
which vascular disease decreases endothelium-dependent relaxation
(EDR). O2 is thought to
inhibit NO-dependent vasorelaxation in hypertension, atherosclerosis,
and diabetes (9, 12, 15, 21, 27, 32). Many studies have examined the
effect of vascular disease on EDR and have implicated
O2 in reduced vasodilation, but none
to our knowledge has demonstrated a resistance to elevated
O2. Perhaps this is because studies examining O2 levels and effects have
focused on one artery or vein from a particular species with little or no comparison of various blood vessels from the same species. The
present experiments were designed to compare various arteries as to
their levels of superoxide dismutase (SOD) isozymes and capacities to
produce O2 and NO, as well as the
response of EDR to elevated levels of
O2.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Male New Zealand White rabbits were anesthetized with pentobarbital sodium (30 mg/kg) and given an anticoagulant (heparin; 150 U/kg) via the marginal ear vein. They were then killed by exsanguination, and the thoracic aorta, abdominal aorta, and carotid artery were quickly placed in cold bicarbonate buffer of the following composition (in mM): 118.3 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 KH2PO4, 1.2 MgSO4, 25.0 NaHCO3, 5.5 dextrose, and 0.026 disodium EDTA. Perivascular adipose tissue was carefully removed from the arteries, which were then cut into 6-mm-long rings. In some studies the endothelium was removed mechanically by placing one tip of a pair of forceps in the lumen and gently rolling the ring on a piece of gauze soaked in bicarbonate buffer.
Organ chamber studies.
Rings were suspended on triangular stainless steel wires, one
stationary and the other connected to a strain-gauge transducer (Grass
FT03, Quincy, MA) coupled to a polygraph (Grass 7D) to measure
circumferential isometric force. Rings were placed in 6-ml organ baths
that contained buffer and were maintained at 37°C and bubbled
continuously with 95% O2-5%
CO2. The rings were stretched in a
stepwise fashion to a tension of 6 g for the thoracic aorta and 7 g for
the carotid artery and abdominal aorta, values that were optimal for
contraction. The tissue was equilibrated for 90 min, during which the
bathing buffer was changed every 20 min. Those vessels treated with
diethyldithiocarbamate (DDC) to inhibit the Cu/Zn form of superoxide
dismutase (SOD) were incubated for 30 min and then washed before
precontraction responses were obtained. SOD (150 U/ml) was added to
some rings before stimulation with ACh. With the addition of
half-logarithmic increments of phenylephrine
(108-105
M), rings were contracted to ~40% of maximal contraction and then
relaxed with the addition of half-logarithmic increases of ACh
(109-105
M) or logarithmic increments of peroxynitrite (1.8 × 107-1.8 × 103 M). Whenever
nitro-L-arginine methyl ester
(L-NAME) was administered, it
was added 50 min before exposure to ACh.
Detection of O2.
Briefly, test tubes containing vascular rings in 5 ml of bicarbonate
buffer were transferred to an incubator at 37°C for a 30-min
equilibration period. The solution was bubbled with 95% O2-5%
CO2 to maintain pH 7.4 and
contained either no additions or DDC (10 mM). After equilibration,
rings were rinsed with prewarmed (37°C) modified Krebs-HEPES buffer
of the following composition (in mM): 119 NaCl, 20 HEPES, 4.6 KCl, 1.0 MgSO4, 0.15 Na2HPO4, 0.4 KH2PO4,
5 NaHCO3, 1.2 CaCl2, and 5.5 glucose (pH 7.4).
HEPES buffer was used to maintain pH at 7.4 in the absence of
O2-CO2 bubbling. Rings were placed in 1 ml of HEPES buffer in a 1.6-ml, 8 × 50-mm polypropylene tube (Evergreen, Los Angeles, CA)
containing lucigenin (250 µM), which was then equilibrated in the
dark for 10 min at 37°C. The tubes were placed in a Turner 20e
luminometer (Mountain View, CA) with the light chamber maintained at
37°C. Our methods of detecting acute changes in
O2 levels over an extended period of
time and at physiological temperature, along with calibration and data
collection, have been described previously in detail (25, 26). Units of
chemiluminescence were converted to nanomoles of
O2 by standardization with the
xanthine oxidase-cytochrome c assay.
Measurements of NO.
NO can react with molecular O2 and
water to form nitrite (NO2), which is
more stable than NO. A purge vessel of a chemiluminescent NO analyzer
(Sievers no. 207B) at room temperature containing glacial acetic acid
and 1% potassium iodide as reducing agents was used to convert
NO2 back to detectable NO. The
analyzer can detect picomole levels on the basis of the reaction
between NO and ozone, which liberates a photon. A photomultiplier tube
detects the photon and feeds an electrical signal into a recorder/integrator (Fisher).
8-3 × 106 M) over 30 min, after which the buffer was collected and the accumulated content
of nitrite analyzed. The rings in each group were challenged with an
ACh concentration response only once. NO2 was integrated and normalized to
the total intimal area of the rings. Picomoles of NO generated by the
arteries were calculated from the standard curves for nitrite resulting from standard injections of authentic NO. The ACh-stimulated release of
NO was determined by subtracting the amount of nitrite contained in a
collection of supernatant produced in the 30 min immediately preceding
the stimulation with ACh. Our group has previously shown that the
release of nitrite stimulated by ACh did not occur if the
endothelium was removed by mechanical rubbing or if the vessel was treated with atropine (5).
Measurement of SOD levels.
Rings of the thoracic aorta and carotid artery were frozen on dry ice
under control conditions or after treatment with DDC and were kept at
70°C. They were shipped on dry ice to the laboratory of S. Marklund, where measurements of Cu/Zn SOD, Mn SOD, and extracellular Cu/Zn SOD were separated (28) and analyzed (17, 18) as described previously.
Synthesis and application of peroxynitrite. Peroxynitrite was produced according to the methods of Beckman et al. (3). Briefly, all solutions were cooled on ice in Erlenmeyer flasks. After synthesis, peroxynitrite (~170-180 mM) was diluted 1:10 or 1:100 in 1.2 M NaOH (4°C) and then applied directly to the organ chambers. Controls were carried out using the vehicle. No relaxation was caused by the addition of equivalent amounts of 1.2 mM NaOH to organ chambers.
Drugs. ACh, DDC, and L-phenylephrine (Sigma, St. Louis, MO) were dissolved in distilled water. Indomethacin (Sigma) was dissolved in 50 mM Na2CO3 and buffered to pH 7.4, and SOD (Fluka, Ronkonkoma, NY) was dissolved in bicarbonate buffer. All values represent final molar concentrations in the organ chambers. All drugs were either prepared the day of the experiment or taken from frozen aliquots.
Statistical analysis. Relaxation responses to all agonists are reported as the maximum relaxation following the addition of each concentration of drug and were calculated as a percentage of the contraction induced by phenylephrine. Data are expressed as means ± SE; geometric means of drug concentrations were analyzed. Statistical evaluation of the cGMP levels and time-course responses were performed using Student's t-test for paired or unpaired comparisons. The relaxation responses were analyzed using ANOVA for repeated measures. Differences between groups at individual concentrations were tested with the Student's t-test for paired comparisons. P < 0.05 was considered statistically significant. For all data, n is the number of animals from which rings were taken.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Comparison of Tiron-inhibitable lucigenin-enhanced chemiluminescence
showed a two- to fourfold higher basal
O2 level in carotid arterial rings
compared with levels in rings from the abdominal and thoracic aortas,
respectively (carotid vs. thoracic aorta,
P < 0.05; Fig.
1A).
However, Table 1 shows that the
activities of the three isoforms of SOD in blood vessels were not
different between the thoracic aorta and carotid artery. DDC [10
mM, a concentration shown to maximally inhibit Cu/Zn SOD levels
(25)] caused significantly higher elevation of
O2 in the abdominal aorta and carotid
artery than in the thoracic aorta (P < 0.05; Fig. 1B), resulting in
levels that were twofold greater in the abdominal aorta and carotid
artery. Furthermore, DDC was equally effective in inhibiting total SOD
in the carotid artery and thoracic aorta (98.1 ± 0.52% and 98.0 ± 0.39%, n = 3 and 4, respectively; Table 1). DNA was 689 ± 63.6 in the thoracic aorta
compared with 553 ± 15.7 µg/g wet wt tissue in the
carotid artery (n = 8 and 7, respectively), indicating a larger ratio of cell number to mass in the
thoracic aorta.
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Comparison of NO levels as measured by nitrite in basal and
ACh-stimulated rings showed that significantly more NO was released from the carotid artery than from the thoracic aorta when expressed per
unit volume of tissue (Fig. 2).
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ACh-induced relaxation of phenylephrine-precontracted thoracic aorta
reached a maximum of 74%, compared with 41% for tissue treated with
DDC (P < 0.01, ANOVA; Fig.
3). Treating DDC-pretreated rings with
exogenous SOD (150 U/ml) caused a partial but not statistically significant shift of the relaxation response curve back to the left.
Abdominal aortic rings relaxed more in response to ACh
(P < 0.01 vs. thoracic aorta,
ANOVA), reaching a maximum of 95%; DDC significantly inhibited this
response, with a maximal relaxation of 67%
(P < 0.01, ANOVA; Fig.
4). Interestingly, applying exogenous SOD
to DDC-pretreated abdominal aortic rings caused a statistically significant reversal of inhibition (P < 0.05, ANOVA). Carotid arterial rings reached a maximum relaxation
at 94% despite higher basal levels of
O2, and this was not significantly affected by pretreatment with DDC (Fig.
5). Exogenous SOD also had no
effect on carotid arterial relaxation, consistent with the lack of
effect of elevated O2. Moreover, SOD
administration had a slight tendency to enhance basal and ACh-induced
relaxations in non-DDC-treated blood vessels (data not shown). However,
those relaxations were not statistically different from control
(n = 10-17).
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To characterize DDC-resistant carotid relaxation,
L-NAME, an NO synthase (NOS)
inhibitor, was used to determine whether NO is a component of this
response. Indeed, L-NAME (300 µM) was completely effective at inhibiting relaxation in both control
and DDC-pretreated carotid artery rings (Fig.
6). Application of
peroxynitrite to phenylephrine-precontracted rings from the thoracic
aorta and carotid artery caused similar concentration responses even
when the rings were pretreated with DDC (Fig.
7).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Our data support the existence of
O2-sensitive NO as the major relaxing
factor in the thoracic aorta. In contrast, EDR appears to be resistant
to O2 in the carotid artery but less
so in the abdominal aorta. To our knowledge, these results also
represent the first report of systematic comparison of the various SOD
isozymes in various rabbit blood vessels and demonstrate the
effectiveness of DDC at inhibiting SOD activity. Furthermore, the fact
that peroxynitrite is a product of the reaction of NO and
O2, and that levels of these
precursors are higher in the carotid artery, suggests that
peroxynitrite is more abundant there as well. The capacity of the
carotid artery to relax in response to peroxynitrite without being
affected by DDC and the ability of
L-NAME to inhibit ACh-induced carotid relaxation support a role for peroxynitrite in this relaxation.
Basal O2 levels varied widely among
the carotid artery and the abdominal and thoracic aortas. This is
likely explained by a difference in the production of
O2, not by differing rates of
catabolism, because the levels of all three SOD isozymes did not differ
among blood vessels. Whereas the carotid artery appeared to have the
greatest capacity to produce O2, this
was not related to a higher cell number per unit mass of tissue; in
fact, this ratio was slightly lower in the carotid artery. This
suggests that the carotid artery has a far greater capacity to produce
O2 than the thoracic aorta, and
differences in O2 levels after DDC
treatment are most likely not related to disparate
O2 catabolism because DDC was equally
effective in reducing total SOD activity in each group. Moreover, we do
not consider such differences to be a result of artificial levels of
oxygen in our experiments for a number of reasons. One reason is that
we have compared the bubbling of aortic rings with 95%
O2-5%
CO2 with the bubbling of rings
with normal air and found no differences in the levels of
chemiluminescence (n = 2). This is not
surprising because of the known Michaelis-Menten constant for oxygen of
NADPH oxidase (10 µM) (1), which is far below even that
for buffers bubbled with room air (2-4 mM). In addition, there is
a very low metabolic rate in blood vessels, and we also have shown that
manipulations of mitochondrial electron transport have no effect on
vascular superoxide generation (24, 25).
ACh elicits relaxation via the release of a product of NOS, which is
susceptible to degradation by O2 (5, 6, 8). Interestingly, however, the aortic response to ACh was not what
was expected from the level of O2 prevalent in each artery. For instance, although basal levels of
O2 were higher in the carotid artery
than in the thoracic aorta, the degree of ACh-induced relaxation in the
absence of DDC was as large or greater than that in the aorta. Consistent with the larger response, the release of NO in the carotid
artery was greater than that in the aorta, suggesting the possibility
of an adaptation to higher levels of basal
O2. Moreover, although DDC caused
similar inhibition of total SOD activity in all three arteries, the
carotid artery and abdominal aorta demonstrated higher increases in
O2 than the thoracic aorta. Despite
the significantly higher O2 levels in
DDC-treated vessels, ACh-induced relaxation was greater in the
abdominal than in the thoracic aorta and was highest in the carotid artery.
One possibility is that O2 or one of
its metabolites plays a role in the improved relaxation. Another
explanation is that a variant of NO, such as nitrosoglutathione, which
can act as an NO donor, is most resistant to
O2 in the carotid artery, less so in
the abdominal aorta, and least of all in the thoracic aorta. Indeed,
various biological forms of NO have been described (10, 11, 19) that
would be more or less susceptible to
O2. As an additional example, sodium
nitroprusside, which is known to be metabolized to NO intracellularly
(13), causes normal vasodilator responses in arteries in which elevated
O2 impairs ACh-induced relaxation (22,
31). This is possibly because sodium nitroprusside releases
NO+ (7), which, unlike NO, does
not react with O2. Hence, a chemical
form of endogenous NO, like that released by nitroprusside, could
explain the novel results in the carotid artery. Because
nitrosoglutathione or nitrosocysteine also release NO+ rather than NO (7), it is
possible that production of one of these nitrosothiol NO donors
explains the capability of ACh-induced EDR to resist elevated levels of
O2 in the carotid artery.
On the basis of levels of chemiluminescence, we calculated the amount
of O2 generated by these arteries by
comparing levels to those produced by xanthine oxidase as previously described (22). O2 levels in the
thoracic aorta and carotid artery in the presence of DDC were 433 and
750 nM, respectively. When the concentration of NO was estimated as the
amount released per square centimeter, the amounts of NO produced in
response to ACh in the thoracic aorta and carotid artery were ~50 and
200 pmol/ml tissue, or 50 and 200 nM, respectively. Importantly, these
data suggest that there is adequate O2 in the carotid artery to react with all the NO produced. The higher production of O2 and NO in the carotid
artery compared with that in the thoracic aorta suggests a greater
likelihood of OONO being
produced in the carotid artery. Moreover, the reaction between
O2 and NO in DDC-treated vessels is favored in the absence of SOD activity, with which NO must normally compete to react with O2 (4). Attempts
to measure OONO levels
directly using luminol-enhanced chemiluminescence were unsuccessful in
the present study because of an apparent lack of sensitivity and
specificity of the assay.
In vitro administration of
OONO reveals that it is a
plausible relaxing factor in these arteries. Indeed, others have
described peroxynitrite as a relaxing factor (14, 16). Although the exogenous amounts of OONO
that relaxed the carotid artery appear high, it is possible that substantially lower amounts of
OONO reached the smooth
muscle, due in part to the bicarbonate in the buffer (16). Nonetheless,
the responses of the thoracic aorta and carotid artery to
OONO were identical and
equally unaffected by DDC. This lack of effect of DDC supports the
potential for peroxynitrite as an
O2-resistant mediator. This is also
supported by the ability of
L-NAME to inhibit ACh-induced
carotid relaxations in the presence of DDC; that is, formation of
OONO from NO and
O2 would be inhibited (4).
OONO has been reported to
react with glutathione (GSH) to form
GSNO2 (2, 33), an NO
donor that would resist O2. Thus the
higher levels of both NO and O2
suggest that OONO, or
possibly a reactant of OONO
with GSH, is responsible for resisting elevated levels of
O2 and results in unimpaired EDR. This
may also be the reason why EDR of the rabbit carotid artery resists the
oxidative stress associated with hypercholesterolemia (20) or diabetes
(29, 30), whereas the aorta demonstrates impaired EDR.
In summary, we propose that the carotid artery has a greater propensity
to produce OONO than the
abdominal or thoracic aorta. This hypothesis is based on the higher
level of the precursors for
OONO in carotid arteries as
well as the resistance of its EDR response to elevated levels of
O2.
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ACKNOWLEDGEMENTS |
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We thank Steven Haller for editorial assistance.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grants R29-HL-55425, HL-31607, HL-55620, HL-55993, and HL-55854 and American Heart Association Grant-in-Aid 95011900.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: P. J. Pagano, Hypertension and Vascular Research Division, E.R. 7044, Henry Ford Hospital, 2799 W. Grand Blvd., Detroit, MI 48202-2689 (E-mail: ppagano1{at}hfhs.org).
Received 28 December 1998; accepted in final form 11 June 1999.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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,
n = 17), DDC-treated (
,
n = 14), and DDC-treated rings
administered exogenous 150 U/ml SOD (
,
n = 8). Data are expressed as means ± SE of %relaxation. ** P < 0.01 by ANOVA.
,
n = 8). Data are expressed as means ± SE of %relaxation. * P < 0.05; ** P < 0.01 by
ANOVA.
) and DDC-treated thoracic aortic rings (
). Data
are expressed as means ± SE of %relaxation.