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Departments of Anesthesiology and Pharmacology, Mayo Clinic, Rochester, Minnesota 55905
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ABSTRACT |
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 Top
 Abstract
 Introduction
Methods
Results
Discussion
References
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The superoxide anion
(O
2·) appears to be an important
modulator of nitric oxide (NO ·) bioavailability. The present
study was designed to characterize the role of copper/zinc superoxide
dismutase (Cu/Zn SOD) in endothelium-dependent relaxations. Cu/Zn SOD
was inhibited with the Cu2+
chelator diethyldithiocarbamic acid (DETCA). In isolated canine basilar
arteries, DETCA (7.6 × 103 M) inhibited total
vascular SOD activity by 46% (P < 0.0001, n = 6-8 dogs). DETCA
(7.6 × 103
M) significantly reduced relaxations to bradykinin and A-23187 (P < 0.05, n = 7-11). The inhibitory effect
of DETCA was abolished by the O2·
scavenger 4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron; 9.4 × 103 M;
P < 0.05, n = 6-13). Tiron significantly
potentiated the relaxations to bradykinin in control rings
(P < 0.05, n = 13), and the nitric oxide synthase
inhibitor N
-nitro-L-arginine
methyl ester (L-NAME; 3 × 104 M) abolished these
relaxations (P < 0.0001, n = 6). DETCA and Tiron had no effect
on the relaxations to diethylamine-NONOate or forskolin
(P > 0.05, n = 6). Our results demonstrate that
endothelium-dependent relaxations mediated by NO · are
impaired after the inhibition of Cu/Zn SOD. Relaxations to bradykinin
(but not A-23187) were significantly augmented by Tiron.
Pharmacological scavenging of O2·
reverses the effect of Cu/Zn SOD inhibition.
A-23187; bradykinin; cerebral vessels; inflammation; Tiron
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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NITRIC OXIDE (NO ·) has been identified as
the endothelium-derived relaxing factor (8, 10, 31). NO · readily reacts with the superoxide anion
(O2·) (6, 33). The favorable
kinetics of the reaction between NO · and O2· (2, 6, 26) intrinsically make vascular O2· levels an important
determinant of NO · biological activity (23, 25). Enzymatic
scavenging of O2· is carried out
by superoxide dismutases (SOD) (20), which differ in their cellular
localization as well as in the identity of the transition metal in
their catalytic sites (3). In eukaryotes, Mn SOD is mitochondrial and
the dimeric Cu/Zn SOD is cytosolic and nuclear, whereas the tetrameric,
proteoglycan-bound Cu/Zn SOD is extracellular (18, 27). Total SOD
distribution between these isoforms varies between species and vascular
beds; however, the predominant activity of SOD in peripheral vessels is
attributed to the Cu/Zn isoforms (27).
The SOD substrate, O2·, can be
produced by a number of cellular processes (3). There is increasing evidence of constitutive O2·
production in the vascular wall by a phagocyte-like NAD(P)H oxidase
(22, 28, 29). Increased vascular
O2· levels have been associated
with a number of vascular diseases, including atherosclerosis,
hypertension, ischemia-reperfusion, inflammation, and vasospasm
(2, 9, 14, 16, 17, 32). Adequate
O2· scavenging appears to be
imperative for normal NO ·-mediated vasomotor function. The
present study was designed to determine the effect of Cu/Zn SOD
inhibition, by chelation of Cu2+
with diethyldithiocarbamic acid (DETCA), on NO ·-mediated
relaxations in cerebral arteries. Previous experiments in the bovine
coronary artery and rabbit aorta showed impairment of
NO ·-mediated relaxations after treatment with DETCA (23,
25). In the present study, we additionally sought to correlate the
physiological effect of DETCA with the biochemical effect on SOD
activity. We also sought to determine the reversibility of the DETCA
effect by pharmacologically scavenging
O2· with
4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron), a cell-permeable
O2· scavenger (5, 21, 22).
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Measurement of vascular SOD activity.
Rings of isolated basilar arteries were initially incubated at 37°C
in 2.5 ml of MEM (with Earle's salts, containing 0.1% BSA, 100 U/ml
penicillin, and 100 µg/ml streptomycin) in a
CO2 incubator (5%
CO2-95% air; Forma Scientific)
for 1 h. After the 1-h equilibration, all rings were transferred to
fresh MEM. Some rings were transferred to MEM containing DETCA (7.6 × 103 M). The rings
were further incubated for 30 min before being frozen in liquid
N2 and stored in a 
80°C
freezer. The rings were homogenized in a chilled phosphate buffer
containing 0.216 M
KH2PO4 and 8.0 N KOH; the final pH of the homogenizing buffer was 7.8. The
homogenates were centrifuged at 14,000 g for 15 min at 4°C. The
supernatant fraction was stored at 80°C until analysis. The pellet fraction was digested in SDS (2%) for 36 h at room temperature. SOD activity was assayed spectrophotometrically by the reduction of
cytochrome c (partially acetylated) as
described previously (12, 20). Protein content in the supernatant and
pellet fractions was determined with the DC Protein Assay Kit (Bio-Rad,
Hercules, CA).
Organ chamber studies.
The experiments were performed on rings of isolated basilar arteries,
4-5 mm in length, obtained from anesthetized (pentothal sodium, 25 mg/kg iv) mongrel dogs (15-20 kg) of either sex. All procedures
were in accordance with institutional guidelines. Vascular reactivity
was studied in modified Krebs-Ringer bicarbonate (control) solution of
the following composition (in mM): 123.2 NaCl, 4.9 KCl, 2.0 CaCl2, 0.6 MgSO4, 1.2 KH2PO4,
26.0 NaHCO3, and 11.6 dextrose. Each ring was connected to an isometric force transducer (Gould) and
suspended in an organ chamber filled with 25 ml of control solution
(37°C, pH 7.4) aerated with a 94%
O2-6%
CO2 gas mixture. Isometric force
was recorded continuously. The rings were allowed to equilibrate in the
organ bath for 1 h before each experiment. Each ring was then gradually
stretched to the optimal point of its length-tension curve as
determined by the contraction to UTP (105 M) (11). The
functional integrity of the endothelium was assessed by observing the
presence of relaxations to substance P
(108 M). All experiments
were carried out in the presence of indomethacin (105 M) to inhibit
cyclooxygenase activity. The incubation time for indomethacin was 45 min before experimentation. DETCA (7.6 × 103 M) was added to the
organ bath 15 min after indomethacin. All organ baths were washed out
30 min after the addition of DETCA. Indomethacin
(105 M) was reapplied 5 min
after washout. In some experiments, Tiron (9.4 × 103 M) was added to the
organ bath for 10 min after readministration of indomethacin.
Submaximal contractions to UTP
(105 M) were obtained
5 min after readministration of indomethacin and were allowed to
stabilize for another 10 min. Concentration-response curves to calcium
ionophore A-23187, bradykinin, diethylamine NONOate (DEA
NONOate), and forskolin were obtained cumulatively. Relaxations were expressed as a percentage of the maximal
relaxation induced by papaverine (3 × 104 M).
Drugs.
The following pharmacological agents were used: A-23187, BSA,
bradykinin, cytochrome c (partially
acetylated), DETCA, Tiron, dimethyl sulfoxide (DMSO), forskolin,
indomethacin, N-nitro-L-arginine
methyl ester (L-NAME),
papaverine, KOH, substance P, UTP, xanthine (sodium salt), and xanthine
oxidase from Sigma (St. Louis, MO); DEA NONOate from Cayman Chemical
(Ann Arbor, MI); EDTA disodium salt from J. T. Baker (Phillipsburg,
NJ); KCN from Fischer Chemical (Fairlawn, NJ); and penicillin, SDS, and streptomycin from GIBCO-BRL (Grand Island, NY). Drugs were dissolved in
distilled water so that volumes 
0.250 ml were added to the organ
baths. DEA NONOate solutions at the highest concentrations were made
daily in 1.5 M Tris buffer, pH 8.8. Stock solutions of A-23187 and
forskolin at the highest concentrations were made in DMSO. The
concentrations of all drugs are expressed as final molar concentrations
in the organ bath.
Statistical analysis. The data are expressed as means ± SE; n refers to the number of dogs from which basilar artery segments were obtained. Statistical analysis was performed using repeated-measures ANOVA with Bonferroni/Dunn's post hoc test. Statistical significance was accepted at a level of P < 0.05.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Effect of DETCA on SOD activity in isolated canine basilar arteries.
In isolated canine basilar arteries with endothelium, incubation with
DETCA (7.6 × 103 M)
for 30 min in MEM significantly decreased vascular SOD activity by 46%
(Fig. 1).
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Endothelium-dependent relaxations to bradykinin.
During contractions induced by UTP
(105 M), bradykinin induced
concentration-dependent relaxations that were significantly impaired
when arterial rings were preincubated with DETCA (7.6 × 103 M; Fig.
2). The effect of DETCA on relaxations to
bradykinin was abolished by the presence of the cell-permeable
O2· scavenger Tiron (9.4 × 103 M; Fig. 2). In control
rings, Tiron (9.4 × 103 M) significantly
potentiated the relaxations to bradykinin (Fig. 3). The relaxations in the presence of
Tiron in control rings were abolished by
L-NAME (3 × 104 M; Fig. 3).
Preincubation of arteries with
L-arginine
(104 M) or sepiapterin
(104 M) did not affect the
potentiation of relaxations to bradykinin observed in the presence of
Tiron (data not shown).
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Endothelium-dependent relaxations to A-23187.
Preincubation with DETCA (7.6 × 103 M) significantly
impaired the concentration-dependent relaxations to A-23187 during
contractions induced by UTP
(105 M; Fig.
4A). The
effect of DETCA on relaxations to A-23187 was abolished by the presence
of Tiron (9.4 × 103
M; Fig. 4A). In control rings, Tiron
had no effect on the relaxations to A-23187 (Fig.
4B).
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Relaxations to DEA NONOate.
In endothelium-intact canine basilar arteries, the
concentration-dependent relaxations to DEA NONOate were not affected by DETCA (7.6 × 103 M;
Table 1). Tiron (9.4 × 103 M) had no effect on the
relaxations to DEA NONOate in rings preincubated with DETCA (Table 1).
Tiron had no effect on the relaxations to DEA NONOate in control rings
(Table 1).
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Relaxations to forskolin.
In arteries with endothelium, the concentration-dependent relaxations
to forskolin were not affected by DETCA (7.6 × 103 M; Table
2). Relaxations to forskolin in control
rings were not affected by Tiron (9.4 × 103 M; Table 2).
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Our study is the first to demonstrate impairment of
NO ·-mediated relaxations after inhibition of Cu/Zn SOD in
cerebral arteries. The mechanism of this impairment appears to be
increased cellular O2· formation
and subsequent chemical inactivation of NO ·.
O2· and NO · are known
to readily react to form peroxynitrite
(ONOO). The rate of
reaction between O2· and NO · exceeds the dismutation reaction rate of
O2· by SOD (2), thus making
vascular O2· concentration an
important determinant of NO · activity (25).
DETCA chelates the Cu2+ cation,
which is necessary for Cu/Zn SOD enzymatic activity (3). In our
experiments, DETCA (7.6 × 103 M) caused a 46%
inhibition of total SOD activity. Previous studies demonstrated that
inhibition of SOD increases vascular
O2· levels (25, 30). Inhibition of
SOD activity by DETCA likewise affected the vascular reactivity of
cerebral arteries. DETCA (7.6 × 103 M) impaired the
relaxations to the nitric oxide synthase (NOS) agonists bradykinin and
A-23187. Tiron (9.4 × 103 M), a cell-permeable
O2· scavenger, abolished the
inhibitory effect of DETCA on NOS-mediated relaxations. Inhibition of
SOD activity after DETCA treatment, therefore, impairs NOS-mediated relaxations by increasing steady-state vascular
O2· levels. We show that the
effect of DETCA on NOS-mediated relaxations is reversed by
pharmacological scavenging of O2·.
In a previous study, Mügge and colleagues (23) demonstrated that in rabbit aortas 5 mM DETCA causes ~60% inhibition of relaxations to acetylcholine and A-23187. In the present study, we used a 7.6 mM concentration of DETCA and obtained ~25-30% reduction in endothelium-dependent relaxations to bradykinin and A-23187. In addition to obvious vascular and species differences, it is important to notice that in our study we incubated cerebral arteries with DETCA for 30 min, whereas Mügge and colleagues (23) incubated rabbit aortas for 45 min. Furthermore, enzymatic activity of SOD appears to be lower in rabbit aorta than in canine basilar artery (unpublished observation). Taken together, these differences may be responsible for less pronounced DETCA-induced inhibition of endothelium-dependent relaxations in cerebral arteries.
Inhibition of SOD with DETCA unmasked a constitutive production of
O2· in vascular tissue. Because our experiments were carried out in the presence of indomethacin (106 M), we can rule out
the contribution of cyclooxygenase to the detected
O2· production (13). Recent biochemical studies have shown that an NAD(P)H oxidase is the major
source of O2· in the vascular wall (22, 28, 29). We could not demonstrate the contribution of NAD(P)H
oxidase to the observed impairment of endothelium-dependent relaxations
because the available flavoprotein inhibitors for the oxidase also
inhibit NOS. However, in preliminary experiments, we have detected
increased O2· production in canine
basilar artery homogenates on addition of exogenous NADH or NADPH. The
increased O2· production was
considerably greater for NADH and abrogated by diphenyliodonium chloride, a flavoprotein inhibitor, suggesting that NAD(P)H oxidase is
a potential source of O2· in
cerebral arteries. Analysis of tetrahydrobiopterin
(BH4) binding to neuronal NOS
indicated that some NOS molecules exist in an uncoupled,
O2·-producing state (4).
Experiments with recombinant endothelial NOS showed that the
O2·-generating potential of this enzyme is inversely dependent on
BH4 availability and independent of exogenous L-arginine (36).
The flavin moiety of endothelial NOS was shown to be the source of
O2· production (36). In the
present study, we could not abolish the formation of
O2· by increasing concentrations
of available BH4 and
L-arginine. The source of the
constitutive O2· production in
cerebral arteries remains to be determined.
The O2· scavenger Tiron had an
interesting differential effect on the relaxations to bradykinin and A-23187 in control arteries (not treated with DETCA). Tiron (9.4 × 103 M)
significantly potentiated the relaxations to bradykinin but did not
affect the relaxations to A-23187.
L-NAME (3 × 104 M) abolished the
relaxations to bradykinin in the presence of Tiron, suggesting that
Tiron was potentiating NO ·-mediated relaxations. Previously,
we showed (12) that L-NAME
(104 M) abolished the
relaxations to A-23187 in control arteries. These differential results
cannot be attributed to the hyperoxic organ chamber environment, which
is known to attenuate NO ·-mediated relaxations (33), because
Tiron did not potentiate the relaxations to both agonists. Experiments
in the presence of exogenous
L-arginine (104 M) or sepiapterin
(104 M) suggested that
bradykinin was not stimulating a dysfunctional NOS pool due to
substrate or BH4 insufficiency. We
cannot rule out the possibility that A-23187 may have stimulated
O2· production that was adequately
scavenged, thus preserving NOS-mediated relaxations. Bradykinin was
shown to stimulate O2· production
in cultured endothelial cells (7, 15), albeit at higher concentrations
than those used in this study. Indomethacin (106 M) inhibited the
bradykinin-induced O2· production
by 60% in cultured cells (7). Our current results indicate a
cyclooxygenase-independent O2· source stimulated by bradykinin. Our previous results in cerebral arteries showed potentiation of relaxations to bradykinin in the presence of exogenous SOD and catalase (10). Studies with pial arterioles of Wistar-Kyoto rats and spontaneously hypertensive rats
also showed enhancement of relaxations to bradykinin in the presence of
exogenous SOD (37). However, because SOD and catalase poorly cross the
cell membrane (1), the above-mentioned earlier findings may only
reflect extracellular O2· and
H2O2
production by bradykinin. In the present study, results with the
cell-permeable O2· scavenger Tiron indicated that bradykinin stimulated
O2· production, which
significantly attenuated the vasodilatory effect of the agonist. The
source and physiological role of the bradykinin-mediated O2· production remain to be
determined, particularly because this
O2· production appears to evade
endogenous SOD. The present finding may be related to the role of
bradykinin and O2· as inflammatory mediators (14, 19, 24, 34, 35).
To determine the selectivity of the DETCA and Tiron, we evaluated
relaxations to the direct NO · donor DEA NONOate and the adenylate cyclase activator forskolin in endothelium-intact basilar arteries. Neither DETCA (7.6 × 103 M) nor Tiron (9.4 × 103 M) affected
relaxations to DEA NONOate or forskolin. The effects of DETCA and
Tiron, therefore, appear to be selective for the agonist-stimulated NOS
pathway in endothelium-intact arteries. We do not have an explanation
for differential effects of DETCA on relaxations mediated by endogenous
nitric oxide versus relaxations induced by exogenous nitric oxide (DEA NONOate).
The present study demonstrates that, in canine basilar arteries, Cu/Zn
SOD activity is necessary for normal NO ·-mediated vasomotor
function. The impairment of NOS-mediated relaxations after the
inhibition of Cu/Zn SOD activity can be reversed by pharmacological
scavenging of O2·. Finally, it
appears that bradykinin concomitantly stimulates NO · and
O2· production in canine basilar
arteries. The exact source of O2· remains to be determined.
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ACKNOWLEDGEMENTS |
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We thank Leslie Smith for technical assistance, Dr. Yasuhiko Iida for valuable advice, and Janet Beckman for typing the manuscript.
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FOOTNOTES |
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This work was supported in part by National Institute of General Medical Sciences Grant R25-GM-55252 (to C. O. Wambi-Kiéssé) and National Heart, Lung, and Blood Institute Grant HL-53524 (to Z. S. Katusic).
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: Z. S. Katusic, Depts. of Anesthesiology and Pharmacology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905 (E-mail: katusic.zvonimir{at}mayo.edu).
Received 5 August 1998; accepted in final form 30 November 1998.
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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