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Departments of Internal Medicine, Pathology, Physiology, and Pharmacology, Cardiovascular Center, University of Iowa College of Medicine, Iowa City, Iowa 52242
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study examined vascular function and
the role of superoxide in mice that chronically express human renin
(R+) and human angiotensinogen (A+). Responses of aortas from R+/A+
mice and from their normotensive littermates (RA
mice) were examined
in vitro. Endothelium-dependent relaxation to acetylcholine was
impaired in vessels from R+/A+ mice (e.g., maximal relaxation to 100 µM acetylcholine was 45 ± 5% and 65 ± 3% in R+/A+ and
RA mice, respectively; P < 0.05). Relaxation was
also impaired to the endothelium-independent dilators authentic nitric
oxide and nitroprusside in vessels from R+/A+ mice. Maximal
vasorelaxation to the endothelium-independent, non-nitric oxide dilator
papaverine was similar in R+/A+ and RA mice. Incubation of vessels
from R+/A+ mice with Tiron (1 mM), a superoxide scavenger, improved
relaxation to acetylcholine, nitric oxide, and nitroprusside. In
contrast, incubation with diethyldithiocarbamate (1 mM), an inhibitor
of copper-containing SODs, reduced acetylcholine- and
nitroprusside-induced relaxation in vessels from both R+/A+ and RA
mice. Basal superoxide levels, measured with lucigenin-enhanced
chemiluminescence (5 µM lucigenin) and hydroethidine-based
fluorescent confocal microscopy, were higher in vessels from R+/A+ mice
and were Tiron and polyethylene glycol-SOD sensitive. These results
suggest that increased superoxide contributes to impaired nitric
oxide-mediated relaxation in this genetic model of chronic angiotensin
II-dependent hypertension.
aorta; high blood pressure; nitric oxide; reactive oxygen species; transgenic mice
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ANGIOTENSIN II AFFECTS vascular tone primarily through AT1 receptor-mediated pathways (31). More recently, effects of angiotensin II on vascular tone were demonstrated to include angiotensin II-mediated increases in superoxide (10, 31). For example, angiotensin II was shown to increase basal superoxide production by nearly threefold in cultured smooth muscle (9). Acute infusion of angiotensin II is associated with increases in arterial pressure and increased superoxide levels in vessels (7, 15, 24, 25) that appear to be mediated through activation of AT receptors because these responses can be normalized by losartan administration (24). These findings suggest that acute administration of large pharmacological pressor doses of angiotensin II produces oxidative stress within vessels. However, despite these initial investigations, relatively little is known regarding the effects of chronic and physiological increases in angiotensin II on vascular function and superoxide levels.
Double-transgenic mice that express human renin (R+) and human angiotensinogen (A+) are chronically hypertensive and demonstrate a threefold increase in plasma angiotensin II levels (19). Thus R+/A+ mice provide an excellent model in which to examine mechanisms associated with chronic hypertension induced by the renin-angiotensin system. Because hypertension mediated by angiotensin II involves multiple signaling pathways that display distinctive temporal characteristics (i.e., short-term vs. long-term signaling events; Refs. 26 and 31), the first goal of the present study was to determine whether endothelium-dependent and nitric oxide-mediated relaxation are impaired in R+/A+ mice. Additionally, because angiotensin II can potentially increase superoxide production, the second goal of the present study was to determine whether impaired nitric oxide-dependent relaxation in R+/A+ mice is related to increases in vascular superoxide.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experimental animals. Double-transgenic (R+/A+) mice were generated by crossbreeding single-transgenic human renin (R+) mice with single-transgenic human angiotensinogen (A+) mice (6, 19). All breeding and genotyping was performed in the transgenic animal facility at the University of Iowa, a virus- and pathogen-free environment. The presence or absence of transgenes in each mouse was assessed by gene- and species-specific polymerase chain reaction of DNA isolated from tail biopsy samples (19).
We showed previously (19), using indwelling arterial catheters, that mean arterial pressure is significantly increased in R+/A+ mice compared with nontransgenic (R/A) and single-transgenic (R/A+ and R+/A) littermates. Strict species specificity exists between the mouse and human renin-angiotensinogen systems
(19). Thus human renin does not proteolytically cleave
mouse angiotensinogen, and mouse renin does not cleave human
angiotensinogen. We also showed previously (6) that
vascular responses to acetylcholine are similar in R/A, R/A+, and
R+/A mice. Therefore, because blood pressure and vascular responses
to acetylcholine are not different between R/A, R/A+, and R+/A
mice, and because of the species specificity reaction, responses from
these three groups are pooled and are referred to as RA. In the
present study, systolic blood pressure was measured in R+/A+ and RA
mice with an automated tail-cuff device (BP-2000, Visitech Systems,
Apex, NC) as described previously (14, 27, 28). All
experimental protocols were approved by the University of Iowa Animal
Care and Use Committee.
Vascular studies. Mice were euthanized with pentobarbital sodium (75-100 mg/kg ip), and the thoracic aorta was quickly removed and placed in Krebs buffer (pH 7.4) with the following ionic composition (mmol/l): 118.3 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgSO4, 1.2 KH2PO4, 25 NaHCO3, and 11 glucose. Loose connective tissue from the adventitial surface was removed, and the aorta was cut into four rings (each 4 mm in length). Vascular rings were mounted on pairs of triangular hooks and suspended in individual organ chambers containing 20 ml of Krebs buffer maintained at 37°C and bubbled continuously with 95% O2-5% CO2. The rings were connected to force transducers, which measured isometric tension (contraction and relaxation). Resting tension was increased stepwise to reach a final resting tension of 0.5 g, which has been found to be optimal for these vessels (1). Vessels were allowed to equilibrate for 45 min before addition of vasoactive agonists. Krebs buffer was replaced with fresh buffer every 15 min throughout the experimental protocol, except during the generation of concentration-response curves. We used these methods previously (1, 6, 27) to examine vascular function in blood vessels from mice.
After equilibration, vessels were contracted submaximally (50-60% of maximum) with PGF2
. After reaching a stable
contraction plateau, concentration-response curves were generated for
the endothelium-dependent dilator acetylcholine (10 nM-100 µM)
and the endothelium-independent dilators authentic nitric oxide
(0.1-10 µM), sodium nitroprusside (10 nM-10 µM), and the
non-nitric oxide dilator papaverine (0.1-100 µM). In separate
experiments, concentration-response curves were generated in the
absence and presence of diethyldithiocarbamate (DETC; 1 mM),
indomethacin (10 µM), or 4,5-dihydroxy-1,3-benzene disulfonic acid
(Tiron; 1 mM) to inhibit copper-containing SODs [i.e., CuZn-SOD and
extracellular (EC)-SOD] and cyclooxygenase and to scavenge superoxide,
respectively. At the end of each experiment, a full
concentration-response curve to PGF2 (10-100 µM)
was generated to determine the maximal contractile response of each vessel.
Measurement of superoxide. Superoxide levels were measured with two approaches. First, lucigenin-enhanced chemiluminescence was performed as described previously (3, 4). Basal (control) levels of superoxide are reported as the value of tissue plus lucigenin-containing buffer minus background. Superoxide levels were normalized to dry weight. In some experiments, vessels were preincubated with Tiron (10 mM) or diphenylene iodonium (DPI; 100 µM) for 30 min to quench the superoxide signal and to access the role of NAD(P)H oxidase, respectively.
Second, superoxide levels were also evaluated with hydroethidine-based (2 µM hydroethidine) confocal microscopy as described previously (16, 20, 21). Images were obtained with a Bio-Rad MRC-1024 laser scanning confocal microscope equipped with a krypton/argon laser. Fluorescence was detected with a 585-nm long-pass filter. Laser settings were identical for acquisition of images, and vessels from R+/A+ mice and RA mice were processed and imaged in parallel. In some
experiments, vessels were preincubated with either vehicle (PBS) or
polyethylene glycol-SOD (PEG-SOD; 50 U/ml) for 30 min before
application of hydroethidine. Relative increases (based on low-,
medium-, and high-intensity fluorescence) in ethidium bromide
fluorescence were determined with Scion Image software for the PC
(version 4.02). Ethidium bromide fluorescence was normalized to the
cross-sectional area of the vessel wall for each section.
Drugs. Acetylcholine, DETC, DPI, indomethacin, papaverine, PEG-SOD, sodium nitroprusside, and Tiron were obtained from Sigma (St. Louis, MO), and all were dissolved in saline with the exception of DPI and indomethacin, which were dissolved in DMSO (final concentration <0.01%) and Na2CO3 (0.1 M), respectively. Hydroethidine was obtained from Molecular Probes (Eugene, OR) and prepared as described previously (20, 21). Authentic nitric oxide was prepared as described previously (5). All other reagents were of standard laboratory grade.
Statistical analysis.
Relaxation is expressed as a percent relaxation to
PGF2-induced contraction. All data are expressed as
means ± SE. Comparisons were made with ANOVA for repeated
measures with Tukey's post hoc test (concentration-response curves),
one-way ANOVA (superoxide levels), and a Student's t-test
(baseline characteristics). A probability value of <0.05 was
considered significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Blood pressure and baseline characteristics.
Systolic blood pressure was higher (P < 0.05) in R+/A+
mice than in RA mice (Table 1),
consistent with what we previously reported (19). In
addition, heart weight-to-body weight ratio (an index of cardiac
hypertrophy) was significantly larger (P < 0.05) in
R+/A+ mice (Table 1). These differences could not be accounted for by
differences in age or body weight, because R+/A+ and RA mice were of
similar age (10 ± 1 and 10 ± 1 mo, respectively;
P > 0.05) and body weight (30 ± 1 and 27 ± 1 g, respectively; P > 0.05).
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Vascular responses.
Relaxation to acetylcholine and authentic nitric oxide was impaired
(P < 0.05) in vessels from R+/A+ mice compared with
RA mice (Fig. 1), as was the
response to nitroprusside (Fig. 2). Although maximal relaxation was similar, a rightward shift was noted in
the concentration-response curve to papaverine in vessels from R+/A+
mice (Fig. 2). Impaired responses to all three endothelium-independent agonists suggest impairment of vascular function that extends beyond
the endothelium. In R+/A+ mice, contraction of the aorta in response to
PGF2 was also significantly higher (P < 0.05) than in RA mice (Table 2). These
findings suggest that relaxation to both endothelium-dependent and
-independent stimuli are impaired (whereas contraction is enhanced) in
vessels from R+/A+ mice.
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mice (Fig.
3). Likewise, DETC inhibited
(P < 0.05; data not shown) relaxation to nitroprusside
by ~45% and 35% in vessels from R+/A+ and RA mice, respectively.
In contrast, DETC had no effect (P > 0.05) on
papaverine-induced relaxation in R+/A+ or RA mice (data not shown).
More importantly, these data demonstrate that an acute increase in
oxidative stress with DETC impairs vascular function in mice (both RA
and R+/A+). This is consistent with the concept that increases in
oxidative stress can produce impairment of nitric oxide-mediated
relaxation in mouse blood vessels.
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(Table 2) nearly (~90%) to normal in vessels from R+/A+ mice. In
contrast, Tiron had no effect (P > 0.05) on
acetylcholine (Fig. 4)- and nitric oxide (Fig. 5)-induced relaxation or
PGF2-induced contraction (Table 2) in vessels from RA
mice. Tiron also had no effect on papaverine-induced relaxation in
vessels from either R+/A+ or RA mice (data not shown). These data
suggest that scavenging of nitric oxide by superoxide (i.e., because of
increased superoxide levels) contributes to impaired nitric
oxide-dependent relaxation in R+/A+ mice.
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mice, suggesting that enhanced cyclooxygenase activity does not
contribute to the impairment of vascular function in the aorta from
R+/A+ mice.
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Superoxide levels.
Basal superoxide levels, as measured with lucigenin-enhanced
chemiluminescence, were higher (P < 0.05) in vessels
from R+/A+ mice than those in RA mice (Fig.
7). Pretreatment with Tiron (10 mM)
markedly reduced the lucigenin signal in vessels from both R+/A+ and
RA mice (Fig. 7), suggesting that the lucigenin signal reflects
superoxide. Preincubation with DPI (100 µM) markedly reduced the
lucigenin signal observed in vessels from both R+/A+ and RA mice
(Fig. 7). These findings with DPI suggest that the difference in basal
superoxide levels between R+/A+ and RA mice may reflect an increase
in NAD(P)H oxidase activity.
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mice (Figs. 8 and
9).
Preincubation of vessel sections with PEG-SOD (50 U/ml) essentially
abolished ethidium bromide fluorescence in both R+/A+ and RA vessels
(Fig. 9). These results obtained with two independent methods of
superoxide detection, in conjunction with our vascular function data,
strongly implicate a role for increased superoxide in vascular
dysfunction in R+/A+ mice.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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There are several major new findings of the present study. First,
endothelium-dependent and endothelium-independent relaxation to nitric
oxide are impaired in aortas from R+/A+ mice. Additionally, contraction
to PGF2 was enhanced in R+/A+ mice. Second, inhibition of copper-containing SODs significantly reduced relaxation to acetylcholine and nitroprusside in R+/A+ and RA mice, suggesting that
acute increases in oxidative stress impair nitric oxide-mediated relaxation in murine blood vessels. Third, impaired nitric
oxide-mediated relaxation in R+/A+ mice was significantly improved by
Tiron, suggesting that increases in superoxide contribute to vascular dysfunction in R+/A+ mice. Consistent with this idea, basal superoxide levels, as measured with two independent methods, were significantly higher in vessels from R+/A+ mice relative to levels in RA mice. The
results obtained with DPI suggest that increases in superoxide in R+/A+
mice are due to increased activity of NAD(P)H oxidase. Thus
superoxide-mediated vascular dysfunction is present in an important
model of hypertension in which genes of the renin-angiotensin system
are overexpressed chronically. From the present data, it cannot be
discerned whether the increase in superoxide and vascular dysfunction
is due to the increase in blood pressure per se or mediated directly
via effects of angiotensin II within the vessel wall.
R+/A+ mice as a model of
angiotensin II-dependent hypertension.
R+/A+ mice are hypertensive and display elevated plasma renin
activity and plasma angiotensin II levels compared with nontransgenic littermates (19). Although several spontaneously
hypertensive mouse and rat strains exist, we suggest that R+/A+ mice
have several distinctive advantages over these other commonly used
models. First, R+/A+ mice represent a defined (angiotensin II induced) and chronic (caused by life-long expression of human renin and human
angiotensinogen) model of hypertension. Previous studies that have
examined the effect of angiotensin II on vascular function and
superoxide levels have primarily used relatively short durations of
angiotensin II infusion (
7 days) with minipumps (7, 15, 24). Second, vascular responses in R+/A+ mice are compared with those from normotensive littermates, which are of a genetically similar
(>99.9% homogeneity) background (C57BL/6J). This is of importance,
because vascular responses become difficult to interpret when
comparisons are made between genetically dissimilar backgrounds (i.e.,
spontaneously hypertensive vs. Wistar-Kyoto rats) (8, 27,
29). Third, a particular advantage of studying R+/A+
mice pertains to the fact that expression of EC-SOD in mice more
closely resembles that observed in humans (12, 18). Most
previous studies related to changes in vascular superoxide during acute angiotensin II-induced hypertension have been performed in the rat
(7, 15, 24, 25). However, the rat may not be particularly representative for these studies because blood vessels from rats have
much less EC-SOD (thought to be a key isoform in blood vessels) than
other species, making them potentially more vulnerable to superoxide-mediated vascular damage (12, 18). Thus R+/A+
mice provide an excellent genetic, rather than pharmacological, model by which to study the long-term mechanism(s) associated with
hypertension induced by the renin-angiotensin system.
Impaired vascular function in R+/A+ mice. Although we have observed impaired endothelium-dependent relaxation in carotid artery of R+/A+ mice (6), the role of superoxide has not been examined in this model previously. Consistent with our previous findings (6), in the present study, endothelium-dependent relaxation in response to acetylcholine was impaired in aortas of R+/A+ mice. Additionally, endothelium-independent relaxation to authentic nitric oxide was significantly reduced in R+/A+ mice. Because exogenous nitric oxide and endogenously produced nitric oxide (released by endothelial nitric oxide synthase) require diffusion through the vessel wall, we anticipated that relaxation to authentic nitric oxide and acetylcholine would be impaired in vessels from R+/A+ mice. It was more difficult to predict whether relaxation to nitroprusside, which appears to require metabolic activation in smooth muscle before it can release nitric oxide (13), would be impaired in vessels from R+/A+ mice. Our observation that relaxation to nitroprusside, in addition to acetylcholine and nitric oxide, was significantly reduced in the aorta from R+/A+ mice suggests that nitric oxide-mediated relaxation is markedly impaired in R+/A+ mice. Although maximal relaxation to the non-endothelium, non-nitric oxide-dependent dilator papaverine was preserved in R+/A+ mice, a rightward shift was noted at lower concentrations, suggesting that vascular dysfunction is not limited to endothelium but may also involve some general (perhaps nonspecific) impairment of function in vascular muscle.
Because oxidative stress has been associated with impaired endothelium-dependent relaxation, we hypothesized that acute inhibition of SOD (i.e., copper-containing SODs) activity with DETC should reduce nitric oxide-dependent relaxation in RA mice and might produce
additional vascular dysfunction in vessels from R+/A+ mice. DETC has
been used previously to induce oxidative stress in blood vessels and
has been shown to increase superoxide and impair endothelium-dependent
relaxation to acetylcholine in the aorta, carotid artery, and cerebral
blood vessels (3, 11, 17, 22, 23). In the present study,
DETC significantly reduced acetylcholine- and nitroprusside-induced
relaxation in vessels from both R+/A+ and RA mice. Interestingly, the
level of vascular impairment produced with DETC in RA mice was
similar to the vascular responses observed in R+/A+ mice in the absence
of DETC. In addition, it was noted that impaired nitric oxide-dependent
relaxation in R+/A+ mice could be reduced further with DETC, suggesting
that vascular dysfunction in R+/A+ mice (in the absence of DETC) is not
mediated solely by the loss of expression or activity of either CuZn-SOD or EC-SOD.
Role of increased superoxide contributing to impaired nitric
oxide-dependent relaxation.
Because increases in oxidative stress with DETC were associated with a
reduction in nitric oxide-dependent relaxation and because angiotensin
II can produce oxidative stress, we explored the possibility that
increased superoxide contributes to vascular dysfunction in R+/A+ mice.
Incubation of vessels with the superoxide scavenger Tiron improved
acetylcholine- and nitric oxide- but not papaverine-induced
vasorelaxation. Tiron also reduced PGF2-induced contraction in R+/A+ mice toward that observed in RA mice. In contrast, Tiron had no effect on relaxation or contraction in vessels
from RA mice, suggesting that the effects of Tiron were selective and
that superoxide influences vascular responses only in R+/A+ mice. These
data are consistent with results obtained with acute (short term)
pharmacological increases in angiotensin II in rats (7, 15, 24,
25) and suggest that enhanced superoxide levels play an
important role in vascular dysfunction in this chronic model of
angiotensin II-induced hypertension (R+/A+ mice).
mice by two independent methods. We
found that basal superoxide levels were significantly higher in aortas
from R+/A+ mice by lucigenin-enhanced chemiluminescence and by
hydroethidine-based confocal microscopy. Both the lucigenin signal and
ethidium bromide fluorescence were markedly reduced by superoxide
scavengers, suggesting that these signals reflected increases in
superoxide. These findings support the conclusion that increases in
superoxide contribute to impaired vascular responses either indirectly,
via decreases in nitric oxide bioavailability, or alternatively via
superoxide-mediated vasoconstriction. The observation that the
lucigenin signal could be markedly reduced by DPI suggests that
increases in superoxide in R+/A+ mice reflect enhanced NAD(P)H oxidase activity.
We showed previously (6) that indomethacin abolishes
acetylcholine-induced contractions in carotid artery of R+/A+ mice. In
the present study of the aorta, enhanced cyclooxygenase activity does
not appear to contribute to impaired vascular function because indomethacin did not improve the response of aortas from R+/A+ mice.
These apparent differences may relate to two factors. First, we did not
observe transient contractions in response to acetylcholine in the
aorta as we had in the carotid artery. Second, in the carotid artery,
indomethacin was only efficacious in abolishing the transiently induced
contractions in response to acetylcholine; however, indomethacin treatment did not restore overall responsiveness of the carotid artery
toward normal.
Both lucigenin-enhanced chemiluminescence and hydroethidine-based
confocal microscopy have been previously shown to be sensitive methods
for detection of superoxide in vascular tissue (3, 4, 16,
20, 21, 30). The use of hydroethidine is advantageous because it
provides additional insight regarding localization of superoxide within
the vascular wall (20, 21). On the basis of previous
studies, we hypothesized that adventitia and possibly endothelium might
be major sources of superoxide in aortas of R+/A+ mice. Although
ethidium bromide fluorescence was higher in those components of the
vessel wall, increases in superoxide were also observed in vascular
muscle in R+/A+ mice. This finding is in contrast with previous studies
in which acute (6-7 days) infusion of angiotensin II was
associated with selective increases in superoxide in endothelium and
adventitia only or smooth muscle only (2, 21, 24). These
differences may reflect the fact that overexpression of human
angiotensinogen and human renin in R+/A+ mice is both systemic and
lifelong. Thus there may be spatial and temporal differences in
production and/or localization of superoxide in R+/A+ mice. There may
also be differences in the mechanisms that lead up to increased
superoxide in the different models (acute vs. chronic). The finding
that vascular function in R+/A+ mice could be improved but not
completely normalized with Tiron suggests that other mechanisms, in
addition to superoxide, may be involved in the chronic model.
In summary, the results of the present study strongly support a role
for increased superoxide in producing vascular dysfunction in
hypertensive mice that express both human renin and human
angiotensinogen transgenes. Enhanced superoxide contributed to
diminished endothelium-dependent and nitric oxide-mediated relaxation,
because a scavenger of superoxide restored responses to acetylcholine
and nitric oxide toward normal. Although the present study did not
directly attempt to identify the enzymatic source responsible for the
increase in vascular superoxide, preliminary studies suggest that an
increase in NAD(P)H oxidase may be involved. The findings also suggest
that R+/A+ mice will be a useful model to further examine mechanisms of
vascular dysfunction during hypertension.
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ACKNOWLEDGEMENTS |
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We thank Pamela K. Tompkins for technical assistance with the hydroethidine assay.
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FOOTNOTES |
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This work was supported by National Institutes of Health Grants NS-24621, HL-38901, HL-48058, HL-55006, HL-61446, and HL-62984 (to F. M. Faraci and C. D. Sigmund), Individual National Service Research Awards HL-10237 and HL-10425 (to S. P. Didion and M. J. Ryan, respectively), and National American Heart Association Scientist Development Award 0230327N (to S. P. Didion).
Address for reprint requests and other correspondence: F. M. Faraci, Dept. of Internal Medicine, E315-GH, Univ. of Iowa College of Medicine, Iowa City, IA 52242-1081 (E-mail: frank-faraci{at}uiowa.edu).
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. Section 1734 solely to indicate this fact.
June 20, 2002;10.1152/ajpheart.00079.2002
Received 25 February 2002; accepted in final form 17 June 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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) and the presence (1 mM; 
)
of diethyldithiocarbamate (DETC) in RA
P < 0.05 vs. respective control.
