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Departments of Internal Medicine and Pharmacology, The Cardiovascular Center, University of Iowa, and Veterans Affairs Medical Center, Iowa City, Iowa 52246
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Previous studies have
demonstrated that responses to endothelium-dependent vasodilators are
absent in the aortas from mice deficient in expression of endothelial
nitric oxide synthase (eNOS 
/ mice), whereas responses in the
cerebral microcirculation are preserved. We tested the hypothesis that
in the absence of eNOS, other vasodilator pathways compensate to
preserve endothelium-dependent relaxation in the coronary circulation.
Diameters of isolated, pressurized coronary arteries from eNOS /,
eNOS heterozygous (+/), and wild-type mice (eNOS +/+ and C57BL/6J)
were measured by video microscopy. ACh (an endothelium-dependent
agonist) produced vasodilation in wild-type mice. This response was
normal in eNOS +/ mice and was largely preserved in eNOS / mice.
Responses to nitroprusside were also similar in arteries from eNOS +/+, eNOS +/, and eNOS / mice. Dilation to ACh was inhibited by NG-nitro-L-arginine, an inhibitor of
NOS in control and eNOS / mice. In contrast,
trifluoromethylphenylimidazole, an inhibitor of neuronal NOS (nNOS),
decreased ACh-induced dilation in arteries from eNOS-deficient mice but
had no effect on responses in wild-type mice. Indomethacin, an
inhibitor of cyclooxygenase, decreased vasodilation to ACh in
eNOS-deficient, but not wild-type, mice. Thus, in the absence of eNOS,
dilation of coronary arteries to ACh is preserved by other vasodilator mechanisms.
nitric oxide synthase; acetylcholine; cyclooxygenase
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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SINCE THE DISCOVERY THAT ENDOTHELIUM releases nitric oxide (NO) to produce vasodilation, numerous studies have attempted to examine the role of NO from the different isoforms of NO synthase (NOS) in blood vessels. The expression of NOS isoforms [endothelial (eNOS), neuronal (nNOS), and inducible (iNOS)] is regulated differentially depending on the tissue type and physiological versus pathophysiological conditions. Identification of the role of NOS isoforms involved in the regulation of vascular function has been dependent on the use of pharmacological inhibitors. Although the use of inhibitors of the different NOS isoforms potentially will provide insight into the contribution of NO from different sources, interpretation of these studies must be made with caution, because most agents inhibit all forms of NOS. Currently, there are no selective inhibitors of eNOS.
Development of genetic models with altered expression of genes encoding
the different NOS isoforms allows more precise studies of the role of
NO in the regulation of vascular tone. Studies of both the aorta and
pulmonary and carotid arteries from eNOS-deficient mice (eNOS /
mice) have demonstrated that NO derived from eNOS is the primary
mediator of relaxation to ACh and A-23187, because responses to these
agonists were absent in these vessels from eNOS / mice (9,
16, 22, 24, 38). NO derived from eNOS is not mandatory for
responses to ACh in all vascular beds, however. In cerebral arterioles
of eNOS / mice, dilation to ACh was normal but mediated by other
mechanisms (26, 27). These differences in responses of
vascular tissue to ACh in eNOS / mice may reflect differences in
the contribution of NO in mediating responses or the ability of other
vasodilator mechanisms to compensate in the face of eNOS deficiency.
Previous studies from our laboratory have demonstrated that in genetic
models of hypercholesterolemia, responses of coronary arteries to ACh
are preserved despite impaired responses of aorta (2, 25).
Results from those studies suggest that the coronary circulation is
resistant or able to compensate in the presence of a risk factor for
vascular disease. The first objective of the present study was to test
the hypothesis that responses to ACh are preserved in coronary arteries
from eNOS / mice. We previously demonstrated that responses of
coronary arteries from normal mice to ACh are mediated primarily by NO
(25). To determine the role of NO derived from eNOS in
responses of coronary arteries to ACh, we measured changes in diameter
of isolated, pressurized segments of coronary arteries from wild-type
control mice, eNOS heterozygote mice (eNOS +/ mice), and eNOS /
mice with video microscopy. The second goal of this study was to test
the hypothesis that nNOS or cyclooxygenase compensates for the loss of
eNOS and mediates responses to ACh, the classic endothelium-dependent agonist.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals.
The animal protocol used in these experiments was reviewed and approved
by the University of Iowa Animal Care and Use Committee. Three groups
of mice were studied: wild-type control mice (C57BL/6J or eNOS +/+
littermates), eNOS heterozygous mice (eNOS +/), and homozygous
eNOS-deficient mice (eNOS /). These mice were originally generated
as a hybrid of 129 × C57BL/6J (35). Mice used in
this study were derived from three to four generations of backcross breeding to C57BL/6J mice. Mice were fed regular chow, and water was
available ad libitum. The ages of mice in the different groups were similar.
, and eNOS /
mice was accomplished as described previously (9, 24, 35).
General preparation.
Mice (40 males and 51 females) were heparinized and anesthetized with
pentobarbital sodium (75-100 mg/kg ip) or 
-chloralose (300-400 mg/kg ip). Hearts were rapidly removed and placed in cold
Krebs buffer consisting of (in mM/l) 118.3 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgSO4, 1.2 KH2PO4, 25 NaHCO3
, and 11 glucose. Left anterior descending or left circumflex coronary arteries
from the left ventricle (62-207 µm in diameter) were isolated
from myocardium under a microscope, placed in an organ chamber filled
with cold Krebs, cannulated with dual micropipettes, and secured with
10-0 monofilament suture. The organ chamber (20 ml) was
continuously circulated with Krebs solution bubbled with 20%
O2, 5% CO2, and 75% N2. Vessels
were pressurized to 40 mmHg under no-flow conditions using two
reservoirs filled with Krebs solution. Images of microvessels were
displayed on a video monitor using a microscope connected to a camera.
An electronic video dimension analyzer measured luminal diameter at
steady state. The distending pressure of the vessels was measured with
a pressure transducer connected to a sidearm of the cannula connected
to one of the micropipettes. Vessels were allowed to equilibrate for 60 min before study. Viability of the vessels was assessed as a minimum of
30-50% constriction in response to 100 mM KCl from resting diameter.
Protocols.
Vessels segments were preconstricted with the thromboxane mimetic
U-46619 (9,11-dideoxy-11a,9a-epoxy-methanoprostaglandin F2
; 7~17 × 108 M) to 30-60%
of the initial vessel diameter. Cumulative dose-response curves to ACh
(109-105 M) were performed. At the
completion of the dose-response curve, nitroprusside (10 µM) or
papaverine (200 µM) was added to the bath. To compare responses of
vascular smooth muscle in arteries from wild-type, eNOS +/, and eNOS
/ mice, cumulative dose-response curves to nitroprusside
(109-105 M) were performed. To
determine the role of NO in responses of coronary arteries to ACh,
dose-response curves to ACh were performed in the presence of
NG-nitro-L-arginine
(L-NNA, 10 or 100 µM), an inhibitor that is not specific
for a single isoform of NOS. The concentrations of L-NNA
were chosen on the basis of previous experiments (2, 9, 16, 24,
38). To determine the role of cyclooxygenase in responses of
coronary arteries to ACh, dose-response curves to ACh were performed in
the presence of indomethacin (10 µM), an inhibitor of cyclooxygenase.
Finally, to determine the role of nNOS in responses of coronary
arteries to ACh, dose-response curves to ACh were performed in the
presence of trifluoromethylphenylimidazole (TRIM, 100 µM), an
inhibitor of nNOS (28). All inhibitors were added to the
organ bath for a minimum of 30 min before the dose-response curves were performed.
-chloralose.
Drugs. U-46619 was obtained from Biomol Research Laboratories and dissolved in 100% ethanol. ACh, nitroprusside, L-NNA, and indomethacin were obtained from Sigma Chemical and dissolved in distilled water. TRIM was obtained from RBI. All concentrations are final molar concentrations in the organ chamber.
Statistical analysis. Data are presented as percent change in diameter from the preconstricted diameter and are presented as means ± SE. One vessel was obtained per mouse, and n represents the number of mice per group. One dose-response curve was performed per vessel. Comparisons were made using a two-way ANOVA with repeated measures followed by Student-Newman-Keuls test to detect individual differences. A P < 0.05 was defined as being statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Responses of coronary arteries from wild-type mice.
Baseline diameters of coronary arteries from wild-type mice (eNOS +/+
littermates and C57BL/6J) were 118 ± 10 µm (n = 12). ACh produced dose-dependent dilation of coronary arteries from wild-type mice (maximal dilation to ACh was 49 ± 6%,
n = 12, Fig. 1). Dilation
in response to ACh was inhibited by 10 µM L-NNA (maximal dilation to ACh with L-NNA was 17 ± 4, n = 8, Fig. 2). A higher concentration of L-NNA (100 µM, n = 4)
inhibited over 90% of the maximal response, suggesting that dilation
to ACh in coronary arteries from wild-type mice is mediated
predominantly by NO. Vasodilation to nitroprusside (10 µM) was
similar in the absence and presence of L-NNA (control = 69 ± 7%, n = 6; L-NNA = 61 ± 17%, n = 4).
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-chloralose. Responses to ACh were similar whether
mice were anesthetized with pentobarbital sodium or -chloralose (Fig. 2). In addition, L-NNA (104 M)
inhibited over 90% of the response to the maximal dose of ACh whether
vessels were obtained from mice anesthetized with pentobarbital sodium
(n = 4) or -chloralose (n = 4, Fig.
2). Thus the contribution of NO in the response to ACh is similar in
coronary arteries obtained from mice anesthetized with pentobarbital sodium or -chloralose.
Responses of coronary arteries from eNOS +/ and eNOS / mice.
Baseline diameters of coronary arteries from eNOS +/ and eNOS /
mice were similar to diameters of wild-type mice (eNOS +/ mice = 120 ± 16 m, n = 6; eNOS / mice = 103 ± 9 µm, n = 9). Arteries from eNOS /
mice dilated in response to ACh (maximal dilation to ACh was 36 ± 7%) (Fig. 1), although slightly reduced compared with eNOS +/+ mice.
Dilation of arteries from eNOS +/ mice to ACh was similar to the
wild-type mice (maximal response to ACh at 10 µM was 59 ± 12%). Dilation of arteries from eNOS +/ (n = 7) and
eNOS / mice (n = 4) in response to nitroprusside was similar to wild-type mice (n = 5, Fig. 1). Thus,
although the aortas and carotid arteries from eNOS / mice do not
relax to ACh, coronary arteries from eNOS +/ and eNOS / mice
dilate in response to ACh.
/ mice, responses to ACh were measured
in the presence of L-NNA. Similar to arteries from wild-type mice, dilation of coronary arteries from eNOS / mice to
ACh was inhibited by L-NNA (maximal response to ACh was
13 ± 7%, n = 5; Fig.
3). Dilation of coronary arteries from
eNOS / mice to nitroprusside was not altered by L-NNA
(data not shown).
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Effect of TRIM on responses to ACh.
To determine the possible role of nNOS in mediating responses of
coronary arteries to ACh, dose-response curves were performed in the
presence of TRIM, a selective inhibitor of nNOS (13, 14,
28). In arteries from wild-type mice, TRIM had no effect on
dilation in response to ACh (maximal response to ACh was 50 ± 16%, n = 4, Fig. 4). In
contrast, in arteries from eNOS / mice, dilation in response to ACh
was inhibited by TRIM (maximal response to ACh was 18 ± 8%,
n = 4, Fig. 4). TRIM had no effect on dilation of
coronary arteries from eNOS +/+ or eNOS / mice in response to
papaverine (data not shown). These findings suggest that in coronary
arteries from eNOS / mice, dilation to ACh is dependent on activity
of nNOS.
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Effect of indomethacin on responses to ACh.
To determine the role of cyclooxygenase in responses of coronary
arteries to ACh, dose-response curves were performed in the presence of
indomethacin (10 µM). In arteries from wild-type mice, dilation in
response to ACh was not significantly altered by indomethacin (maximal
response to ACh was 59 ± 10%, n = 6) (Fig.
5). In contrast to responses in eNOS +/+
mice, dilation of coronary arteries from eNOS / mice in response to
ACh was decreased by indomethacin (maximal response to ACh at 10 µM
was 4 ± 4%, n = 6) (Fig. 5). Indomethacin had no
effect on dilation of coronary arteries from eNOS +/+ or eNOS /
mice to papaverine (data not shown). These findings suggest that in
coronary arteries from eNOS / mice, dilation in response to ACh is
dependent in part by activity of cyclooxygenase.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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There are several major findings in this study. First, deletion of
a single copy of the gene for eNOS (in eNOS +/ mice) had no
significant effect on responses of coronary arteries to ACh. Dilation
of coronary arteries from eNOS / mice in response to ACh was
largely preserved. The latter results are in marked contrast to reports
that responses to ACh are absent in the aortas and pulmonary and
carotid arteries from eNOS / mice (9, 16, 24, 38).
Second, dilation of coronary arteries from wild-type mice to ACh was
mediated very predominantly by NO. This finding confirms our previous
study in which dilation of coronary arteries from C57BL/6J mice in
response to ACh was inhibited markedly by L-NNA or an
inhibitor of soluble guanylate cyclase (25). Third, in contrast to wild-type mice, dilation of coronary arteries from eNOS
/ mice in response to ACh was inhibited by either indomethacin or
TRIM, suggesting that responses to ACh were dependent on activity of
cyclooxygenase and nNOS. These inhibitors had no effect on dilator
responses of coronary arteries from wild-type mice, indicating selectivity of the inhibitory effect in eNOS / mice. Thus, unlike other vascular tissue (9, 16, 22, 24, 38), in the absence of eNOS, other vasodilator pathways compensate to maintain near-normal coronary arterial function.
Reactivity of normal coronary arteries.
In a previous study from our laboratory, we examined mechanisms of
vascular reactivity of coronary arteries from normal mice. Depending on
species, organ, or location within the vascular tree, endothelium-dependent relaxation to ACh can be mediated by NO, prostaglandins, or endothelium-derived hyperpolarizing factors (40). Results of the present study confirmed and extended
our previous finding that in coronary arteries from normal mice,
dilation to ACh is primarily mediated by NO (25). In the
present study, indomethacin and TRIM did not alter dilation of coronary
arteries from wild-type mice to ACh, suggesting cyclooxygenase and nNOS are not involved in the response. Responses to ACh in mouse coronary arteries are similar to responses in the aortas, carotid, and pulmonary
arteries and cerebral arterioles that are largely mediated by NO in
normal mice (2, 9, 26, 27, 37, 38). These findings are
also consistent with studies in both experimental animals and humans in
which NO was found to be the primary mediator of responses to
endothelium-dependent agonists (8, 11, 12, 21, 23, 24,
33). Because vasodilation to ACh was inhibited by ~90% by an
inhibitor of NOS (present study) or
1H-(1,2,4)oxadiazolo(4,3-)quinoxalin-1-one, an inhibitor of
soluble guanylate cyclase (25, 29-31), these findings
suggest that other vasodilator mechanisms play a very minimal role in
this response in normal murine coronary arteries. These findings are
similar regardless of which anesthetic is used.
Role of eNOS in dilation to ACh.
Several studies have demonstrated abnormal vascular responses in
arteries isolated from mice deficient in the expression of the gene for
eNOS (4, 9, 16, 22, 24, 38). In the aortas and carotid and
pulmonary arteries from eNOS / mice, relaxation in response to ACh
was absent (4, 9, 16, 22, 24, 38). Thus studies of aorta
and other large arteries from normal and eNOS / mice have provided
direct evidence that release of NO from eNOS is the primary mechanism
of relaxation to ACh.
/ mice. These results are surprising, because acute inhibition of
NOS significantly attenuated dilation to ACh in both our previous study
(25) and in the present study. Because acute inhibition of
NOS significantly attenuated dilation to ACh, we concluded that
responses to ACh are primarily mediated by NO under normal conditions.
However, studies of coronary arteries from eNOS / mice suggest that
in a state of chronic eNOS deficiency, other vasodilator pathways can
compensate for the loss of eNOS. We assumed that responses to ACh are
endothelium dependent but cannot exclude the possibility that
nonendothelium-dependent mechanisms may be contributing to responses in
eNOS / mice.
Role of cyclooxygenase in dilation to ACh.
While the present study was underway, a study of isolated perfused
hearts was published that suggested that vasodilation to ACh was
preserved in eNOS / mice (10). However, in contrast to
the present study, ACh-induced vasodilation in both normal and eNOS
/ mice was dependent (in part) on activity of cyclooxygenase (10). Flow-mediated dilation of skeletal muscle arterioles
is also, in part, dependent on activity of cyclooxygenase in normal mice, but in eNOS / mice, the response to flow is entirely mediated by a cyclooxygenase-dependent mechanism (39). Dilation to
ACh in the present study was dependent on activity of cyclooxygenase only in eNOS / mice. Inhibition of cyclooxygenase had no effect on
responses to ACh in coronary arteries from wild-type mice. This
observation is important because it demonstrates that the effects of
indomethacin on responses to ACh in eNOS / mice were selective.
This difference in the role of cyclooxygenase in mediating responses to
ACh may be related to differences in the segment of vasculature studied
in the different preparations in the present study and the previous
study. In the present study, we measured responses of isolated coronary
arteries from mice. Vasodilator responses to intravascularly
administered ACh in an isolated perfused Langendorff preparation may
reflect responses of more distal vessels in the mouse heart. In other
species, 100-µm vessels (similar in size to mouse coronary arteries
used in these experiments) contribute to the control of vascular
resistance (5). The distribution of microvascular
resistance in the mouse heart is not known.
Role of nNOS in dilation to ACh.
In addition to the coronary circulation, responses to ACh are preserved
in at least some other vascular beds in eNOS / mice. ACh also
produces dilation of cerebral arterioles in eNOS / mice similar to
responses in normal mice (26, 27, and our unpublished observations).
Similar to the present study, dilation of cerebral arterioles in eNOS
/ mice to ACh was inhibited by L-NNA (27). In addition, responses of cerebral arterioles to ACh in eNOS / mice
were blocked by an inhibitor of nNOS (7-nitroindazole)
(26). Thus Meng et al. (26, 27) suggested
that vasodilation to ACh is mediated by nNOS in eNOS / mice. These
findings suggest that responses of cerebral and coronary vessels in
eNOS / mice to ACh are likely because of a compensatory mechanism
expressed in response to chronic eNOS deficiency. Although inhibition
of nNOS (7-nitroindazole) attenuated dilation to ACh in eNOS /
mice, effects of indomethacin were not tested in the previous studies of cerebral arterioles (26, 27).
/ mice. These data suggest that during
complete eNOS deficiency, dilation to ACh is mediated by nNOS. Our
finding that a selective inhibitor of nNOS (TRIM) abolished dilation to
ACh in coronary arteries from eNOS / mice is consistent with the
studies of Meng at al. (26) in cerebral arterioles
from the same mice. The coupling between ACh and production of NO by
nNOS in the coronary circulation is unknown, and additional studies
will be needed to examine expression and mechanisms of activation of
nNOS in coronary arteries from eNOS / mice. Although one approach
to this question would be to examine expression of nNOS by Northern or
Western blotting, the small size of the mouse coronary arteries makes
such measurements unrealistic or at least extremely difficult.
Because the conclusion related to nNOS in this study is based largely
on the findings obtained with TRIM, it is important to consider the
specificity of this inhibitor. Both TRIM and 7-nitroindazole are known
to be effective inhibitors of nNOS when used in vivo and in vitro
(28). In vitro, however, 7-nitroindazole also inhibits eNOS (28). In contrast, TRIM does not inhibit eNOS
(13, 28), and TRIM did not inhibit responses to ACh in
vessels from wild-type mice in the present study. Although TRIM has
some inhibitory effect on iNOS (13, 28), iNOS is not
present in blood vessels normally, and we are not aware of any data
suggesting that iNOS is upregulated in eNOS / mice. More
importantly, TRIM was used to test the role of NOS in responses to ACh,
which is a calcium-dependent, receptor-mediated response. Activity of
iNOS is calcium independent and is not activated by receptor-mediated
stimuli such as ACh. Thus TRIM appears to be the best available
inhibitor to examine the role of nNOS in responses of vessels from eNOS
/ mice.
Although there is little evidence for expression of nNOS in blood
vessels (in the endothelium or vascular smooth muscle) under normal
conditions, nNOS expression may occur in vessels in some disease
states. For example, nNOS is expressed in vascular muscle from
spontaneously hypertensive rats (3) and in atherosclerotic vessels (including humans) (41). Collectively, these
studies suggest that in disease states associated with decreased
expression or activity of eNOS (or NO), expression of nNOS may occur.
The present results in eNOS / mice are consistent with this concept.
Responses of coronary arteries from eNOS / mice to ACh were
inhibited by indomethacin or TRIM. These findings suggest an interaction between cyclooxygenase and nNOS in the response to ACh in
coronary arteries from eNOS / mice. Interactions between cyclooxygenase and NOS have been described in several studies but are
very complex and not well defined particularly in blood vessels. For
example, a similar interaction may be involved in the cerebral vascular
response to hypercapnia where indomethacin or inhibitors of nNOS
attenuate increases in cerebral blood flow (17, 18). In
the coronary and renal circulation, there is also evidence that acute
or chronic inhibition of NOS enhances the role of cyclooxygenase in the
regulation of vascular resistance (19, 32, 34) and
stimulates cyclooxygenase production of vasodilator prostaglandins
(1, 15, 29). In the coronary circulation of humans with
atherosclerosis or coronary risk factors, inhibitors of both NOS or
cyclooxygenase greatly reduce flow-mediated responses (an
endothelium-dependent response) (7). Our data are
consistent with other studies, including in humans, suggesting a
potential interaction between cyclooxygenase and NOS. The mechanism that accounts for this interaction has not been determined. However, cyclooxygenase is heme containing, and NO can interact with
heme-containing proteins and increase cyclooxygenase activity
(19, 20, 36). Thus interactions between products of
cyclooxygenase and NOS involved in regulating vascular responses have
been described, but the mechanisms involved in this interaction are unknown.
In summary, we demonstrated that, in both eNOS +/ and eNOS
/ mice, responses of coronary arteries to ACh are largely
preserved. In coronary arteries from wild-type mice, dilation to ACh is
mediated primarily by NO and not cyclooxygenase or nNOS. In contrast,
in coronary arteries from eNOS / mice, dilation to ACh appears to
be dependent on activity of nNOS and/or cyclooxygenase. The data
suggest that the coronary circulation has the ability to compensate for
the loss of normal vasodilator mechanisms.
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ACKNOWLEDGEMENTS |
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We acknowledge Dr. Curt Sigmund and the University of Iowa Transgenic Core for genotyping the mice used in these studies.
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FOOTNOTES |
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This work was supported by grants from the National Institutes of Health (HL-39050, HL-38901, NS-24621, HL-62984) and a grant from the American Heart Association. K. G. Lamping and F. M. Faraci are Established Investigators of the American Heart Association.
Address for reprint requests and other correspondence: K. G. Lamping, Medical Services (111), VA Medical Center, 601 Highway 6 West, Iowa City, IA 52246 (E-mail: klamping{at}blue.weeg.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.
Received 7 September 1999; accepted in final form 12 May 2000.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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diameter) of coronary arteries
from normal mice [endothelial nitric oxide synthase (eNOS) +/+ and
C57BL/6J], eNOS heterozygous (eNOS +/
