(Circulation. 1999;99:2951-2957.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Exercise Improves Flow-Mediated Vasodilatation of Skeletal Muscle Arteries in Rats With Chronic Heart Failure
Role of Nitric Oxide, Prostanoids, and Oxidant Stress
From the Department of Pharmacology, VACOMED, Rouen University Medical School, Rouen, France.
Correspondence to C. Thuillez, MD, PhD, Service de Pharmacologie, CHU de Rouen, 76031 Rouen Cedex, France. E-mail Christian.Thuillez{at}chu-rouen.fr
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Abstract |
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Background—Flow-mediated dilatation (FMD) of the peripheral arteries may be impaired in chronic heart failure (CHF), and this could contribute to the increased peripheral resistance and exercise intolerance that occur with this disease. Physical exercise improves the FMD of large conduit arteries in CHF, but whether a similar impairment also occurs in smaller arteries is unknown. The mechanisms of the changes in FMD after CHF or exercise are also unknown.
Methods and Results—FMD was assessed in isolated, perfused, and
preconstricted gracilis muscle arteries from sham-operated rats or CHF
rats (coronary artery ligation) who were either sedentary or
exercised (30-minute swimming period twice a day for 10 weeks, starting
7 days after ligation). In animals with hemodynamic and
echographic signs of CHF, FMD was abolished and converted into
vasoconstriction (percent change in diameter after 370 µL/min flow:
sham, 42±5%; CHF, -4±3%; P<0.05). Exercise
partially restored FMD (18±3%; P<0.05 versus CHF). In
sham rats, FMD was abolished by the nitric oxide–synthase
inhibitor
N
-nitro-L-arginine (L-NA) but
unaffected by the cyclooxygenase
inhibitor diclofenac or the free radical scavenger
N-(2-mercaptopropionyl)-glycine (MPG). In arteries from sedentary CHF
rats, FMD was not modified by L-NA, but it was partially restored by
diclofenac or MPG. In exercised CHF rats, FMD was abolished by L-NA and
only moderately improved by diclofenac or MPG. Likewise,
endothelial nitric oxide synthase mRNA expression
(determined by reverse transcription polymerase chain reaction at the
level of the gracilis muscle) was reduced by CHF, and this was
prevented by exercise.
Conclusions—CHF abolishes the FMD of small arteries by impairing the nitric oxide pathway, increasing oxidant stress, and releasing a prostanoid-contracting factor. Exercise partially restores FMD by increasing expression of endothelial nitric oxide synthase and preventing the production of vasoconstrictor prostanoids and free radicals. Such restoration of FMD might contribute to the increase in exercise capacity after physical exercise in CHF.
Key Words: exercise • dilatation • heart failure • muscle, skeletal • prostaglandins • nitric oxide synthase
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Introduction |
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Exercise capacity is reduced in patients with chronic heart failure (CHF) because of modifications in the complex interplay of cardiac, systemic, and/or local vascular mechanisms.1 2 3 A reduced increase of nutrient blood flow in response to a given level of exercise, caused by the impairment of the dilator response of small skeletal muscular arteries, can explain this diminished exercise capacity. Furthermore, physical exercise augments exercise capacity and increases limb blood flow during exercise in patients with CHF.4
Recent in vivo4 5 and in vitro6 7 8 studies show that CHF induces a marked reduction in the production and/or release of endothelium-derived vasodilator factors, such as nitric oxide (NO), in response to acetylcholine. However, whether CHF also affects the release of NO induced by a more physiological stimulus, such as flow (ie, flow-mediated vasodilatation) at the level of resistance arteries, is largely unknown. Moreover, although impaired endothelium-dependent vasodilatation may simply be the consequence of decreased production of NO, other factors may also contribute, such as oxygen-derived free radicals or prostanoids. However, the relative contribution of these different factors in the impaired flow-mediated vasodilatation observed in heart failure is unknown.
The impaired endothelium-dependent vasodilatation of the peripheral resistance arteries observed in CHF may be related in part to long-term adaptations secondary to the long-term decrease in blood flow.9 10 Thus, it is possible that repeated increases in blood flow, as is the case with physical exercise, may improve flow-mediated vasodilatation in CHF. Indeed, exercise increases flow-dependent, NO-mediated vasodilatation of peripheral conduit arteries in human CHF.11 However, whether a similar improvement occurs at the level of smaller peripheral arteries is unknown. Moreover, the relative roles of NO and of other vasoactive factors in the changes induced by exercise are also largely unknown.
Thus, we investigated in a rat model of CHF whether physical exercise affects flow-mediated dilatation of peripheral muscular arteries; we also investigated the relative roles of NO, prostanoids, and oxidant stress in these changes.
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Methods |
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Animals and Treatment
Myocardial infarction was produced in 10-week-old male Wistar rats (Charles River, Saint Aubin Les Elbeuf, France) by left coronary artery ligation using the method of Pfeffer et al12 that has been modified in our laboratory.13 14 Seven days after ligation, rats with CHF were randomized into 2 groups (either sedentary or exercised). Physical training consisted of a 30-minute swimming period in the morning (in a 150-L water tank; water temperature, 27°C to 28°C), which was followed at least 6 hours later by a second 30-minute swimming period. Swimming sessions were supervised to avoid floating and/or clinging of individual animals. Sedentary rats were not placed in the water tank. This protocol was applied 5 days a week for 10 weeks, starting 7 days after ligation.
Hemodynamic Parameters Assessed in
Anesthetized Rats
After 10 weeks, rats were anesthetized with
pentobarbital (50 mg · kg-1 IP). The
right carotid artery and the right external jugular vein were
cannulated with a micromanometer-tipped catheter
(SPR 407, Millar Instruments) and advanced into the aorta and thoracic
vena cava, respectively, to record arterial and central
venous pressures. The aortic catheter was then advanced into the left
ventricle (LV) to record LV pressure and its maximal rate of rise
(dP/dtmax). All tracings were recorded on a
physiological recorder (Windowgraph, Gould,
France). At the end of the hemodynamic studies, rats
were euthanized, and the heart was taken out, weighed, and placed in
Bouin fixative. Cardiac collagen density was then assessed, as
described previously,3 15 in the viable tissue (ie,
septum) of the LV. Perivascular collagen was excluded from the
measurement.
Transthoracic Doppler echocardiographic studies were performed as previously described14 16 using an echocardiographic system equipped with a 7-MHz transducer (Acuson 128 XP/10C). Measurements were performed by a single observer (P.M.) who was blinded to prior results and treatment groups.
In Vitro Vascular Studies
After assessment of the hemodynamic
parameters, an artery of the gracilis muscle was carefully
isolated under a dissection microscope and transferred to an
arteriograph filled with oxygenated (95%
O2 and 5% CO2), PSS
composed of (in mmol/L): NaCl 119, NaHCO3
24, KCl 4.7, KH2PO4 1.18,
MgSO4·7H2O 1.17,
CaCl2 1.6, and glucose 5.5. The artery was
mounted on 2 glass micropipettes (Living Systems Instrumentation). Both
proximal (inflow) and distal (outflow) micropipettes were connected
with silicone tubing to a pressure-servo syringe system. The vessel
segments were stretched to their in vivo length, and intraluminal
pressure was set to 30 mm Hg, as described
previously.3 17
Experimental Procedure
After the equilibration period, the pressurized arteries were
preconstricted by adding phenylephrine, after which,
cumulative concentrations of acetylcholine (10-9
to 10-4 mol/L) were added at 0 flow. The vessels
were then washed and again preconstricted with
phenylephrine to assess basal flow-mediated dilatation
(FMD). For this purpose, perfusate flow rate was increased from
0 to 370 µL · min-1 in a stepwise
manner by changing the inflow and outflow pressures. Each flow rate was
maintained for 
2 minutes to allow the vessel to reach steady-state
diameter. Three separate series of experiments were performed in
arteries obtained from different rats; in these experiments, the roles
of prostaglandins, NO, and free radicals were assessed
using the cyclooxygenase inhibitor
diclofenac (10-5 mol/L), the NO synthase
inhibitor
N-nitro-L-arginine
(L-NA; 10-5 mol/L) or the free radical scavenger
N-(2-mercaptopropionyl)-glycine (MPG;
10-5 mol/L), respectively. In each vessel, FMD
was assessed twice: first in the absence of inhibitor
(basal values) and then 20 minutes after the administration of the
corresponding inhibitor. Preliminary experiments showed
that repetitions of the flow-diameter curves in the absence of
treatment led to similar responses, thus ruling out a time-related
effect.
At the end of each experiment, maximal vasodilatation was assessed by the response to sodium nitroprusside (10-4 mol/L) under zero-flow conditions.
Semiquantitative PCR
Total RNA was extracted from rat muscle using acid guanidinium
thiocyanate–phenol-chloroform extraction.18 Then, 4 µg
of total RNA were reverse transcribed in 30 µL (final volume) of a
reaction buffer made of the following (in mmol/L): Tris-HCl 30 (pH
8.3), DTT 10, KCl 85, MgCl2 3, and each dNTP 10
(each), as well as 80 U of RNAsin (Promega), 800 U of reverse
transcriptase (GIBCO BRL), and 8.3 pmol of random hexamer primer
(Pharmacia). The mixture was incubated for 60 minutes at 37°C and
then heated at 95°C for 5 minutes. Ten aliquots of the reverse
transcription (RT) product was used for the polymerase chain
reaction (PCR) amplification. This was added to 50 µL of PCR
mix containing 5 µL of 10x PCR buffer, 1 µL of dNTPs (2
mmol/L each), 1 µCi of 33P-dATP, 5 µL of MgCl
(2.25 mmol/L), 1.25 U of DNA Taq polymerase (Promega),
and 2 µL of 3' and 5' DNA-specific primers (100 mmol/L for
endothelial NO synthase [eNOS] and 50 mmol/L for
GAPDH [Bioprobe Systems]). Primers were chosen to have a GC
content of 40% to 60%. The primer sequences and the sizes of the
expected PCR products are shown in Table 1
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The number of PCR cycles was 30 for eNOS and 20 for GAPDH. PCR products were electrophoresed through 7.5% polyacrylamide gel. Molecular weight markers were from Pharmacia. Gels were stained in deionized water containing 0.5 mg/mL ethidium bromide, illuminated with UV light, and photographed using Polaroid films. They were measured by quantitative scanning densitometry of autoradiographs (Biocom).
Statistical Analysis
All reported values are given as mean±SEM. The responses to
acetylcholine and sodium nitroprusside and the responses to flow are
expressed as percentages of the reversal of the
phenylephrine-induced constriction. Differences between
the sham, sedentary, and exercised CHF rats, as well as the effect of
the pretreatment with L-NA, diclofenac, and MPG were determined using
ANOVA for repeated measurements (SYSTAT software, SPSS Inc).
Moreover, the hemodynamic,
echocardiographic, and morphometric
parameters in the sham, sedentary, and exercised CHF rats
were compared by t test or by ANOVA followed by a Tukey test
for multiple comparisons. Differences were considered significant at
the level P<0.05.
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Results |
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Mortality and Exclusions
A total of 94 rats (27 sham, 35 CHF[sedentary], and 32 CHF plus exercise [Ex]) were included in the study. During the treatment period, 8 sedentary and 6 exercised rats died. Furthermore, 9 animals were excluded from the study because of technical difficulties during dissection.
Hemodynamic Measurements in Anesthetized
Rats
Figure 1 illustrates the cardiac
hemodynamics and central venous pressure (CVP) measured
in anesthetized animals 10 weeks after ligation. As compared
with sham-operated animals, CHF decreased LV systolic pressure
(LVSP) and LV dP/dtmax and increased both LV
end-diastolic pressure (LVEDP) and CVP. Compared with
sedentary CHF rats, physical exercise did not modify LVSP and LV
dP/dtmax; however, exercise did significantly
reduce both LVEDP and CVP.
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P<0.05 vs
sedentary CHF rats (n=10 in each group).
Echocardiographic Studies
Ten weeks after surgery, exercise reduced the CHF-induced
increases in LV end-diastolic and systolic
diameters, as well as LV wall thickness (Table 2). Exercise also tended to improve LV
fractional shortening and posterior wall thickening. Compared with
sedentary rats with CHF, exercise also increased cardiac output,
cardiac index, and stroke volume.
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In Vitro Vascular Studies
The basal values of arterial diameter before or
after phenylephrine (preconstricted) were similar in the 3
groups (Table 3).
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Acetylcholine-Mediated Dilatation
Figure 2 illustrates the responses to
acetylcholine in the 3 groups. Compared with sham-operated animals, CHF
induced a moderate but significant impairment in the vasodilator
response to acetylcholine (maximal responses: sham, 81±3; CHF,
63±3%; P<0.05). Exercise normalized the dilator response
to acetylcholine (82±2%). Neither CHF nor exercise affected the
response to the NO donor sodium nitroprusside (Table 3
).
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) or CHF rats, either sedentary (•) or exercised (
). Results
are expressed as mean±SEM. *P<0.05 vs sham;
Flow-Mediated Dilatation
Figure 3 illustrates the changes in
arterial diameter in response to stepwise increases in
intraluminal flow at the baseline. In arteries isolated from sham
animals, increases in flow induced a progressive dilatation with a
maximum dilatation of 42±5% at 370 µL ·
min-1. CHF abolished FMD and converted it into a
vasoconstriction. This constrictor response was more marked at low
levels (at 17 µL · min-1, it was
-8±3%) than at high levels of flow (at 370 mL ·
min-1, it was -4±3%). Exercise restored a
significant degree of flow-mediated vasodilatation, and this effect was
observed at all levels of flow except the lowest. At the highest level
of flow (370 µL · min-1), the increase
in diameter was 18±3%. However, this vasodilator response remained
significantly lower than that obtained in the arteries of sham-operated
rats. Finally, in contrast to rats with CHF, pilot experiments showed
that exercise did not affect FMD in sham rats (370 mL ·
min-1: sedentary sham, 42±5%; exercised sham,
35±9%; n=7; P=NS).
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Mechanisms of Flow-Mediated Vasodilatation
Figure 4 illustrates the effects of the
NO synthase inhibitor L-NA on FMD in the 3 groups. In
arteries isolated from sham-operated animals, FMD was abolished by
L-NA. Indeed, at the highest value of flow (370 µL ·
min-1), L-NA reduced FMD from the basal value of
42±5% to 2±8% (P<0.05). In sedentary CHF rats, FMD was
not affected by L-NA (FMD at 370 µL ·
min-1 before and after L-NA: -4±3% and
1±2%, respectively). Similar to sham animals, the FMD of arteries
from exercised CHF rats was abolished by L-NA. Indeed, at the highest
value of flow tested, L-NA reduced FMD from 18±3% to 2±1%
(P<0.05).
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Figure 5 shows the effects of the
cyclooxygenase inhibitor diclofenac on
FMD in the 3 groups. In sham-operated animals, FMD was unaffected by
diclofenac (FMD at 370 µL · min-1
before and after diclofenac: 37±10% and 35±8%, respectively). In
contrast, in sedentary CHF rats, diclofenac partially restored
flow-induced dilatation (FMD at 370 µL ·
min-1 before and after diclofenac: -10±2% and
19±5%, respectively; P<0.05). Diclofenac also slightly
and nonsignificantly improved FMD in arteries from exercised CHF rats.
This effect seemed limited compared with that observed in sedentary CHF
rats (FMD at 370 µL · min-1 before and
after diclofenac: 12±1% and 19±3%, respectively).
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The effects of MPG on FMD are shown in Figure 6. MPG did not affect the responses obtained
in sham rats. In CHF rats, MPG abolished the flow-induced
vasoconstriction and reestablished a moderate degree of active
vasodilatation (FMD at 370 µL · min-1
before and after MPG: -9±6% and 6±3%, respectively;
P<0.05). MPG also slightly and nonsignificantly improved
FMD in arteries taken from exercised CHF rats (FMD at 370 µL ·
min-1 before and after MPG: 10±1% and 14±1%,
respectively). Again, this effect was less marked than in arteries from
sedentary CHF rats.
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Expression of eNOS
The effect of CHF or exercise on eNOS mRNA expression in the
gracilis muscle is shown in Figure 7. In
pilot experiments, we verified (by immunohistochemistry) that eNOS was
absent from the skeletal muscle and was confined to
endothelial cells (data not shown). eNOS mRNA
expression was significantly reduced in the CHF group, and it was
normalized by exercise (eNOS/GAPDH ratio: sham, 26±3; CHF,
10±3 [P<0.05 versus sham]; exercise, 21±4
[P<0.05 versus sedentary CHF and NS versus sham]).
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Cardiac Histomorphometry
Table 4 shows the values for infarct
size, scar length, scar surface, heart weight, body weight, heart
weight/body weight ratio, and collagen density in the noninfarted LV.
Infarct size, scar length, and the scar surface of animals euthanized
after 10 weeks were identical in sedentary and exercised CHF rats.
Compared with sham-operated animals, CHF induced significant increases
in heart weight, heart weight/body weight ratio, and LV collagen
density. Exercise did not modify heart weight, but it did decrease body
weight, and thus it increased the heart weight/body weight ratio.
Exercise also decreased LV collagen density.
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Discussion |
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The present study performed using the rat model of CHF induced by coronary artery ligation shows (1) that CHF abolishes FMD at the level of small peripheral arteries and unmasks a flow-mediated vasoconstriction. This alteration is mainly because of an altered release of bioactive NO, together with the release of a vasoconstrictor prostanoid. The altered release of NO is associated with a reduced expression of eNOS and with the production of reactive oxygen species, which are known to inactive NO. The study also shows (2) that physical exercise markedly increases FMD in CHF, both through an increased released of NO (associated with an increased eNOS expression and a decreased production of reactive oxygen species), and a decreased release of vasoconstrictor prostanoids.
In our experiments, 10 weeks after induction of myocardial infarction, the increase in LVEDP and CVP and the marked decrease in LVSP and LV dP/dtmax illustrated the presence of CHF. Moreover, echographic results showed marked LV dilatation and a decrease in fractional shortening, cardiac output, and stroke volume. In this context of severe CHF, we were also able to demonstrate significant beneficial cardiac effects of long-term exercise, both in terms of hemodynamics (reduced LVEDP and CVP, increased cardiac index) and in terms of remodeling (decreased LV dilatation assessed by echocardiography and decreased LV collagen density). Moreover, the fact that infarct size, which is the major determinant of the severity of CHF in rats,12 was similar in the 2 groups of rats suggests that the hemodynamic and vascular changes observed in our study are not caused by initial differences in the severity of CHF before the start of exercise but represent true effects of exercise.
In CHF, most of the evaluation of endothelial dysfunction has been performed using pharmacological stimuli such as acetylcholine.3 4 5 6 8 Indeed, in our experiments, we confirmed that CHF moderately reduced the vasodilator response to acetylcholine. However, apart from 1 study in human large peripheral arteries,11 no experiments have assessed the effect of CHF on the endothelial responses to changes in intraluminal flow, which represent a major physiological stimulus for endothelium-dependent vasodilatation. In this context, our experiments demonstrate that CHF abolished the dilator response to changes in intraluminal flow and even unmasked a flow-induced vasoconstriction. In human peripheral conduit arteries, CHF reduces but does not abolish flow-mediated vasodilatation.11 Although comparisons between the 2 studies must be performed with caution, they do suggest that CHF affects the endothelial function of small arteries more markedly than that of large conductance vessels, as previously demonstrated with acetylcholine.8
One of the major mechanisms by which CHF affects FMD is through a decrease of flow-induced, NO-mediated vasodilatation. Indeed, in arteries isolated from sham rats, the NO synthase inhibitor L-NA abolished FMD, but L-NA did not affect FMD in arteries isolated from CHF rats, suggesting that NO-mediated vasodilatation was absent in this situation.
The impaired NO-mediated vasodilatation could be caused either by a decreased production of NO or an increased degradation of NO, for example, secondary to an increased production of reactive oxygen species that are potent inactivators of NO.19 In our experiments, evaluation by RT-PCR of eNOS mRNA expression at the level of the gracilis muscle (in which eNOS expression is limited to endothelial cells) shows that CHF markedly reduces this expression; this is in agreement with previous results obtained at the level of the dog aorta.20 Likewise, the fact that a free radical scavenger improves FMD in arteries from rats with CHF but not in those isolated from sham rats suggests that CHF is indeed associated with an increased production of reactive oxygen species. This is in agreement with recent human data showing that intra-arterial infusion of vitamin C improves brachial artery dilatation in response to hyperemia in humans with CHF, suggesting that oxidant stress is involved in impaired vasodilatation in this context.21 Taken together, our data suggest that the impaired NO-mediated response in CHF is due at least in part both to a decreased expression of eNOS and to an increased degradation of NO by reactive oxygen species. However, it is not known whether other factors contribute to this impairment, for example, changes in the transduction pathway linking shear stress to activation of NO synthase.
In the context of marked decrease of NO, long-term physical exercise partially restored FMD. In these arteries, FMD could be abolished by the NO-synthase inhibitor L-NA, suggesting that it is mediated by NO. Because the impaired eNOS mRNA expression that we observed in CHF was prevented by exercise, we suggest that the increased NO response after exercise is due, at least in part, to prevention of the impaired eNOS expression. In addition, the fact that the effect of MPG was attenuated in arteries from exercised CHF rats compared with those of sedentary CHF animals suggests that exercise also attenuates the production of reactive oxygen species, and this could also contribute to the increased NO-mediated responses through a reduced degradation of NO.
Several hypotheses could explain the modifications of eNOS expression after CHF or exercise. First, a long-term increase in flow (because of an arteriovenous fistula) is associated with increased endothelium-dependent relaxations to acetylcholine9 10 and with increased aortic eNOS expression.22 Thus, it is likely that the long-term decrease in tissue flow observed in our model of CHF (as indirectly demonstrated by the decreased cardiac output) is a major stimulus for decreased eNOS expression.23 In contrast, the increased tissue flow induced by exercise (which increased cardiac output in our experiments) is a trigger for the increased eNOS expression in this context. This hypothesis is also supported by recent experiments performed in dogs without CHF, in which long-term exercise increases eNOS expression and production of NO.24
Alternatively, changes in eNOS expression might reflect modifications
of eNOS mRNA stability. Indeed, tumor necrosis factor-
, which is
elevated in CHF,25 26 27 decreases eNOS expression by
shortening the half-life of mRNA.28 Furthermore, CHF may
be associated with local tissue hypoxia,29 which
reduces eNOS expression.30 Thus, in theory, both the
increased production of cytokines and the development
of hypoxia may contribute to altered eNOS expression in
CHF.
Our results with MPG indirectly suggest that increased oxidant stress may also contribute to the impaired NO-mediated responses in CHF. Because NO inactivates oxygen-derived free radicals, especially superoxide anions, it is possible that the reduced production of NO may by itself increase oxidant stress, as demonstrated in cultured endothelial cells after NO synthase inhibition.31 Alternatively, increased oxidant stress in CHF may be a consequence of the activation of the renin-angiotensin system, as angiotensin II may induce activation of reduced NADH/NAPDH oxidases, leading to severe endothelial dysfunction.32
In our experiments, the cyclooxygenase inhibitor diclofenac partially restored FMD in arteries from CHF rats, but it had no effect in arteries from sham animals. Thus, in addition to the decreased NO-mediated response, a concomitant production of a vasoconstrictor prostaglandin also contributes to impaired FMD and is probably responsible for the flow-induced vasoconstriction that was observed in this situation. A similar increased cyclooxygenase-dependent contraction has already been observed in spontaneously hypertensive rats.33 The fact that the effect of diclofenac was attenuated by exercise suggests that it also attenuates the production of vasoconstrictor prostanoids, and this could also contribute to improved FMD after exercise.
In conclusion, our study demonstrates that CHF abolishes flow-mediated vasodilatation of skeletal muscular arteries and unmasks a vasoconstrictor response. Long-term physical exercise partially restores flow-mediated vasodilatation. This impaired response seen in CHF is due both to decreased production of NO (associated with decreased eNOS expression and increased inactivation of NO by free radicals) and to the production of a vasoconstrictor prostanoid. The beneficial effect of physical exercise on FMD is related to an increase in eNOS mRNA expression, decreased oxidant stress, and a blunted release of the vasoconstrictor prostanoids. Changes in the FMD of such peripheral arteries may have important consequences, both in terms of local tissue perfusion and of exercise tolerance.
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Acknowledgments |
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This work was supported in part by a research grant from Institut de Recherches Internationales, Servier, France.
Received September 24, 1998; revision received March 9, 1999; accepted March 9, 1999.
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