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Section of Vascular Medicine, Divisions of 1 Cardiovascular Medicine and 2 Pediatric Cardiology, Stanford University, Stanford, California 94305
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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We tested
whether supplementation with L-arginine can augment aerobic
capacity, particularly in conditions where endothelium-derived nitric
oxide (EDNO) activity is reduced. Eight-week-old wild-type (E+) and apolipoprotein E-deficient mice (E
)
were divided into six groups; two groups (LE+ and
LE) were given L-arginine (6% in drinking
water), two were given D-arginine (DE+ and
DE), and two control groups (NE+ and
NE) received no arginine supplementation. At 12-16
wk of age, the mice were treadmill tested, and urine was collected
after exercise for determination of EDNO production. NE
mice demonstrated a reduced aerobic capacity compared with
NE+ controls [maximal oxygen uptake
(
O2 max) of NE = 110 ± 2 (SE) vs. NE+ = 122 ± 3 ml
O2 · min1 · kg1,
P < 0.001]. This decline in aerobic capacity was
associated with a diminished postexercise urinary nitrate excretion.
Mice given L-arginine demonstrated an increase in
postexercise urinary nitrate excretion and aerobic capacity in both
groups (O2 max of LE = 120 ± 1 ml
O2 · min1 · kg1,
P < 0.05 vs. NE;
O2 max of LE+ = 133 ± 4 ml
O2 · min1 · kg1,
P < 0.01 vs. NE+). Mice
administered D-arginine demonstrated an intermediate
increase in aerobic capacity in both groups. We conclude that
administration of L-arginine restores exercise-induced EDNO
synthesis and normalizes aerobic capacity in hypercholesterolemic mice.
In normal mice, L-arginine enhances exercise-induced EDNO
synthesis and aerobic capacity.
oxygen uptake; vascular reactivity; hypercholesterolemia; apolipoprotein E knockout; D-arginine; endothelium-derived relaxing factor
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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SKELETAL MUSCLE ARTERIOLES vasodilate in response to exercise to augment nutrient and oxygen delivery to working muscles (29, 33). Since its discovery as an endogenous vasodilator, the role of endothelium-derived nitric oxide (EDNO) in mediating this vasodilatory response to exercise has been investigated with conflicting results reported (7, 11, 13, 20, 23, 34). Our laboratory recently reported that EDNO contributes to exercise hyperemia and is a determinant of aerobic capacity in exercising mice (20). In that study, exercise was associated with increased blood flow to the hindlimb muscles and an acute increase in urinary excretion of nitrogen oxides (used as a measure of EDNO production; Ref. 3) after exercise. Both of these effects were prevented by administration of the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine. Furthermore, hypercholesterolemic mice manifest decreased excretion of urinary nitrates after exercise, reduced endothelial vasodilator function, and reduced aerobic capacity. These data suggest that conditions of reduced EDNO synthesis or activity (e.g., hypercholesterolemia) result in an inadequate exercise hyperemic response that is rate limiting to oxygen transport and exercise capacity. If so, L-arginine supplementation may improve exercise performance in these conditions.
The present study was performed to determine whether supplementation
with L-arginine would prevent the decline in aerobic capacity observed in hypercholesterolemic mice. In pilot studies, we
determined that the exercise capacity of wild-type (E+) and
apolipoprotein E-deficient mice (E) are the same at 8 wk
of age when the cholesterol levels of both strains are low. After 8 wk
of age, the cholesterol levels of E mice rise rapidly to
>1,000 mg/dl by 12 wk of age. At the same time, the principal measure
of exercise capacity, maximal oxygen uptake
(O2 max), declines to about 85% of
controls. This decline is associated with endothelial vasodilator
dysfunction and reduced urinary nitrate excretion. The present study
was designed with the intention of averting the impairment in aerobic
capacity associated with hypercholesterolemia through chronic
supplementation of L-arginine.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals.
Eight-week-old female E+ and E C57BL/6J mice
[Jackson Laboratories, Bar Harbor, ME, and Stanford Department of
Comparative Medicine (DCM)] were entered into experimental protocols
after a 1-wk period of acclimation in the housing facilities of the DCM. All mice were inspected before the study by the DCM veterinarian and monitored daily by DCM technicians and investigators. All experimental protocols were approved by the Administrative Panel on
Laboratory Animal Care of Stanford University and were performed in
accordance with the recommendations of the American Association for the
Accreditation of Laboratory Animal Care. All mice were housed three to
four per cage. They were maintained on a 12:12-h light-dark cycle and
given unlimited access to food and water for the duration of the study.
All mice were taught to run on a treadmill with shock-plate incentive
(Exer-4 Treadmill, Columbus Instruments, Columbus, OH) but were
otherwise confined to cages for the duration of the study.
mice were generated from targeted disruption of the
apolipoprotein E gene in the 129 embryonic stem cell line. Germ-line chimeras were mated and backcrossed for 10 generations with C57BL/6J wild-type mice (25).
Experimental protocol.
Eight-week-old E+ and E mice were divided
into six groups (Table 1): two groups
were supplemented with L-arginine (6% drinking water,
LE+; n = 16 and LE;
n = 16); two were administered D-arginine
(the optical isomer of L-arginine, which is not a
considered a substrate for NOS, 6% drinking water, DE+;
n = 8 and DE; n = 8); and
two received regular drinking water (NE+; n = 27 and NE; n = 24). The mice were kept
sedentary for 4-8 wk. At 12-16 wk of age, the mice were
treadmill tested in random order by an investigator blinded to the
identity of its group to measure indexes defining exercise capacity.
Because this study was designed to determine the effect of chronic
enhancement of EDNO production rather than an acute effect of arginine,
all water bottles containing arginine were replaced with regular water
48 h before treadmill testing. Urine was collected after treadmill
exercise for determination of urinary nitrogen oxides
(NOx). Mice were killed after treadmill testing by overdose
of methoxyflurane (Pitman-Moore, Mundelein, IL) inhalation anesthesia.
Blood was collected from the right atrium for measurement of serum
total cholesterol levels.
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Indexes of exercise capacity.
O2 max was defined as the plateau in
oxygen uptake despite increasing work intensity. In a few cases in
which a plateau was not reached, the
O2 max was approximated by the peak oxygen uptake attained by the animal before exhaustion. The running distance is the total distance run to exhaustion. The respiratory quotient (RQ) is carbon dioxide output divided by oxygen uptake at a
given time and is used as an indirect indicator of anaerobic work performance. RQ begins to rise after the anaerobic threshold is
attained and continues to rise with increasing anaerobic workload until
exhaustion (32). RQ at exhaustion was used as a measure of
the contribution of anaerobic work.
Treadmill testing. Each mouse was placed on a treadmill at a constant 8° angle enclosed by a metabolic chamber capable of measuring oxygen and carbon dioxide outflow once every minute (model CT-2, Columbus Instruments). After a 15-min period of acclimation, basal measurements were obtained over 7 min. The treadmill was then started at 10 m/min, and the speed was incrementally increased 1 m/min every minute until the mouse reached exhaustion. Exhaustion was defined as spending time on the shocker plate without attempting to reengage the treadmill within 10 s. Oxygen uptake, carbon dioxide production, and running distance to exhaustion data were collected and stored on hard disk (Oxymax software, Columbus Instruments).
Measurement of urinary nitrogen oxides.
On a day separate from treadmill testing, mice were treadmill-exercised
by a standardized protocol (22 min to a final treadmill speed of 32 m/min), thereby providing the same exercise stimulus for all mice. The
mice were then placed in metabolic chambers for postexercise urinary
nitrate collection. Metabolic chambers were constructed as described
previously (20). Urine was collected in test tubes
containing 100 µl of isopropyl alcohol submerged in ice water for the
duration of the 5-h collection period. Urine was centrifuged at 4,000 rpm for 5 min, and the supernatant was collected, diluted 1:9 in
distilled water, and stored at 
80°C for measurement of
NOx and creatinine.
and NO3 to NO,
which is then detected by the chemiluminescence apparatus after
reacting with ozone. Signals from the detector were analyzed by
computerized integration of curve areas. Standard curves for NaNO2/NaNO3 were linear over the range of 50 pM
to 10 nM. Urine creatinine was measured by the modified method of Slot
developed by Sigma Diagnostics (10).
Hematology and biochemistry.
Blood samples were collected at the time of death. These were
immediately centrifuged at 3,000 rpm for 15 min. The serum was separated and stored at 80°C until analysis. Total serum
cholesterol was analyzed using the enzymatic method of Allain et al.
(1) as developed by Sigma Diagnostics.
Data analysis. Four of the 99 mice died before study completion and were excluded from data analysis. Data are expressed as means ± SE. Comparisons of single means from multiple populations were made by one-factor univariate one-way ANOVA followed by Fisher's protected least significant difference. A P value <0.05 was accepted as statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Effect of hypercholesterolemia on aerobic capacity and nitric oxide
production.
The body weights of the NE+ and NE mice were
the same at the end of the study (Table
2). The cholesterol levels of the
NE mice were significantly elevated compared with
NE+ mice (1,073 ± 80 vs. 157 ± 13 mg/100 ml
serum, P < 0.0001). Similar to our previous report,
both indexes of aerobic capacity of the 12- to 16-wk-old
NE mice were reduced compared with NE+
controls (Fig. 1) (19).
O2 max of the NE mice was
89% (P < 0.001) that of NE+ mice, and
running distance was 77% (P < 0.005) that of
NE+ mice. Our laboratory has previously reported that
postexercise urinary nitrate levels are reduced in NE
compared with NE+ mice (20). Similarly, in the
present study, postexercise urinary nitrate levels were less in the
NE compared with the NE+ mice (157 ± 25 vs. 433 ± 100 pmol/mg creatinine) (Fig.
2).
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Effect of arginine on aerobic capacity and nitric oxide production.
Supplementation with L-arginine for 4-8 wk had no
effect on body mass or cholesterol level in either strain. Mice in both strains supplemented with L-arginine demonstrated an
increase in both indexes of exercise capacity. LE mice
measured a 9% increase in O2 max
(P < 0.05) and a 61% increase in running distance
(P < 0.0001) compared with NE. The
improvement in aerobic capacity was accompanied by a fivefold increase
in postexercise urinary nitrate excretion (156 ± 25 to 750 ± 145 pmol/mg creatinine, P < 0.05). Mice treated
with D-arginine exhibited a trend toward an improvement in
O2 max [7%, not significant (NS)]
and an intermediate improvement in running distance (39%,
P < .01). The D-arginine-treated mice also
had a trend toward an increase in postexercise urinary nitrate
excretion (61%, NS).
O2 max (P < 0.01) as
well as a trend toward an increase in running distance compared with
NE+. Postexercise urinary nitrate excretion also appeared
to increase with L-arginine supplementation of the
E+ strain (NS). DE+ mice exhibited little
improvement in O2 max but did manifest
a significantly greater running distance. DE+ mice also
trended toward an increase in postexercise urinary nitrate excretion.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The salient findings of this study are that administration of L-arginine normalizes exercise-induced EDNO synthesis and aerobic exercise capacity in hypercholesterolemic mice and somewhat unexpectedly enhances exercise capacity in normal mice as well. This study confirms our previous finding that hypercholesterolemic mice manifest a reduced aerobic exercise capacity compared with normocholesterolemic controls (20). The effect observed with L-arginine, together with our previous observations of reduced limb blood flow, exercise capacity, and postexercise nitrogen oxide excretion in both hypercholesterolemic animals and animals administered NG-nitro-L-arginine (20), indicates that not only exercise hyperemia but also exercise capacity depends on the integrity of the NOS pathway.
That exercise hyperemia is dependent on the integrity of the NOS pathway has been both supported and refuted by earlier studies. Persson et al. (24) showed that hyperemia in response to electrically stimulated contractions was unaffected by infusion of NOS inhibitor. Similarly, Wilson and Kapoor (34) reported that forearm exercise hyperemia in response to repetitive wrist flexion was unaffected by NOS inhibitor. In contrast, Dyke et al. (7) reported a diminution of forearm exercise hyperemia during prolonged handgripping exercises in humans with infusion of NOS inhibitor. Similarly, Hirai and colleagues (11) reported that exercise hyperemia in certain rat hindlimb muscles, as measured by delivery of radioactive microspheres, is dependent on EDNO release. Other studies suggest that EDNO is involved at low-intensity but not at high-intensity exercise (23) or is only partly responsible for exercise hyperemia because NOS inhibitors only partially reverse hyperemia (13).
That exercise capacity is dependent on the integrity of the NOS pathway is supported in the literature as well. For example, several investigators have shown that the endothelial dysfunction that occurs in heart failure can be reversed by measures that restore EDNO activity and, through this process, blood flow and exercise capacity are improved (9, 12, 14, 16, 26). Although these measures restore EDNO activity, they likely also act to improve cardiac function in heart failure, and this effect may also contribute to enhanced exercise capacity in these patients. In the present study, the hypercholesterolemic mice had evidence of impaired endothelial vasodilator dysfunction and EDNO activity but no evidence of impairment of cardiac function (as determined by organ chamber studies and cardiac histology, data not shown). Thus the effect of L-arginine was likely due to its ability to restore EDNO activity.
Our finding is consistent with the accumulating data indicating that supplemental L-arginine has a beneficial effect on exercise capacity in other conditions in which the NOS pathway is disturbed. Of particular note is the finding of increased maximum workload attained during treadmill testing before the onset of ST segment depression in patients with coronary artery disease (6). In this clinical condition, exercise capacity is restricted by flow-limiting stenoses and coronary vasomotor dysfunction. L-Arginine likely restores the vasomotor function sufficiently to improve blood flow and delay the onset of ischemia. L-Arginine infusion has also been shown to improve walking distance in patients with intermittent claudication (4). Similar to patients with coronary artery disease, exercise capacity of patients with claudication is limited by both atherosclerotic lesions and EDNO-mediated vasomotor dysfunction.
We were surprised to observe the effect that supplemental L-arginine had on the aerobic capacity of healthy mice. The magnitude of the increase on exercise capacity achieved by L-arginine was equivalent to that produced by exercise training mice for 2 h daily, 6 days/wk for 4 wk (22). Exercise training has been shown by Sessa and colleagues (27) to enhance EDNO activity. Our finding leads us to speculate that prolonged intense exercise may lead to a state of NOS impairment that becomes limiting to oxygen uptake and aerobic capacity. The mechanism of the impairment could be one or more of those proposed for vascular diseases (i.e., production of an endogenous inhibitor of NOS, increased superoxide generation, or depletion of L-arginine in the region of NOS) (21). Regardless of the mechanism, this finding could have important implications for the athlete.
Critique of methods. Several limitations to this study are worth noting. It was our intention to use the D enantiomer of arginine, which is not a substrate for NOS, as a negative control, and we were surprised to find a modest effect of the inactive enantiomer on exercise capacity. This fact might suggest that the actions of L-arginine on aerobic performance are mediated through mechanisms independent of the NOS pathway. Indeed, both enantiomers are known to stimulate growth hormone, insulin, and insulin-like growth factor-1 release (8, 15, 17, 31). Hormone activity was not measured in this study, and the possibility that chronic enhancement of these hormones affected exercise capacity in our study cannot be ruled out. These enantiomers may also have an unequal effect on substrate utilization during exercise; however, there was no difference in respiratory quotients between treatment groups either during rest or at exercise termination, suggesting that substrate utilization did not change.
An alternative explanation for this observation is that a sufficient quantity of D-arginine is capable of being racemized to L-arginine to have a pharmacological effect. In human and rat liver extracts, D-arginine is converted to urea and D-ornithine; however, a portion can be inverted to L-arginine (2). Although this is not usually a consideration in studies of acute administration, it should be regarded when D-arginine is given chronically and is supported in this study by the trends toward an increase in postexercise urinary nitrate excretion observed in both strains administered D-arginine. Racemization of D-arginine to L-arginine may also explain the discordant relationships of enhancedO2 max to enhanced running
distances observed in the normocholesterolemic mice. In our study, the
L-arginine-treated mice demonstrated an 8% increase in
O2 max with a similar increase in
running distance. In contrast, the D-arginine-treated mice
increased their O2 max no more than 2%
yet they increased their running distance by 30%. This observation
might be explained by an excessive production of nitric oxide in the
heavily L-arginine-supplemented mice. In addition to
promoting exercise hyperemia, nitric oxide plays a role in cardiac and
skeletal myocyte function. In these cells, a reduction in nitric oxide
stimulates, whereas excess nitric oxide uncouples, mitochondrial
respiration (5, 18, 28). Therefore, although vasodilation
and delivery of oxygen may be enhanced with moderate increases in
plasma L-arginine, excessive L-arginine
availability may reduce the efficiency of oxygen utilization by
myocytes. In our study, racemization may have been a rate-limiting step
to excessive L-arginine availability, an effect that might
also be achieved by supplementing with less L-arginine.
To conclude, L-arginine enhances systemic nitric oxide
production and increases aerobic exercise capacity in normal and
hypercholesterolemic mice. This finding supports the role of EDNO in
mediating exercise hyperemia and in determining aerobic capacity.
Furthermore, in conditions whereby EDNO activity is reduced, there may
be a benefit of L-arginine supplementation on exercise capacity.
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ACKNOWLEDGEMENTS |
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This work was supported in part by a grant from the National Heart, Lung, and Blood Institute (1RO1-HL-58638) and was done during the tenure of a Grant-in-Aid Award from the American Heart Association and Sanofi Winthrop.
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FOOTNOTES |
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A. J. Maxwell is the recipient of a Bugher Foundation Fellowship of the American Heart Association. J. P. Cooke is an Established Investigator of the American Heart Association.
Address for reprint requests and other correspondence: A. J. Maxwell, 1404 Old County Rd., Belmont, CA 94002 (E-mail: amaxwell{at}cookepharma.com).
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 15 August 2000; accepted in final form 21 August 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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 C. Napoli, S. Williams-Ignarro, F. de Nigris, L. O. Lerman, F. P. D'Armiento, E. Crimi, R. E. Byrns, A. Casamassimi, A. Lanza, F. Gombos, et al. Physical training and metabolic supplementation reduce spontaneous atherosclerotic plaque rupture and prolong survival in hypercholesterolemic mice PNAS, July 5, 2006; 103(27): 10479 - 10484. [Abstract] [Full Text] [PDF]
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 G. K. McConell, N. N. Huynh, R. S. Lee-Young, B. J. Canny, and G. D. Wadley L-Arginine infusion increases glucose clearance during prolonged exercise in humans Am J Physiol Endocrinol Metab, January 1, 2006; 290(1): E60 - E66. [Abstract] [Full Text] [PDF]
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 C. Ojaimi, W. Li, S. Kinugawa, H. Post, A. Csiszar, P. Pacher, G. Kaley, and T. H. Hintze Transcriptional basis for exercise limitation in male eNOS-knockout mice with age: heart failure and the fetal phenotype Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1399 - H1407. [Abstract] [Full Text] [PDF]
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 J. Suzuki Microvascular angioadaptation after endurance training with L-arginine supplementation in rat heart and hindleg muscles Exp Physiol, September 1, 2005; 90(5): 763 - 771. [Abstract] [Full Text] [PDF]
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C. Napoli, S. Williams-Ignarro, F. de Nigris, L. O. Lerman, L. Rossi, C. Guarino, G. Mansueto, F. Di Tuoro, O. Pignalosa, G. De Rosa, et al. Long-term combined beneficial effects of physical training and metabolic treatment on atherosclerosis in hypercholesterolemic mice PNAS, June 8, 2004; 101(23): 8797 - 8802. [Abstract] [Full Text] [PDF]
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J. R. McMullen, T. Shioi, L. Zhang, O. Tarnavski, M. C. Sherwood, P. M. Kang, and S. Izumo Phosphoinositide 3-kinase(p110{alpha}) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy PNAS, October 14, 2003; 100(21): 12355 - 12360. [Abstract] [Full Text] [PDF]
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F. de Nigris, L. O. Lerman, S. W. Ignarro, G. Sica, A. Lerman, W. Palinski, L. J. Ignarro, and C. Napoli From the Cover: Beneficial effects of antioxidants and L-arginine on oxidation-sensitive gene expression and endothelial NO synthase activity at sites of disturbed shear stress PNAS, February 4, 2003; 100(3): 1420 - 1425. [Abstract] [Full Text] [PDF]
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 O. J. Kemi, J. P. Loennechen, U. Wisloff, and O. Ellingsen Intensity-controlled treadmill running in mice: cardiac and skeletal muscle hypertrophy J Appl Physiol, October 1, 2002; 93(4): 1301 - 1309. [Abstract] [Full Text] [PDF]
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D. Tousoulis, C. Antoniades, C. Tentolouris, G. Goumas, C. Stefanadis, and P. Toutouzas L-Arginine in cardiovascular disease: dream or reality? Vascular Medicine, August 1, 2002; 7(3): 203 - 211. [Abstract] [PDF]
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J. N. Rottman, D. Bracy, C. Malabanan, Z. Yue, J. Clanton, and D. H. Wasserman Contrasting effects of exercise and NOS inhibition on tissue-specific fatty acid and glucose uptake in mice Am J Physiol Endocrinol Metab, July 1, 2002; 283(1): E116 - E123. [Abstract] [Full Text] [PDF]
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M. Manohar, T. E. Goetz, and A. S. Hassan Nitric oxide synthase inhibition does not affect the exercise-induced arterial hypoxemia in Thoroughbred horses J Appl Physiol, September 1, 2001; 91(3): 1105 - 1112. [Abstract] [Full Text] [PDF]
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