(Circulation. 1999;99:2113-2117.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Decreased Activity of the L-Arginine–Nitric Oxide Metabolic Pathway in Patients With Congestive Heart Failure
From Columbia Presbyterian Medical Center, Division of Circulatory Physiology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY.
Correspondence to Stuart D. Katz, MD, Columbia Presbyterian Medical Center, Division of Circulatory Physiology, Room MHB5-435, 177 Fort Washington Ave, New York, NY 10032.
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Abstract |
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Background—Impaired endothelium-dependent, nitric oxide (NO)–mediated vasodilation may contribute to increased vasomotor tone in patients with heart failure. Whether decreased endothelium-dependent, NO-mediated vasodilation in patients with heart failure is due to decreased synthesis or increased degradation of NO is unknown.
Methods and Results—To specifically assess the synthetic activity of the L-arginine–NO metabolic pathway, urinary excretion of [15N]nitrates and [15N]urea was determined after a primed continuous intravenous infusion of L-[15N]arginine (40 µmol/kg) in 16 patients with congestive heart failure and 9 age-matched normal control subjects at rest and during submaximal treadmill exercise. After infusion of L-[15N]arginine, 24-hour urinary excretion of [15N]nitrates was decreased in patients with congestive heart failure at rest (2.2±0.5 versus 8.0±2.3 µmol/24 h) and during submaximal exercise (2.4±1.2 versus 11.4±4.0 µmol/24 h) compared with control subjects (both P<0.01). After infusion of L-[15N]arginine, 24-hour urinary excretions of [15N]urea at rest in patients with congestive heart failure and control subjects were not different (1.1±0.3 versus 1.2±0.2 mmol/24 h, P>0.20).
Conclusions—A specific decrease in synthetic activity of the L-arginine–NO metabolic pathway contributes to decreased endothelium-dependent vasodilation in patients with congestive heart failure.
Key Words: endothelium • vessels • nitric oxide • metabolism • isotopes
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Nitric oxide (NO) is a potent vasodilating substance that plays an important role in the normal regulation of vasomotor tone, vascular structure, and blood pressure homeostasis.1 NO is synthesized in endothelial cells in response to a diverse array of hormonal and physical stimuli by a constitutively expressed enzyme, NO synthase (NOS).2 Endothelial NOS (eNOS) catalyzes oxidation of the guanidino nitrogen of the amino acid L-arginine to produce NO and L-citrulline in a calcium-requiring reaction that uses flavin mononucleotide, flavin adenine dinucleotide, and tetrahydrobiopterin as cofactors.2
Endothelium-dependent NO-mediated vasodilation in response to hormonal agonists and shear stress during exercise is decreased in the skeletal muscle and coronary circulations of patients with congestive heart failure compared with normal subjects.3 4 5 Impaired endothelium-dependent vasodilation in heart failure may be attributable to decreased endothelial synthesis of NO or to increased degradation of endothelium-derived NO by oxygen free radicals. Previous clinical studies, which have used indirect methods to assess NO synthesis, have yielded conflicting findings.5 6 7 8 9
The present study was undertaken to specifically assess synthetic activity of the endogenous L-arginine–NO metabolic pathway in patients with heart failure and normal subjects by use of isotopic tracer techniques. Urinary excretion of [15N]nitrates (the stable metabolite of [15N]NO) was measured after intravenous infusion of L-arginine labeled with stable nitrogen isotopes in its guanidino nitrogen positions (L-[15N]arginine).10 11 12 Because increased endothelial shear stress during exercise is an important physiological stimulus for endothelial NO synthesis,5 10 the activity of the L-arginine–NO metabolic pathway was measured both at rest and during submaximal exercise. To determine whether alterations of L-arginine metabolism in heart failure are specific to the L-arginine–NO metabolic pathway, the urinary excretion of labeled [15N]urea (produced from the guanidino nitrogens of L-[15N]arginine via arginase in the urea cycle) was also measured.13
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Study Population
Fourteen men and 2 women with stable chronic congestive heart failure of
3 months' duration participated in the study. The mean
age of the patients was 48±11 years (range, 32 to 75 years). The mean
left ventricular ejection fraction determined by
radionuclide angiography was 22%. Left ventricular
dysfunction was due to idiopathic dilated
cardiomyopathy in 14 patients and ischemic
cardiomyopathy in 2 patients. According to the
criteria of the New York Heart Association, 4 patients were in
functional class II and 12 patients were in functional class III at the
time of the study. Cardiovascular medications, which
included diuretics, ACE inhibitors, and digoxin in
all patients and long-acting nitrates in 6, were administered without
interruption during the study. Long-acting nitrates were withheld for
12 hours before and for 24 hours after each isotope infusion. Patients
with a history of diabetes mellitus,
hypercholesterolemia, or active tobacco use
were excluded from the study. Eight men and 1 woman without a history of chronic medical illness participated as normal control subjects. The mean age of these subjects, 42±13 years (range, 31 to 55 years), was not statistically different from the mean age of the patients with congestive heart failure. The control subjects were nonsmokers; they had normal physical examinations, normal serum cholesterol, and normal blood glucose concentrations and were not taking chronic medications. Patients and normal subjects with clinical evidence of infection or inflammation were excluded from the study. All patients and normal subjects received instruction to reduce dietary nitrate content for 24 hours before and after each isotope infusion. The study was approved by the ethical review board of the Columbia Presbyterian Medical Center. All patients and normal subjects gave written informed consent before the study.
Isotopic Tracer Administration
The isotopic tracer solution of
L-[15N]arginine (>99% atom
percent excess, MassTrace Inc) was prepared as a sterile, pyrogen-free
solution in 5% dextrose in water. The tracer solution was administered
via an infusion pump through a 20-gauge catheter placed in a forearm
vein. Subjects received a bolus infusion of 10 µmol/kg over 3
minutes and a maintenance infusion of 10 µmol ·
kg-1 · h-1 for 3
hours as previously described.11
Urine and Serum Collection and Analysis
A complete 24-hour urine collection was obtained for
determination of total (unlabeled) nitrate excretion,
[15N]nitrate excretion, total (unlabeled) urea
excretion, [15N]urea excretion, and
creatinine beginning with each isotopic tracer infusion.
Urine was collected in opaque polyethylene containers containing 5 mL
of 10N NaOH. Serum was collected via venipuncture just
before the isotope infusion and 24 hours after the infusion for
determination of unlabeled nitrate and creatinine
concentrations. Chemical nitrate content was measured by
chemiluminescence after acidic vanadium reduction with an NO
analyzer (Sievers model 280) as previously
described.14 Atom percent excess (APE, defined as the
ratio of 15N:14N determined
by atomic mass) of urine nitrate and urea was determined by gas
chromatography–mass spectrometry with electron
ionization as previously described.13 15 Determination of
15N enrichment of urine nitrate and urea was
performed by Dr David Wagner, Metabolic Solutions, Inc,
Merrimack, NH.
Venous Occlusion Plethysmography
To determine lower-extremity blood flow (shear-stress stimulus)
at rest and during submaximal exercise, calf blood flow (mL ·
min-1 · 100 mL-1
limb volume) was determined with venous occlusion strain-gauge
plethysmography as previously described in detail.16
Briefly, with the calf resting comfortably 10 cm above the right
atrium, a mercury-in-Silastic strain gauge was placed around the widest
portion of the midportion of the gastrocnemius muscle. The strain gauge
was electrically coupled to a plethysmograph calibrated to measure
percent change in volume. For each measurement, lower-limb venous blood
flow was occluded just proximal to the knee with the rapid inflation of
a blood pressure cuff to 40 mm Hg. Calf blood flows (mL ·
min-1 · 100 mL-1
calf volume) were determined at rest and immediately after 3 minutes of
unloaded rhythmic dorsiflexion/plantarflexion exercise.
Study Protocol
The study was conducted on 2 days separated by a 5- to 7-day
interval. Before the infusion of
L-[15N]arginine on each study day,
subjects voided to empty their bladders and provide baseline urine
samples for determination of background levels of naturally occurring
15N and 13C isotopes. After
a baseline urine and serum sample had been obtained, the primed
continuous 3-hour infusion of
L-[15N]arginine (total, 40 µg/kg)
was administered via an infusion pump. On 1 study day, the infusion was
completed while the subjects remained at rest, either supine or
sitting. On the other study day, all subjects performed 30 minutes of
submaximal treadmill exercise (1.5 mph, 0% grade) during the last 30
minutes of the infusion. Calf blood flow at rest and during
dorsiflexion/plantarflexion exercise was measured with venous occlusion
plethysmography just before treadmill exercise. The order of infusion
(rest versus submaximal exercise) was randomly assigned. Subjects were
instructed to remain sedentary for 24 hours after the isotope infusion
on both study days. Subjects returned the next day with the completed
urine collection. A second serum sample and spot urine sample were
obtained 24 hours after completion of the isotope infusion. Total urine
volume was recorded, and aliquots of urine and serum were stored
for later analysis at -80°C.
Data Analysis
All values are stated as mean±SEM. Total (unlabeled) urinary
nitrate excretion, urinary [15N]nitrate
excretion, total (unlabeled) urea excretion,
[15N]urea excretion, serum
creatinine and nitrate concentration,
creatinine and nitrate clearances, and calf blood flows at
rest and during exercise in patients with heart failure and normal
subjects were compared by Student's t test for unpaired
samples. Within-group comparisons between rest and exercise were
analyzed by Student's t test for paired samples. A
2-tailed probability value <0.05 was considered statistically
significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Urinary Nitrate Excretion
Twenty-four–hour [15N]nitrate excretion was decreased in patients with congestive heart failure at rest and during submaximal exercise compared with normal subjects (2.2±0.5 versus 8.0±2.3 µmol/24 h at rest and 2.4±1.2 versus 11.4±4.0 µmol/24 h during submaximal exercise, both P<0.05, Figure 1
).
Twenty-four–hour [15N]nitrate excretion tended
to increase during submaximal exercise compared with rest in normal
subjects (P=0.12) but not in patients with heart failure
(P>0.20). Twenty-four–hour total (unlabeled) urinary
nitrate excretion and nitrate APE at rest and during submaximal
exercise was decreased in patients with heart failure compared with
normal subjects (Table 1).
Twenty-four–hour urine volumes were greater in patients with heart
failure at rest and during submaximal exercise than in normal subjects
(Table 1).
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Urea Excretion
Twenty-four–hour [15N]urea excretion at
rest was not different in patients with congestive heart failure and
normal subjects (1.1±0.3 versus 1.2±0.2 mmol/24 h,
P>0.20, Figure 2).
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Creatinine and Nitrate Clearance
Twenty-four–hour creatinine excretion at rest was not
different in patients with congestive heart failure and normal subjects
(1752±358 versus 1239±174 mg/24 h, P>0.20). Serum
creatinine concentration was significantly increased and
creatinine clearance was significantly decreased in
patients with heart failure compared with normal subjects (Table 2). Serum nitrate concentrations in
patients with heart failure were not different from those in normal
subjects, and nitrate clearance was significantly decreased in patients
with heart failure compared with normal subjects (Table 2). When
urinary [15N]nitrate excretion was normalized
to urinary creatinine excretion (expressed as nmol
[15N]nitrate/mg creatinine),
[15N]nitrate excretion was significantly
decreased in patients with heart failure compared with normal subjects
(Table 2). Serum nitrate concentrations before and after the
isotope infusion were not different in patients with heart
failure and normal subjects (27.1±6.4 versus 29.0±7.5
µmol/L and 27.1±7.9 versus 23.5±8.1 µmol/L, respectively,
P>0.20 for within-group comparisons). In a spot urine
sample obtained after completion of the 24-hour urine collection,
[15N]nitrate was not detectable in either
patients with heart failure or normal subjects.
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Calf Blood Flow
Calf blood flows determined by venous occlusion plethysmography
were not different in patients with congestive heart failure and normal
subjects at rest (1.7±0.3 versus 2.3±0.2 mL ·
min-1 · 100 mL-1,
P>0.20) and in response to submaximal
dorsiflexion/plantarflexion exercise (6.0±1.4 versus 5.8±1.1 mL
· min-1 · 100
mL-1, P>0.20).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present data demonstrate that after infusion of L-[15N]arginine, urinary excretion of [15N]nitrates but not [15N]urea is decreased in patients with congestive heart failure at rest and during submaximal exercise compared with that of normal subjects. These findings indicate a specific decrease in the activity of the L-arginine–NO metabolic pathway in patients with congestive heart failure.
The present findings are in accord with previous studies of experimental heart failure, which demonstrated reduced levels of mRNA for eNOS in aortic endothelial cells and decreased synthesis of NO from isolated coronary microvessels obtained from dogs with heart failure induced by rapid ventricular pacing compared with control animals.17 18 Previous clinical studies, which used indirect methods to assess NO synthesis, have yielded conflicting findings. NO production in expired gases during exercise is decreased in patients with heart failure compared with that of normal subjects.6 Plasma nitrate concentrations are increased in patients with heart failure compared with normal subjects.7 However, plasma nitrate levels do not provide a reliable estimate of endogenous NO synthesis because of the confounding effects of nitrate derived from exogenous sources, such as diet and therapeutic nitrate preparations.19 Studies of hemodynamic responses to regional and systemic administration of inhibitors of NOS to assess basal NO synthesis have yielded inconsistent findings.5 8 9
Decreased activity of the L-arginine–NO metabolic pathway in patients with heart failure may be related to specific changes in the expression or regulation of eNOS or increased plasma concentration of endogenous inhibitors of eNOS, such as asymmetrical dimethylarginine or NG-monomethyl-L-arginine.2 20 21 Decreased eNOS activity in heart failure was not due to decreased shear-stress stimulus, because, in accord with past studies, limb blood flows at rest and during low-level submaximal exercise were not different in nonedematous patients with compensated heart failure and normal subjects.5 8 22 The preservation of skeletal muscle blood flow during submaximal exercise in patients in heart failure may be related to the redundancy of the metabolic vasodilatory mechanisms in the skeletal muscle circulation and favorable effects of background ACE inhibition and diuretics on metabolic hyperemia in the skeletal muscle vasculature.23 24 25
Three distinct isozymes of NOS have been identified in
endothelial cells (eNOS), neuronal cells (nNOS), and
inflammatory cells (iNOS).2 The isotopic tracer methods
used in the present study cannot distinguish the relative
contributions of each isozyme to total synthetic activity of the
L-arginine–NO metabolic pathway. The finding
that urinary [15N]nitrate excretion tended to
increase in response to identical submaximal exercise work rates in
normal subjects but not in patients with heart failure suggests that
shear stress–dependent activity of eNOS is decreased in patients with
heart failure. This interpretation is concordant with a previous study
that demonstrated the absence of shear stress–induced, NO-mediated
vasodilation in response to submaximal exercise in the skeletal muscle
circulation of patients with heart failure.5 However,
endothelium-dependent vasodilation was not directly
assessed in the present study population. Despite exclusion of
subjects with clinically evident infections or inflammation,
cytokine-dependent activation of iNOS may have contributed to
whole-body NO synthesis in patients with heart failure, because
increased activity of tumor necrosis factor-
and other
cytokines has been reported in this patient
population.26 27 28 Increased gene expression, protein
content, and enzymatic activity of iNOS have been reported in failing
human myocardium.29 30
Although creatinine and nitrate clearances were decreased
in patients with congestive heart failure compared with normal
subjects, it is unlikely that altered renal function in heart failure
accounts for decreased 24-hour urinary
[15N]nitrate excretion in heart failure, for
several reasons. First, 24-hour urinary
[15N]nitrate excretion normalized to urinary
creatinine excretion (expressed as nmol
[15N]nitrate/mg creatinine) was
significantly decreased in patients with heart failure compared with
normal subjects (Table 2
). Second, renal clearance
represents the volume of plasma that can be cleared of a given
substance in a given unit of time and is not a determinant of the
24-hour excretion of that substance in steady state.31
Serum nitrate concentrations before and after the isotope infusion were
unchanged in patients with heart failure and normal subjects. Last, in
agreement with a previous study in hypertensive patients that used
similar isotope-labeling techniques,12 urinary excretion
of [15N]nitrate was completed within 24 hours
after infusion of L-[15N]arginine
in both patients with heart failure and normal subjects, because
[15N]nitrate in a spot urine sample collected
after completion of the 24-urine collection was not different from
preinfusion background levels. Changes in tissue uptake of
L-arginine probably did not contribute to our findings,
because 24-hour [15N]urea excretion was similar
in normal subjects and patients with heart failure.
L-Arginine uptake is increased in erythrocytes from
patients with heart failure compared with normal
subjects.32 Other metabolic pathways of
L-arginine, which include its incorporation into creatine
(via the action of glycine transamidinase) and putrescine and other
polyamines (by conversion to ornithine by arginase and subsequent
action of ornithine decarboxylase), may have competed with NO synthesis
and arginase for L-arginine as substrate.33
However, the guanidino nitrogens of arginine are not involved in the
metabolic conversion to polyamines. Moreover, these
additional metabolic pathways are generally
activated in response to tissue injury and trauma and therefore
are unlikely to account for our findings.33
Because background medications, with the exception of long-acting nitrates, were continued without interruption during the study, a contribution of the pharmacological actions of these agents to our findings cannot be excluded. In a previous study, background cardiac medications did not immediately alter endothelium-dependent vasodilation in patients with heart failure.34 ACE inhibitors have been reported to enhance endothelium-dependent vasodilation in the coronary circulation of patients with atherosclerotic heart disease.35 Background medications may also have contributed to differences in renal function observed between patients with heart failure and normal subjects. However, as discussed above, differences in creatinine and nitrate clearance cannot account for the study findings.
In summary, the present findings provide the first specific assessment of the synthetic activity of the L-arginine–NO metabolic pathway in normal subjects and patients with heart failure. The findings demonstrate that decreased synthesis of NO contributes to decreased endothelium-dependent NO-mediated vasodilation in patients with heart failure. Therapeutic strategies aimed at increasing endogenous NO synthesis or supplying exogenous sources of NO may enhance endothelium-dependent vasodilation in heart failure.
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Acknowledgments |
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This study was funded by grant R29-HL-51433 from the National Heart, Lung, and Blood Institute.
Received October 8, 1998; revision received December 30, 1998; accepted January 25, 1999.
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S. D. Katz, K. Hryniewicz, I. Hriljac, K. Balidemaj, C. Dimayuga, A. Hudaihed, and A. Yasskiy Vascular Endothelial Dysfunction and Mortality Risk in Patients With Chronic Heart Failure Circulation, January 25, 2005; 111(3): 310 - 314. [Abstract] [Full Text] [PDF]
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M. Valgimigli, G. M. Rigolin, A. Fucili, M. D. Porta, O. Soukhomovskaia, P. Malagutti, A. M. Bugli, L. Z. Bragotti, G. Francolini, E. Mauro, et al. CD34+ and Endothelial Progenitor Cells in Patients With Various Degrees of Congestive Heart Failure Circulation, September 7, 2004; 110(10): 1209 - 1212. [Abstract] [Full Text] [PDF]
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Y. Liao, M. Asakura, S. Takashima, A. Ogai, Y. Asano, Y. Shintani, T. Minamino, H. Asanuma, S. Sanada, J. Kim, et al. Celiprolol, A Vasodilatory {beta}-Blocker, Inhibits Pressure Overload-Induced Cardiac Hypertrophy and Prevents the Transition to Heart Failure via Nitric Oxide-Dependent Mechanisms in Mice Circulation, August 10, 2004; 110(6): 692 - 699. [Abstract] [Full Text] [PDF]
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 T. B. Horwich, W. R. MacLellan, and G. C. Fonarow Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure J. Am. Coll. Cardiol., February 18, 2004; 43(4): 642 - 648. [Abstract] [Full Text] [PDF]
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H. Adachi, S. Oshima, S. Sakurai, T. Toyama, H. Hoshizaki, K. Taniguchi, and H. Ito Nitric oxide exhalation correlates with ventilatory response to exercise in patients with heart disease Eur J Heart Fail, October 1, 2003; 5(5): 639 - 643. [Abstract] [Full Text] [PDF]
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 W. Linz, G. Itter, L. W Dobrucki, T. Malinski, and G. Wiemer Ramipril improves nitric oxide availability in hypertensive rats with failing hearts after myocardial infarction Journal of Renin-Angiotensin-Aldosterone System, September 1, 2003; 4(3): 180 - 185. [Abstract] [PDF]
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 S. P. Jones, J. J. M. Greer, R. van Haperen, D. J. Duncker, R. de Crom, and D. J. Lefer Endothelial nitric oxide synthase overexpression attenuates congestive heart failure in mice PNAS, April 15, 2003; 100(8): 4891 - 4896. [Abstract] [Full Text] [PDF]
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D. M. McNamara, R. Holubkov, L. Postava, R. Ramani, K. Janosko, M. Mathier, G. A. MacGowan, S. Murali, A. M. Feldman, and B. London Effect of the Asp298 Variant of Endothelial Nitric Oxide Synthase on Survival for Patients With Congestive Heart Failure Circulation, April 1, 2003; 107(12): 1598 - 1602. [Abstract] [Full Text] [PDF]
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 A. Avogaro, G. Toffolo, E. Kiwanuka, S. V. de Kreutzenberg, P. Tessari, and C. Cobelli L-Arginine-Nitric Oxide Kinetics in Normal and Type 2 Diabetic Subjects: A Stable-Labelled 15N Arginine Approach Diabetes, March 1, 2003; 52(3): 795 - 802. [Abstract] [Full Text] [PDF]
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 D. M. Kaye, M. M. Parnell, and B. A. Ahlers Reduced Myocardial and Systemic L-Arginine Uptake in Heart Failure Circ. Res., December 13, 2002; 91(12): 1198 - 1203. [Abstract] [Full Text] [PDF]
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 J. H. Traverse, Y. Chen, M. Hou, and R. J. Bache Inhibition of NO production increases myocardial blood flow and oxygen consumption in congestive heart failure Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2278 - H2283. [Abstract] [Full Text] [PDF]
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 A. Lass, A. Suessenbacher, G. Wolkart, B. Mayer, and F. Brunner Functional and Analytical Evidence for Scavenging of Oxygen Radicals by L-Arginine Mol. Pharmacol., May 1, 2002; 61(5): 1081 - 1088. [Abstract] [Full Text] [PDF]
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T. Kihara, S. Biro, M. Imamura, S. Yoshifuku, K. Takasaki, Y. Ikeda, Y. Otuji, S. Minagoe, Y. Toyama, and C. Tei Repeated sauna treatment improves vascular endothelial and cardiac function in patients with chronic heart failure J. Am. Coll. Cardiol., March 6, 2002; 39(5): 754 - 759. [Abstract] [Full Text] [PDF]
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J. M. Cotton, M. T. Kearney, P. A. MacCarthy, R. M. Grocott-Mason, D. R. McClean, C. Heymes, P. J. Richardson, and A. M. Shah Effects of Nitric Oxide Synthase Inhibition on Basal Function and the Force-Frequency Relationship in the Normal and Failing Human Heart In Vivo Circulation, November 6, 2001; 104(19): 2318 - 2323. [Abstract] [Full Text] [PDF]
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 L. L. Clark Perioperative Treatment of Congestive Heart Failure Seminars in Cardiothoracic and Vascular Anesthesia, November 1, 2000; 4(4): 223 - 235. [Abstract] [PDF]
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P. Forte, N. Benjamin, S. D. Katz, T. Khan, G. A. Zeballos, L. Mathew, P. Potharlanka, M. Knecht, and J. Whelan Nitric Oxide Synthesis and Congestive Heart Failure Response Circulation, August 8, 2000; 102 (6): e37 - e38. [Full Text] [PDF]
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L. E. Spieker, V. Mitrovic, G. Noll, R. Pacher, M. R. Schulze, J.o. Muntwyler, C. Schalcher, W. Kiowski, T. F. Luscher, and on behalf of the ET 003 Investigators Acute hemodynamic and neurohumoral effects of selective ETA receptor blockade in patients with congestive heart failure J. Am. Coll. Cardiol., June 1, 2000; 35(7): 1745 - 1752. [Abstract] [Full Text] [PDF]
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D. B. Haitsma, D. Merkus, J. Vermeulen, P. D. Verdouw, and D. J. Duncker Nitric oxide production is maintained in exercising swine with chronic left ventricular dysfunction Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2198 - H2209. [Abstract] [Full Text] [PDF]
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G. D. Thomas, W. Zhang, and R. G. Victor Impaired Modulation of Sympathetic Vasoconstriction in Contracting Skeletal Muscle of Rats With Chronic Myocardial Infarctions : Role of Oxidative Stress Circ. Res., April 27, 2001; 88(8): 816 - 823. [Abstract] [Full Text] [PDF]
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