© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Exercise Training Increases Basal Nitric Oxide Production From the Forearm in Hypercholesterolemic Patients
From the Alfred and Baker Medical Unit, Baker Medical Research Institute, Prahran, Australia.
Correspondence Dr Bronwyn Kingwell, Alfred and Baker Medical Unit, Baker Medical Research Institute, Commercial Rd, Prahran 3181, Australia. E-mail b.kingwell{at}alfred.org.au
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Abstract—The objective of this study was to investigate the effects of cycle training on basal nitric oxide (NO) production and endothelium-dependent dilator capacity in hypercholesterolemic patients in whom acetylcholine responsiveness is impaired. Nine sedentary hypercholesterolemic volunteers (total plasma cholesterol >6.0 mmol/L; 2 female) aged 44±3 years (mean±SEM) participated in the study. Subjects remained sedentary for 4 weeks and performed 4 weeks of home-based cycle training (3x30 minutes/week at 65% maximum oxygen consumption [VO2max]) in a randomized order. Arteriovenous nitrate/nitrite (NOx) gradient was assessed and plethysmography was used to measure the forearm blood flow responses to arterial infusions of acetylcholine, sodium nitroprusside, and NGmono methyl L-arginine. Training increased VO2max from 30.4±1.9 to 34.3±1.4 mL · kg-1 · min-1 (P=0.01). Intrabrachial diastolic blood pressure was reduced from 70±3 to 68±3 mm Hg (P=0.02) with training, whereas systolic pressure did not change. Plasma triglycerides and total, LDL, and HDL cholesterol were not different between interventions. In the sedentary state, there was a positive forearm arteriovenous difference in plasma NOx indicating net extraction (6.8±4.0 nmol · 100 mL-1 · min-1), whereas in the trained state this difference was negative, indicating net production (-5.8±5.8 nmol · 100 mL-1 · min-1; P=0.03). NGmono methyl L-arginine, at a dose of 4 µmol/min, caused a greater vasoconstriction after training (79.6±3.4% versus 69.9±6.8%; P=0.05). Acetylcholine and sodium nitroprusside induced dose-dependent elevations in forearm blood flow that were unaffected by training. These data suggest that basal release of endothelium-derived NO is increased with 4 weeks of home based training in hypercholesterolemic patients, independently of lipid profile modification. This may contribute to the cardiovascular protective effects of exercise training, including reduced blood pressure.
Key Words: exercise • endothelium-dependent vasodilation • acetylcholine • lipids • hyperlipidemia
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Introduction |
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Nitric oxide (NO) has received much recent attention as one potential mediator of some of the vascular benefits derived from regular exercise.1 A number of studies in both animals and humans have recognized that endothelially derived NO plays a role in blood flow regulation during acute, dynamic exercise.2 In particular, it has been postulated that vasodilatation in active muscle promotes a pressure gradient and thus increased blood flow that stimulates NO production from upstream arteries.3 NO mediated dilation of "feed" arteries can therefore permit increased microvascular flow without reduction in muscle perfusion pressure. With regular exercise it appears that there are adaptations in this system that may be partly responsible for the reduction in cardiovascular risk associated with the trained state.
Studies in rats and rabbits have provided evidence for enhanced aortic endothelial dependent vasodilatation and basal release of NO with exercise training.4 5 6 7 8 Importantly, similar improvements in response to training have been observed in the coronary vasculature of pigs and dogs.9 10 11 12 13 14 All training related studies of endothelial function in humans have been carried out in peripheral vessels. Our laboratory has shown that 4 weeks of cycle training increases basal production of NO from the forearm.15 In this study, forearm blood flow and blood viscosity were elevated by 230% and 16%, respectively, immediately after a single 30-minute bout of exercise, and 60 minutes after cessation of exercise, forearm blood flow remained elevated by 75%. We postulate that these effects combined with heart rate and pulse pressure elevation would increase shear stress and thus provide a potent stimulus for nitric oxide production.16 17 Forearm acetylcholine responsiveness was unaffected by training in this previous study. Increased basal production of NO may therefore contribute to the reduction in blood pressure we and others have previously observed after only 4 weeks of regular exercise.18 19 20 21
In the current study, we aimed to determine whether similar exercise induced adaptations occur in hypercholesterolemic patients who show impaired forearm responsiveness to acetylcholine.22 23 24 It is clear from previous studies that total and LDL cholesterol levels are negatively correlated with reactivity to acetylcholine.25 To determine whether mechanisms independent of plasma cholesterol reduction could convey beneficial endothelial adaptations in hypercholesterolemic patients, we used a moderate exercise intervention of only 4 weeks duration that we have previously shown not to alter cholesterol levels in normocholesterolemic individuals.15 In a randomized crossover design, we compared this with 4 weeks of sedentary activity. At the end of each intervention, basal nitric oxide release was examined via both measurement of arteriovenous differences in the nitric oxide metabolites nitrate and nitrite (NOx) and the use of forearm venous occlusion plethysmography to measure blood flow responses to intrabrachial infusion of the NO synthase inhibitor, NG-monomethyl-L-arginine. Intrabrachial acetylcholine was used to study endothelium-dependent vasodilator reserve and sodium nitroprusside to study smooth muscle sensitivity to NO.
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Methods |
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All subjects were recruited from our lipid management clinic on the basis of their elevated total cholesterol and gave their written informed consent for participation in the study, which was performed with the approval of The Ethics Committee from The Alfred Healthcare Group and carried out in accordance with the Declaration of Helsinki (1989) of the World Medical Association. Participants were healthy, unmedicated, nonsmokers, with a body mass index <29 kg/m2, blood pressure <140/90 mm Hg, cholesterol >6.0 mmol/L, triglycerides <4 mmol/L, and maximum oxygen consumption (VO2max) <50 mL · min-1 · kg-1. No patient had evidence of significant coronary disease on history, examination, or exercise electrocardiogram. The first laboratory visit for all participants included a medical examination, routine hematological and biochemical blood tests, assessment of blood pressure, and VO2max.
Study Design
Nine sedentary volunteers (2 female, aged 44±3 years;
mean±SEM) remained sedentary for 4 weeks and performed 4 weeks of
cycle training in random order. After each intervention subjects were
required to attend the laboratory on 2 separate days. The first of
these was for VO2max assessment. On the second
occasion, which occurred at least 48 hours after the last exercise
bout, forearm arteriovenous NOX gradient and
forearm vascular reactivity to acetylcholine, sodium nitroprusside, and
NGmono methyl L-arginine (L-NMMA) was assessed as
described below.
Throughout the study, subjects were advised to make no changes to their lifestyle, especially diet, including alcohol intake and recreational physical activity.
Exercise Training
Exercise bikes were provided for home use and training consisted
of 30-minute cycling sessions 3 times per week performed at 65% of
predetermined maximum heart rate. This was calculated as resting heart
rate plus 65% of the difference between resting and maximum heart
rate. Each session was preceded by a 5-minute warm-up during which
workload was incremented to achieve the target workload at the
completion of the warm-up. A 5-minute cool-down concluded each session.
Compliance was assessed by diary and validated with maximum oxygen
consumption assessment.
VO2max
VO2max was assessed during a graded
exercise test on an electrically braked cycle ergometer as described
previously.26 This test consisted of 1-minute periods of
bicycle exercise commencing at zero workload and increasing by 20 watts
each minute until any further increase in workload was prevented by
fatigue. The criteria for establishment of VO2max
included a plateau in the oxygen consumption with increasing work rate,
a respiratory exchange ratio >1.1, and failure to maintain the
required workrate despite encouragement. We defined
VO2 max as the average
VO2 during the final 30 seconds of
exercise. Oxygen and carbon dioxide measurements were made using a
Medical Graphics Corporation 2001 CAD/Net Cardiopulmonary
Exercise System. Heart rate was derived from R-R interval,
measured throughout the exercise test using electrocardiographic
recordings from a Hewlett Packard 43120A
defibrillator.
Forearm Vascular Reactivity Studies
Subjects were studied after an overnight fast and a 24-hour
abstinence from caffeinated foods and beverages. The subject rested in
the supine position throughout each study in a quiet temperature
controlled room maintained at 22°C. The brachial artery of the left
arm was cannulated using a 3.0 F, 5-cm catheter (Cook) under strict
aseptic conditions after local anesthesia (1% lignocaine;
Astra) to permit both intraarterial blood pressure
measurement (Spacelabs Inc), drug infusions, and blood sampling. To
enable sampling of venous blood draining the forearm musculature, a
second catheter (5.0F, Cook) was inserted retrogradely 4 to 8 cm into a
deep vein of the left forearm. Correct positioning was validated with
oxygen saturations of <65%.27 After cannulation,
subjects were rested for 30 minutes before commencement of the
study.
Simultaneous 10-mL blood samples were drawn from the brachial artery and deep vein at the completion of the 30-minute rest period for analysis of NOX. Forearm blood flow was measured using venous occlusion plethysmography with a sealed alloy-filled (gallium and indium), double-strand strain gauge (Medasonic) and recorded for 10 out of every 20 seconds. Hand blood flow was excluded via a wrist cuff inflated to 200 mm Hg, and venous occlusion pressure on the upper arm was between 40 and 50 mm Hg. Before each drug, basal blood flow was obtained from an average of at least 3 measurements. Responses to local sequential infusions (2 mL/min) given in the following order were obtained: the endothelium-dependent vasodilator acetylcholine (24, 48 µg/min), the endothelium-independent vasodilator sodium nitroprusside (0.4, 0.8 µg/min), and the NO synthase inhibitor L-NMMA (2, 4 µmol/min). For acetylcholine and sodium nitroprusside, the peak response was ascertained when 3 consecutive measurements showed no further increase in flow (approximately 1 to 2 minutes). The response to L-NMMA was measured after a 10-minute infusion. For all drugs, the response was recorded as the average of 3 steady-state measurements. Rest periods of 5 minutes between drug doses and 15 minutes between drug types was sufficient for flows to return to resting levels for acetylcholine and sodium nitroprusside. For L-NMMA, the rest period between doses was 15 minutes. Intraarterial brachial mean blood pressure was recorded both during measurement of basal flows and immediately after each intervention to ensure that there were no systemic drug effects. Forearm blood flow measurements were made by a research assistant unaware of the training status of the study participants.
Biochemical Analyses
Blood for NOx analysis was
collected into ethylenediamine-tetraacetic acid tubes,
deproteinized, and plasma concentrations were determined using the
Griess reaction28 with the Cayman chemical kit 780001.
This assay reduces all nitrate to nitrite and measures total nitrite by
photoabsorbance at 540 nm of the deep purple azo conversion
product. We calculated arteriovenous differences in
NOx and multiplied this value by forearm blood
flow to derive net forearm consumption or production. This
method provides a more accurate assessment of nitric oxide
production form the forearm than single measures of
venous or arterial NOx, which are
susceptible to the effects of changes in volume of distribution and
nitrate accumulation.29
Blood for lipid analysis was collected into ethylenediamine-tetraacetic acid tubes and placed immediately on ice and then centrifuged at 3000 rpm within 10 minutes of collection. Plasma was frozen at -20°C and analyzed within 5 days of collection. Plasma (5-ml) was loaded into an ultracentrifuge tube, overlaid with normal saline (density 1.006), sealed, and spun at 40 000 rpm for 16 hours at 20°C. The tube was sliced and the "bottom" fraction, containing LDL and HDL, was collected volumetrically. Apo B–containing lipoproteins (LDL and IDL) were precipitated by the addition of heparin and manganous chloride leaving only HDL in the supernatant. Cholesterol and triglyceride levels were determined enzymatically in the plasma, and cholesterol was measured in the HDL fraction using a Cobas-BIO Centrifugal Analyser (Roche Diagnostic Systems).
Statistics
Results are expressed as the mean±SEM. A Student’s paired
t test was used to compare biochemical, anthropometric, and
blood pressure data after each intervention. Vascular reactivity
dose-response curves in the sedentary and trained states were compared
using repeated measures ANOVA (SPSS/PC Statistical data
analysis; SPSS Inc) to determine the effects of training, dose,
and order of intervention. Data were analyzed both as absolute
flows and as a percentage of basal flow before each infusion. The level
of significance used was P<0.05.
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Results |
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We verified that acetylcholine responses were indeed impaired (P<0.05) in the hypercholesterolemic individuals by comparison with an age-matched (42±3 years; n=8) control group with a total plasma cholesterol of 4.42±0.24 mmol/L and triglycerides of 1.39±0.14 mmol/L (P<0.001 compared with hypercholesterolemic patients for both; Figure 1
).
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indicates normocholesterolemic
controls (n=8); 
, hypercholesterolemic patients
(sedentary, n=9). *Denotes significant differences between groups
(P<0.05).
Training did not alter body mass index, resting heart rate, or
intrabrachial systolic or mean arterial pressure,
whereas intrabrachial diastolic blood pressure was
significantly lower after training (Table 1). Compliance to the training
regimen was assessed by diary and confirmed by a significant elevation
in VO2max (Table 1). There was no
difference in total, LDL, or HDL cholesterol or
triglycerides between interventions (Table 2).
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Basal Forearm Blood Flow and Vascular Resistance
There was a trend for lower basal forearm blood flow measured
before each drug infusion in the trained state, but this failed to
reach statistical significance (P=0.14; Figure 2, upper panel). Basal blood flow did,
however, fall slightly over the course of the experiment
(P=0.05). Forearm vascular resistance was not different
after the training and sedentary interventions (P=0.15) nor
altered during the course of the protocol (P=0.53; Figure 2, lower panel). There were no order-related influences on basal
forearm blood flow (P=0.44) or vascular resistance
(P=0.43).
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Basal Release of NO
In the sedentary state, there was, on average, a positive forearm
NOx arteriovenous difference (2.1±0.9
mmol/L) indicating net consumption of NOx
(6.8±4.0 nmol · 100 mL-1 ·
min-1; Figure 3).
After training, however, there was, on average, a negative forearm
NOx arteriovenous difference (-1.55±1.75
mmol/L; P=0.02) indicating net production of
NOX (-5.8±5.8 nmol · 100
mL-1 · min-1;
P=0.03). These data are consistent with increased
basal production of nitric oxide in the trained state compared
with the sedentary state.
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L-NMMA was used to inhibit NO synthase as a functional measure of basal
NO release. When absolute blood flows were analyzed using
repeated measures ANOVA, a significant dose-dependent
vasoconstriction was evident (P=0.002). Blood flow in
response to L-NMMA infusion was also lower after the training
intervention (P=0.009). Because there was a trend for lower
basal forearm blood flow before infusion of L-NMMA in the trained
state, we also expressed the responses to L-NMMA infusion as a
percentage of basal blood flow. This analysis showed a
significant interaction between dose and training status
(P=0.05), indicating a greater vasoconstriction after
training at the higher but not the lower dose of L-NMMA (79.6±3.4%
versus 69.9±6.8%; P=0.05; Figure 4, upper panel).
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Endothelium-Dependent and -Independent
Vasodilatation
Acetylcholine caused a dose-dependent increase in forearm blood
flow (P=0.03) in both the sedentary and the trained states,
which was not different between interventions (P=0.19;
Figure 4
, center panel). Infusion of the
endothelium independent agonist sodium nitroprusside
also caused a dose dependent increase in forearm blood flow
(P=0.005), which was not altered by training
(P=0.46; Figure 4, lower panel).
The order of intervention (sedentary versus trained) did not significantly influence any of the blood flow responses to drug infusions.
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Discussion |
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This is the first study to provide evidence of enhanced basal NO production after 4 weeks of moderate home based aerobic training in hypercholesterolemic subjects. Because basal forearm blood flow and vascular resistance were not different between interventions, our findings suggest that training alters the regulation of basal NO production such that more NO is produced at any given flow. At higher flows, this regulatory shift may contribute to increased dilatory capacity. These changes occurred in the absence of any changes in lipid profile. Training did not alter stimulated NO release in response to acetylcholine infusion. Similarly, training did not induce vascular smooth muscle adaptations in reactivity to NO because responses to the NO donor, sodium nitroprusside, were not different between interventions.
The conclusion that basal NO release is increased with training is inferred from both the greater vasoconstriction to L-NMMA and the more negative NOx arteriovenous difference observed after the training intervention. Evidence of augmented basal NO production has previously been documented in coronary arteries excised from canines after 10 days of treadmill running9 and in forearm resistance arteries of healthy, previously sedentary, normocholesterolemic humans after 4 weeks of cycle training.15 Data from the current study indicate that despite impaired vasodilation to acetylcholine, hypercholesterolemic individuals show similar adaptive patterns to normocholesterolemic subjects. We postulate that elevation in shear stress during exercise via increased blood viscosity17 and elevated heart rate and increased pulse pressure16 increases production of NO from the forearm during leg exercise. Previous work from our laboratory has documented elevation in both forearm blood flow and blood viscosity immediately after a 30-minute bout of acute exercise.15 Our findings imply that NO production may remain elevated between training sessions perhaps through upregulation of NO synthase (isoform III)9 and may subsequently contribute to the blood pressure reduction,18 19 20 21 vascular adaptations, and increased exercise capacity30 that occur with training. Other mechanisms, including changes in circulating factors, may also be involved.
Responsiveness to acetylcholine has been shown previously to be impaired in the presence of lipid elevation,22 whereas basal release of NO, as assessed by vasoconstrictor responses to L-NMMA, is similar in hypercholesterolemic individuals and normal healthy subjects.23 31 We have also previously shown that training increases basal nitric oxide production but not responsiveness to acetylcholine in normocholesterolemic individuals.25 L-NMMA and acetylcholine influence NO production through distinct mechanisms. L-NMMA blocks basal nitric oxide production, which is released in response to endothelial shear stress. Acetylcholine, however, acts via the M3 muscarinic receptor on endothelial cells.32 It is possible that these mechanisms are differentially affected by training. In particular, it is likely that shear stress induced NO release would be modulated by training because exercise acutely increases factors influencing shear stress, including blood flow, blood viscosity, vessel calibre, and heart rate.15 16 17 In addition, the signal transduction mechanisms for shear stress and agonist stimulated NO release appear to be distinct. Although the shear stress signaling mechanism is not well understood, it appears to involve a pertussis toxin sensitive G protein,33 which is distinct from the G protein, predominantly involved in coupling of the endothelial M3 muscarinic receptor32 34 35 36 via which acetylcholine elicits NO release.
It is possible that the intensity of the training program or the short-term nature of the study contributed to the lack of change in acetylcholine responses because enhanced responsiveness to acetylcholine has been demonstrated using more intense or longer duration programs9 37 and in highly-trained athletes.25 Although most previous studies have not documented whether or not blood lipid changes occurred with training, our previous experience with highly-trained athletes has suggested that enhancement of acetylcholine responsiveness may be related, at least partly, to reduction in total cholesterol.25 Like improvement in acetylcholine responsiveness, such modifications in lipid profile usually only occur after intense, long-duration training programs.
As expected, 4 weeks of training did not significantly alter any of the lipoprotein parameters measured. In studies that have reported an increase in HDL cholesterol38 and a decrease in LDL cholesterol39 and triglycerides,40 41 subjects have usually trained at between 70% to 90% of their predetermined maximum heart rate, 3 to 5 times per week for at least 14 weeks.41 42 43 Furthermore, Superko reported jogging for at least 6 km/wk for 7 months was required to induce a change in lipid profile.44 Prescription of high-intensity exercise to alter lipid levels may not be appropriate for hypercholesterolemic patients who are at elevated risk of myocardial ischemia. However, it is evident from the current study that exercise may convey benefit beyond lipid profile modification via elevation in basal NO production.
In conclusion, the current study provides evidence that a home-based exercise program increases the basal production of NO in hypercholesterolemic patients. Such effects may contribute to the lower blood pressure observed in this and previous studies.18 19 20 21 These changes occurred in the absence of both lipid profile modification or improvement in acetylcholine mediated vasodilation. Thus moderate training for hypercholesterolemic patients has beneficial effects additional to lipid profile modification and may be considered a useful adjunct to conventional lipid lowering therapy.
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Acknowledgments |
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We are grateful for the assistance of Leonie Johnston, Karen Murchie, Luke Robinson, and Tanya Medley. Dr Kingwell is a National Health and Medical Research Council Research Fellow. This work was also supported by the National Heart Foundation of Australia.
Received January 27, 1999; accepted March 31, 1999.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. McAllister R. Endothelial-mediated control of coronary and skeletal muscle blood flow during exercise: introduction. Med Sci Sports Ex. 1995;27:1122–1124.
2.
Dyke C, Proctor D, Dietz N, Joyner M. Role of nitric
oxide in exercise hyperaemia during prolonged rhythmic handgripping in
humans. J Physiol. 1995;488:259–265.
3. Green D, O’Driscoll G, Blanksby B, Taylor R. Control of skeletal muscle blood flow during dynamic exercise. Sports Med. 1996;21:119–146.[Medline] [Order article via Infotrieve]
4.
Delp M, McAllister R, Laughlin M. Exercise training
alters endothelium-dependent vasoreactivity of rat
abdominal aorta. J Appl Physiol. 1993;75:1354–1363.
5. Hsiung Yen M, Hua Yang J, Rong Sheu Y, Mei Lee Y, An Ding Y. Chronic exercise enhances endothelium-mediated dilation in spontaneously hypertensive rats. Life Sci. 1995;57:2205–2213.[Medline] [Order article via Infotrieve]
6.
Koller A, Huang A, Sun D, Kaley G. Exercise training
augments flow dependent dilation in rat skeletal muscle arterioles.
Circ Res. 1995;76:544–550.
7. Parker J, Oltman C, Muller J, Myers P, Adams H, Laughlin M. Effects of exercise training on regulation of tone in coronary arteries and arterioles. Med Sci Sports Exerc. 1994;26:1252–1261.[Medline] [Order article via Infotrieve]
8.
Parker J, Mattox M, Laughlin M. Contractile
responsiveness of coronary arteries from exercise-trained rats.
J Appl Physiol. 1997;83:434–443.
9.
Sessa W, Pritchard K, Seyedi N, Wang J, Hintze T.
Chronic exercise in dogs increases coronary vascular nitric
oxide production and endothelial cell nitric
oxide synthase gene expression. Circ Res. 1994;73:829–838.
10. Wang J, Wolin M, Hintze T. Chronic exercise enhances endothelium-mediated dilation of epicardial coronary artery in conscious dogs. Circ Res. 1993;73:829–838.
11.
Oltman C, Parker J, Adams H, Laughlin M. Effects of
exercise training on vasomotor reactivity of porcine coronary
arteries. Am J Physiol. 1992;263:H372–H382.
12.
Muller J, Myers P, Laughlin M. Vasodilator responses of
coronary resistance arteries of exercise-trained pigs.
Circulation. 1994;89:2308–2314.
13.
Laughlin M, McAllister R. Exercise training-induced
coronary vascular adaptation. J Appl Physiol. 1992;73:2209–2225.
14. Laughlin M. Endothelium-mediated control of coronary vascular tone after chronic exercise training. Med Sci Sports Exerc. 1995;27:1135–1144.[Medline] [Order article via Infotrieve]
15.
Kingwell B, Sherrard B, Jennings G, Dart A. Four weeks
of cycle training increases basal production of nitric oxide
from the forearm. Am J Physiol. 1997;272:H1070–H1077.
16.
Hutcheson IR, Griffith TM. Release of
endothelium-derived relaxing factor is modulated both
by frequency and amplitude of pulsatile flow. Am J
Physiol. 1991;261:H257–H262.
17. Wieczorek K, Brewer A, Myatt L. Shear stress may stimulate release and action of nitric oxide in the human fetal-placental vasculature. Am J Obstet Gynecol. 1995;173:708–713.[Medline] [Order article via Infotrieve]
18. Arroll B, Hill D, White G, Sharpe N, Beaglehole R. The effect of exercise episode duration on blood pressure. Hypertension. 1994;12:1413–1415.
19. Kingwell B, Jennings G. A comparison of the effects of walking and other exercise programs upon blood pressure in normal subjects. Med J Aust. 1993;158:234–238.[Medline] [Order article via Infotrieve]
20. Nelson L, Jennings G, Esler M, Korner P. Effect of changing levels of physical activity on blood pressure and hemodynamics in essential hypertension. Lancet. 1986;2:473–476.[Medline] [Order article via Infotrieve]
21.
Jennings G, Nelson L, Nestel P, Esler M, Korner P,
Burton D, Bazelmans J. The effects of changes in physical activity on
major cardiovascular risk factors,
hemodynamics, sympathetic function, and glucose
utilization in man: a controlled study of four levels of activity.
Circulation. 1986;73:30–40.
22. Chowienczyk P, Watts G, Cockcroft J, Ritter J. Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolemia. Lancet. 1992;340:1430–1432.[Medline] [Order article via Infotrieve]
23. Chin J, Dart A. Therapeutic restoration of endothelial function in hypercholesterolaemic subjects: effect of fish oils. Clin Exp Pharmacol Physiol. 1994;21:749–755.[Medline] [Order article via Infotrieve]
24.
Casino PR, Kilcoyne CM, Quyyumi AA, Hoeg JM, Panza JA.
The role of nitric oxide in endothelium-dependent
vasodilation of hypercholesterolemic patients.
Circulation. 1993;88:2541–2547.
25.
Kingwell B, Tran B, Cameron J, Jennings G, Dart A.
Enhanced vasodilation to acetylcholine in athletes is associated with
lower plasma cholesterol. Am J Physiol. 1996;270:H2008–H2013.
26. Jennings GL, Bobik A, Fagan ET, Korner PI. Pindolol pharmacokinetics in relation to time course of inhibition of exercise tachycardia. Br J Pharmacol. 1979;7:245–256.
27. Moreira MF, Mottram RF, Werner AY. The effect of venous pressure on the oxygen content of venous blood in the deep forearm vein. J Physiol Lond. 1956;133:255–265.
28. Green GL, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum S. Analysis of nitrate, nitrite and 15N-nitrate in biological fluids. Anal Biochem. 1982;126:131–138.[Medline] [Order article via Infotrieve]
29.
Zeballos G, Berstein R, Thompson C, Forfia N, Seyedi N,
Shen W, Kaminski P, Wolin M, Hintze T. Pharmocodynamics of plasma
nitratr/nitrite as an indication of nitric oxide formation in conscious
dogs. Circulation. 1995;91:2982–2988.
30.
Maxwell A, Schauble E, Bernstein D, Cooke J. Limb blood
flow during exercise is dependent on nitric oxide.
Circulation. 1998;98:369–374.
31.
Gilligan DM. Selective loss of microvascular
endothelial function in human
hypercholesterolaemia. Circulation. 1994;90:35–41.
32.
Bruning TA, Chang PC, Hendriks MGC, Vermeij P,
Pfaffendorf M, Zwiten PAv. In vivo characterization of muscarinic
receptor subtypes that mediate vasodilation in patients with essential
hypertension. Hypertension. 1995;26:70–77.
33.
Redmond EM, Cahill PA, Sitzmann JV. Flow-mediated
regulation of G-protein expression in co-cultured vascular smooth
muscle and endothelial cells. Arterioscler Thromb
Vasc Biol. 1998;18:75–83.
34.
Bruning TA, Hendriks MG, Chang PC, Kuypers EA, van
Zwieten PA. In vivo characterization of vasodilating
muscarinic-receptor subtypes in humans. Circ Res. 1994;74:912–919.
35. Eglen RM, Whiting RL. Heterogeneity of vascular muscarinic receptors. J Auton Pharmacol. 1990;10:233–245.[Medline] [Order article via Infotrieve]
36.
Miller VM, Flavahan NA, Vanhoutte PM. Pertussis toxin
reduces endothelium-dependent and independent responses
to alpha-2-adrenergic stimulation in systemic canine arteries and
veins. J Pharmacol Exp Ther. 1991;257:290–293.
37.
Chen H, Li H-T. Physical conditioning can modulate
endothelium-dependent vasorelaxation in rabbits.
Arterioscler Thromb. 1993;13:852–856.
38.
Williams P, Krauss R, Vranizan K, Wood P. Changes in
lipoprotein subfractions during diet-induced and exercise-induced
weight loss in moderately overweight men. Circulation. 1990;81:1293–1304.
39. Peltonen P, Marniemi J, Hietanen E, Vuori I, Ehnholm C. Changes in serum lipids, lipoproteins, and heparin releasable lipolytic enzymes during moderate physical training in man: a longitudinal study. Metabolism. 1981;30:518–526.[Medline] [Order article via Infotrieve]
40.
Houmard JA, Bruno NJ, Brunner RK, McCammon MR, Israel
RG, Barakat HA. Effects of exercise training on the chemical
composition of plasma LDL. Arterioscler Thromb. 1994;14:325–330.
41.
Marrugat J, Elosua R, Covas MI, Molina L, Rubies-Prat
J. Amount and intensity of physical activity, physical fitness,
and serum lipids in men. The MARATHOM Investigators. Am J
Epidemiol. 1996;143:562–569.
42. Keins G, Jorgensen I, Lewis S, Jensen G, Lithell H, Vessby B, Hoe S, Schnohr P. Increased plasma HDL cholesterol and apoA-1 in sedentary middle aged men after physical conditioning. Eur J Clin Invest. 1980;10:203–209.[Medline] [Order article via Infotrieve]
43.
Thompson PD, Cullinane EM, Sady SP, Flynn MM, Bernier
DN, Kantor MA, Saritelli AL, Herbert PN. Modest changes in high-density
lipoprotein concentration and metabolism with prolonged
exercise training. Circulation. 1988;78:25–34.
44. Superko HR. Exercise training, serum lipids, and lipoprotein particles: is there a change threshold? Med Sci Sports Exerc. 1991;23:677–685.[Medline] [Order article via Infotrieve]
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C. K. Roberts and R. J. Barnard Effects of exercise and diet on chronic disease J Appl Physiol, January 1, 2005; 98(1): 3 - 30. [Abstract] [Full Text] [PDF]
|
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|
|
D. J Green, A. Maiorana, G. O'Driscoll, and R. Taylor Effect of exercise training on endothelium-derived nitric oxide function in humans J. Physiol., November 15, 2004; 561(1): 1 - 25. [Abstract] [Full Text] [PDF]
|
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|
 |
|
 J. H. Walsh, G. Yong, C. Cheetham, G. F. Watts, G. J. O'Driscoll, R. R. Taylor, and D. J. Green Effects of exercise training on conduit and resistance vessel function in treated and untreated hypercholesterolaemic subjects Eur. Heart J., September 2, 2003; 24(18): 1681 - 1689. [Abstract] [Full Text] [PDF]
|
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 |
|
 J. K. Williams, J. R. Kaplan, I. H. Suparto, J. L. Fox, and S. B. Manuck Effects of Exercise on Cardiovascular Outcomes in Monkeys With Risk Factors for Coronary Heart Disease Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 864 - 871. [Abstract] [Full Text] [PDF]
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 M. E. Davis, H. Cai, L. McCann, T. Fukai, and D. G. Harrison Role of c-Src in regulation of endothelial nitric oxide synthase expression during exercise training Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1449 - H1453. [Abstract] [Full Text] [PDF]
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 G. Fuchsjager-Mayrl, J. Pleiner, G. F. Wiesinger, A. E. Sieder, M. Quittan, M. J. Nuhr, C. Francesconi, H.-P. Seit, M. Francesconi, L. Schmetterer, et al. Exercise Training Improves Vascular Endothelial Function in Patients with Type 1 Diabetes Diabetes Care, October 1, 2002; 25(10): 1795 - 1801. [Abstract] [Full Text] [PDF]
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D. Green, C. Cheetham, C. Reed, L. Dembo, and G. O'Driscoll Assessment of brachial artery blood flow across the cardiac cycle: retrograde flows during cycle ergometry J Appl Physiol, July 1, 2002; 93(1): 361 - 368. [Abstract] [Full Text] [PDF]
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P. Chandrruangphen and P. Collins Exercise-Induced Suppression of Postprandial Lipemia: A Possible Mechanism of Endothelial Protection? Arterioscler Thromb Vasc Biol, July 1, 2002; 22(7): 1239 - 1239. [Full Text] [PDF]
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 J. A. Beckman, M. A. Creager, and P. Libby Diabetes and Atherosclerosis: Epidemiology, Pathophysiology, and Management JAMA, May 15, 2002; 287(19): 2570 - 2581. [Abstract] [Full Text] [PDF]
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 C. Giannattasio, F. Achilli, A. Grappiolo, M. Failla, E. Meles, G. Gentile, I. Calchera, A. Capra, J. Baglivo, A. Vincenzi, et al. Radial Artery Flow-Mediated Dilatation in Heart Failure Patients: Effects of Pharmacological and Nonpharmacological Treatment Hypertension, December 1, 2001; 38(6): 1451 - 1455. [Abstract] [Full Text] [PDF]
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 S. P. Didion, D. D. Heistad, and F. M. Faraci Mechanisms That Produce Nitric Oxide-Mediated Relaxation of Cerebral Arteries During Atherosclerosis Stroke, March 1, 2001; 32(3): 761 - 766. [Abstract] [Full Text] [PDF]
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 B. A. Kingwell, G. L. Jennings, A. M. Dart, Y. Higashi, S. Sasaki, S. Kurisu, A. Yoshimizu, N. Sasaki, H. Matsuura, G. Kajiyama, et al. Exercise and Endothelial Function Response Circulation, November 28, 2000; 102 (22): e179 - e179. [Full Text] [PDF]
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 B. A. KINGWELL Nitric oxide-mediated metabolic regulation during exercise: effects of training in health and cardiovascular disease FASEB J, September 1, 2000; 14(12): 1685 - 1696. [Abstract] [Full Text]
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