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Alfred and Baker Medical Unit, Baker Medical Research Institute, Melbourne 8008, Australia
1Correspondence: 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 |
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 TOP ABSTRACT INTRODUCTIONNO AS A METABOLIC...EFFECTS OF EXERCISE TRAINING...IMPLICATIONS OF IMPAIRED NO...EFFECTS OF EXERCISE TRAINING...CONCLUSIONREFERENCES |
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Key Words: coronary disease • glucose uptake • hypercholesterolemia • hypertension • vascular reactivity
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONNO AS A METABOLIC...EFFECTS OF EXERCISE TRAINING...IMPLICATIONS OF IMPAIRED NO...EFFECTS OF EXERCISE TRAINING...CONCLUSIONREFERENCES |
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2
3
4)
. The production of NO from L-arginine is catalyzed by the dioxygenase, nitric oxide synthase (NOS), which closely resembles cytochrome P450. Three isoforms of NOS, termed NOS I (neuronal), NOS II (inducible), and NOS III (endothelial), have been recognized. NO has been implicated in such diverse processes as vasodilation, inhibition of platelet aggregation, immune function, cell growth, neurotransmission, metabolic regulation, and excitation-contraction coupling. This review will focus predominantly on the constitutively expressed, low-output neuronal (n) and endothelial (e) NOS isoforms that produce NO as a signaling mechanism. In humans, in addition to its expression in endothelial cells, endothelial NOS is found in smooth and cardiac muscle, male and female reproductive tract and brain, whereas neuronal NOS is expressed in brain, spinal cord, sympathetic ganglia, peripheral nerves, pancreas, epithelial cells of the stomach, lung, uterus, and skeletal muscle. From a functional perspective, emphasis will be placed on the role of NO in hemodynamic and metabolic control during exercise, the adaptations that occur with training, and how these may contribute to the preventative and therapeutic effects associated with physical activity and fitness.
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NO AS A METABOLIC REGULATOR DURING EXERCISE |
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TOPABSTRACTINTRODUCTIONNO AS A METABOLIC...EFFECTS OF EXERCISE TRAINING...IMPLICATIONS OF IMPAIRED NO...EFFECTS OF EXERCISE TRAINING...CONCLUSIONREFERENCES |
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as well as increased urinary excretion of the NO
second messenger cyclic GMP and the NO metabolite nitrate during
performance of exercise in athletes (6)
. The potential
mechanisms of NO release and its specific actions are discussed in the
following section.
Skeletal muscle perfusion
The mechanisms controlling skeletal muscle blood flow during
exercise are complex and involve neural, metabolic, endothelial,
myogenic, and muscle pump control. These mechanisms modulate blood flow
via effects on perfusion pressure and the caliber of resistance
vessels. Traditionally, vessel caliber has been thought to represent a
balance between vasodilation mediated directly by production of
metabolites from the exercising muscle and sympathetic activation via
muscle metabo- and mechanoreceptor stimulation. NO derived from both
the endothelium (endothelial NOS, type III) and skeletal muscle
(neuronal NOS, type I) may, however, play an important role in matching
tissue perfusion to demand. In support of this argument, Roberts et al.
have recently shown that a 45 min exhaustive exercise bout increases
both neuronal and endothelial NOS activity in rats (7)
Even though it is undisputed that stimuli such as adenosine, acidity,
temperature, pO2, pCO2,
magnesium, and potassium ions contribute to dilation of the
microvessels, it has become clear that other mechanisms mediate
upstream dilation of larger ‘feed’ arteries. Vascular shear stress
that is determined by blood flow and viscosity is now a
well-established stimulus for elevation of intraendothelial
Ca2+ levels and release of NO from the vascular
endothelium. NO formed from this reaction then diffuses to underlying
vascular smooth muscle cells, where it activates guanylate cyclase to
produce cGMP from GTP and ultimately vasodilation. Thus, microvessel
dilation in response to accumulation of vasodilatory metabolites
creates a pressure gradient that stimulates flow-mediated dilation of
upstream arteries by shear stress-induced release of NO from the
endothelium (Fig. 1, 2a and 2b
) (8)
. This hypothesis is consistent with the lag time of
several seconds between metabolic dilation and flow-induced dilation of
feed arteries (9)
.
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NO-mediated dilation of feed arteries permits increased microvascular
flow without reduction in muscle perfusion pressure. In addition, this
system allows a greater capacity for regulation of systemic vs. local
perfusion demands since the feed arteries are a major site of
sympathetic nervous control of vascular tone. NO may exert control on
sympathetic function peripherally at the level of the feed arteries
(10)
but also in the central nervous system
(11)
, inducing functional sympatholysis (Fig. 1, 3)
. In
the periphery, catecholamine stimulation of endothelial
2-adrenoreceptors causes NO release (12)
.
2-Adrenoreceptor-induced vasoconstriction is particularly sensitive
to the inhibitory effects of NO (12)
. Prejunctional
inhibition of norepinephrine release by NO is also known to occur
(13)
Acetylcholine may represent another mechanism mediating NO-dependent
dilation during physical activity. Although acetylcholine has been
widely used to activate endothelial muscarinic receptors to study
endothelium-dependent NO-mediated vascular reactivity, a physiological
role for acetylcholine is more controversial. The neuromuscular
junction of motor nerves that synthesize, store, and release
acetylcholine may represent a physiological source of acetylcholine
during exercise that stimulates endothelial release of NO, triggering
vasorelaxation and increased blood flow (Fig. 1, 1)
. Segal and
colleagues have also postulated that during physical activity,
acetylcholine released from the neuromuscular junction triggers
hyperpolarization, which is conducted along the endothelial cell layer
via gap junctions between cells (14)
, causing vasodilation
of the arteriole network. This effect does not, however, appear to be
dependent on NO. Acetylcholine of neuronal origin may also be important
in the myocardium, particularly during exercise-induced ischemia, when
NO production from the heart is increased (15)
and the
vagally mediated Bezold-Jarisch reflex is thought to be activated
(16)
. Non-neuronal acetylcholine has also been
demonstrated in platelets and leukocytes as well as endothelial cells
from human skin (17)
and rat (18)
and in
porcine brain vessels (19)
. Although the role of such
non-neuronal acetylcholine has not been fully elucidated, acetylcholine
is released from endothelial cells under basal conditions and in
response to flow (20)
. Thus, acetylcholine is likely to
play a role in control of vascular tone both at rest and during
exercise.
Despite the plausibility of these hypotheses and the associated
in vitro evidence, there is still much controversy regarding
the role of NO in exercise hyperemia, due largely to methodological
difficulties associated with the study of exercise hyperemia in intact
animals and humans. There have been six recent studies in humans
examining the effects of NOS inhibition during exercise (4
, 21
22
23
24
25)
. Three have examined responses in small (arm) muscle
groups, with one showing no effect (22)
, one a small
effect (24)
and the other a moderate effect
(21)
. All three studies measured blood flow using venous
occlusion plethysmography, which necessitates cessation of exercise
during measurement, thus limiting blood flow measurements to the period
immediately after exercise. Hickner and colleagues showed a significant
effect of NOS inhibition, but measured leg blood flow using
microdialysis probes, a technique that requires further validation and
at best measures only blood flow localized to the area immediately
surrounding the probe (23)
. In contrast, Radegran and
Saltin found no effect of NOS inhibition on femoral blood flow assessed
using noninvasive Doppler during knee extensor exercise
(25)
. In an attempt to overcome the methodological
limitations of small muscle exercise and indirect blood flow
measurement techniques, leg blood flow was measured using constant
infusion thermodilution during dynamic cycling exercise with
intrafemoral infusion of either saline or L-NMMA (4)
.
During an exercise bout of 30 min duration performed at 60% of each
subject’s maximum capacity, there was no effect of NOS inhibition on
leg blood flow or oxygen consumption (Fig. 2
, lower panel) (4)
. These data suggest that either NO plays
no role in the hyperemic response to exercise or that there are
redundancies in the vasodilatory mechanism such that NO does not have
an obligatory role in exercise hyperemia if other mechanisms are
functional. Resolution of these two possibilities will be difficult but
may be possible with inhibition of other major metabolic dilator
mechanisms including adenosine, prostacyclin, and
K+ATP channels.
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Coronary perfusion
Similar controversy surrounds the mechanisms controlling coronary
vasodilation during exercise. It is well established that
hyperpolarization of vascular smooth muscle cell membranes brought
about by opening of K+ATP channels is very
important for metabolic coronary vasodilation (26
, 27)
.
Blockade of vascular smooth muscle K+ATP channels
in chronically instrumented dogs, however, did not attenuate the
coronary blood flow response to exercise (27)
, although
both adenosine and K+ATP channel blockade reduced
the exercise-induced increase in coronary flow by half
(28)
. When NOS blockade was added to adenosine and
K+ATP channel blockade, coronary flow was reduced
to levels below that of resting control conditions (29)
.
In the presence of adenosine and K+ATP channel
blockade, NO can produce approximately one-quarter of the coronary
vasodilation normally produced during exercise with all systems intact.
However, NOS inhibition alone or combined with adenosine receptor
blockade did not influence either resting or exercise coronary flow,
indicating that when K+ATP channels are intact,
neither NO nor adenosine-dependent mechanisms are obligatory for
maintaining coronary flow. Thus, all three systems are important for
coronary vasodilation during exercise, but like metabolic skeletal
muscle, vasodilation there is certainly substantial redundancy in the
coronary system.
In addition to the obvious relationship between coronary vessel
vasodilation and flow, coronary perfusion may also be influenced by
aortic properties, which in turn are affected by vascular reactivity to
dilators and constrictors, including NO. Simulated aortic stiffening
induced in dogs by aortic bandaging (30)
limits
subendocardial perfusion, particularly in the setting of a coronary
occlusion, in response to a reduction in diastolic blood pressure. At
the same time, aortic stiffening increases systolic pressure and
cardiac afterload, further stressing the relationship between cardiac
systolic performance and myocardial perfusion. The NOS inhibitor L-NAME
increases vascular impedance in rats (31)
whereas organic
nitrates improve arterial wall viscoelasticity in mini pigs
(32)
, together indicating that NO reduces arterial
stiffness. The most likely mechanism involves NO-induced vasodilation,
which in the physiological pressure range transfers wall stress from
the stiffer collagen fibers to the more distensible elastin matrix.
Although there are currently no studies that have directly examined a
role for NO in modulation of large artery stiffness in the context of
exercise, the known relationship between vascular properties and
vasodilation plus the fact that NO is released during exercise suggests
that NO is probably an important contributor to ventriculo-vascular
coupling and to coronary perfusion via this mechanism during physical
activity. In support of this hypothesis, large artery compliance is
increased immediately after an acute exercise bout (33)
Skeletal muscle metabolism
Both neuronal and endothelial NOS isoforms are constitutively
expressed in rat skeletal muscle fibers whereas in humans, nNOS is
found in skeletal muscle fibers and eNOS is present in the endothelium
of vessels perfusing muscle (34
35
36)
. The neuronal NOS
isoform expressed in human skeletal muscle is a splice variant
incorporating an additional 102 bp, and termed nNOSµ
(37)
. In rodent muscle, neuronal NOS is predominantly
found in type II (fast twitch) muscle fibers (38)
, whereas
in humans and subhuman primates, neuronal NOS is more homogeneously
distributed between type I and II fibers (for review, see ref
39
). Immunoreactivity is predominantly found near the
sarcolemma of muscle spindle fibers, particularly nuclear bag fibers
(which are type I), and localized to motor end plates
(38)
. The dystrophin–glycoprotein complex mediates the
association of nNOS with the sarcolemma, either directly or linked to
1-syntrophin through PDZ domain (PSD-95 (postsynaptic
density protein, Mr 95K), D1g
(discs-large protein), and ZO-1 (zonula occludens-1)
interactions (39)
.In rodents the endothelial NOS isoform
is homogeneously distributed between fast and slow twitch fibers, with
immunohistochemical staining showing a strong correlation between
expression and mitochondrial content (visualized histochemically by
succinate dehydrogenase) in skeletal muscle (35)
. Type II
or inducible NOS is not expressed constitutively in skeletal muscle but
can be induced in response to inflammation.
Balon and Nadler have demonstrated that NO production is increased more
than twofold during electrical stimulation of isolated rat extensor
digitorum longus muscle (1)
. NO production from skeletal
muscle has been implicated in metabolic control via effects on blood
delivery, glucose uptake, oxidative phosphorylation, contractility, and
excitation-contraction coupling. The immunohistochemical association of
nNOS with the sarcolemma suggests that it is this isoform that
influences blood delivery, glucose uptake, and excitation-contraction
coupling. Expression of eNOS is seen in association with the
mitochondria in rodents and correlates with mitochondrial
respiration, and therefore most likely influences oxidative
phosphorylation (40)
.
Blood delivery and glucose uptake
A role for nNOS in control of blood flow during exercise comes
from studies of dystrophin-deficient (mdx) mice in which expression of
this enzyme is greatly reduced (Fig. 1, 4)
. During contraction,
arteriolar dilation was less in contracting skeletal muscle from mdx
mice than controls (41)
. It is possible that reduced blood
flow via this mechanism may contribute to impaired exercise capacity in
the early stages of Duchenne muscular dystrophy prior to the occurrence
of muscle wasting.
The blood flow effects of NO are consistent with those on muscle
metabolism that work to preserve intracellular energy stores by
promoting glucose uptake and by inhibiting glycolysis, mitochondrial
respiration, and phosphocreatine breakdown. Experimentally, NO
modulates carbohydrate metabolism through enhancement of glucose uptake
(1)
and inhibition of glyceraldehyde-3-phosphate
dehydrogenase, and therefore glycolysis (42)
. More recent
rat studies using isolated muscle (2)
and sarcolemmal
vesicular preparations (3)
indicate that NO-mediated
glucose uptake occurs during exercise. The first evidence that
NO-mediated glucose uptake during exercise is important in humans was
published recently (4)
. In this study, the NOS inhibitor
L-NMMA infused into the femoral artery during cycling reduced glucose
uptake by 48% compared with a control, saline infusion (Fig. 2
, upper
panel). This effect occurred in the absence of any changes in blood
flow, suggesting that L-NMMA directly affected the ability of skeletal
muscle to extract glucose from the blood (Fig. 2
, lower panel). The
precise mechanism for this action has not been elucidated, but nNOS
stimulation may be linked to the rise in intracellular calcium
associated with contraction (43)
. Furthermore, since
insulin and NO have additive effects on glucose uptake and
insulin-mediated glucose uptake is not affected by NOS inhibition,
insulin and NO appear to recruit discrete pools of the glucose
transporter GLUT-4 (44)
Oxygen consumption
It is well known that large local concentrations of NO produced in
response to inducible NOS activation inhibit cellular respiration in a
pathophysiological setting. Studies in conscious dogs, however, support
the notion that tissue oxygen consumption is modulated physiologically
in vivo by constitutively produced NO (45
, 46)
.
In these studies, NO synthase inhibition significantly increased
whole-body and skeletal muscle oxygen extraction above levels expected
purely as a result of vasoconstriction, so that under normal
physiological conditions NO inhibits oxygen extraction. More recent
data from dogs also confirm this hypothesis in the heart
(47)
.
The mechanism by which NO reduces oxygen extraction appears to relate
to effects on enzymes involved in oxidative phosphorylation
(48)
and transfer of high-energy phosphates
(49)
as well as c-GMP-dependent pathways
(50)
. Of these mechanisms, perhaps the most well described
is the reversal inhibition of cytochrome c oxidase by NO or
its derivative peroxy nitrite (ONOO-) at low
(nanomolar) concentrations through competition with oxygen
(51)
. At higher concentrations, NO inhibits other
respiratory chain enzymes through nitrosylation and oxidation
(50)
. The expected reduction in contractility as a result
of inhibition of these processes by NO has been observed in the heart
(47)
and skeletal muscle (52)
. Definitive
in vivo evidence for regulation of mitochondrial respiration
by NO is still lacking, particularly in the setting of exercise.
Indeed, in the only animal study examining oxygen extraction during
exercise, NO favored aerobic rather than anaerobic metabolism in
horses, as evidenced by higher plasma lactate during NOS inhibition
with L-NAME (53)
. Whether such effects related to reduced
oxygen delivery as a result of lower blood flow is unclear. NOS
inhibition has not been shown to affect oxygen uptake during exercise
in humans (4)
.
Contractility
Endogenous NO production decreases submaximal skeletal muscle
force by modulating excitation-contraction coupling (38)
.
In addition, NO donors and cGMP depress contractile function whereas
NOS inhibition, extracellular NO chelation, and guanylyl cyclase
inhibition augment contractile function (38
, 40)
. Although
these findings support a cGMP-dependent inhibition of contraction, NO
may also modulate contractile function directly through inhibition of
opening of calcium release channels of the sarcoplasmic reticulum
(54)
. On the other hand, NO may be an essential component
for active shortening by facilitating cross-bridge cycling
(55)
. These opposing actions of NO on contractile function
must be interpreted in the light of studies showing that contraction
induces a decline in muscle NOS activity, which if localized to the
mitochondria might represent a compensatory mechanism through which
muscle contractility and mitochondrial function are protected from the
inhibitory influence of NO (56)
.
Cardiac muscle function
In addition to the role of endothelially derived NO in the
coronary vasculature, human cardiac muscle expresses both eNOS
(57)
and nNOS (58)
whereas iNOS is inducible
in disease states, including cardiomyopathy (59)
. Recent
studies suggest that nNOS is expressed in cardiac sarcoplasmic
reticulum and that the expressed enzyme may be a novel isoform
(58)
. As in skeletal muscle, NO appears to inhibit
contractile function and oxygen consumption (60)
,
particularly in the setting of endotoxin exposure and iNOS expression
(61)
. In contrast to skeletal muscle, however, NO appears
to inhibit glucose uptake in the myocardium at rest (62)
.
The contractile effects are consistent with myocardial relaxation and
reduced diastolic tone (61)
and are mediated in part by
inhibition of respiratory chain enzymes and creatine kinase
(60)
. However, findings are not homogeneous, and there are
many examples where NO acts as a mild inotrope (for review, see ref
63
).The reasons for these discrepancies are currently
unresolved but may relate to methodological (in vivo vs.
in vitro) and species differences.
Although few studies have examined the role of NO in the myocardium
during exercise, Bernstein and colleagues have shown that acute
treadmill exercise in dogs increases NO production from the coronary
circulation (64)
. Blockade of NO prevented NO release,
increased myocardial oxygen consumption, and reduced myocardial free
fatty acid consumption for comparable levels of coronary blood flow and
work. These metabolic changes occurred in the absence of alterations in
myocardial glucose or lactate consumption.
Summary
NO potentially affects metabolic control during exercise via
multiple mechanisms, including:
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EFFECTS OF EXERCISE TRAINING ON NO FUNCTION IN HEALTHY INDIVIDUALS |
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Animal studies
The effects of training on resting NO release and reactivity in
isolated vessels have been reviewed extensively elsewhere and will not
be expanded on in this review (65)
. In brief, vessels
exposed to elevated flow during exercise, including the aorta,
coronaries, and vessels from the active muscle bed, generally show
evidence of increased NO production, gene expression, and/or reactivity
(66)
. In dog models, exercise training enhanced reactivity
to NO-dependent agonists in both proximal coronary arteries (66
, 67)
and coronary microvessels (66)
, but the
opposite was true in rats (68)
and pigs (69)
.
There are clear species and regional differences in the NO response to
training, highlighting the importance of human studies.
Human studies
Evidence in humans for chronic changes in the NO system with
training is accumulating. Recent work suggests that
endothelium-dependent dilation may be altered by training in the rest
period between exercise bouts and that the effect may not be restricted
to the trained muscle bed (70
71
72)
. Moderate cycle
training for 4 wk increased basal NO production in the forearm
(Fig. 3
, center panel; ref 71
) and a 10 wk program increased
forearm flow-mediated dilation (72)
. These data indicate
first that whole-body dynamic exercise may represent a powerful
stimulus for adaptations in the NO system, and second that increased
vascular shear stress as a result of elevation in heart rate, pulse
pressure, blood viscosity, and blood flow may alter NO function in
nonexercising muscle beds (71)
. In contrast, athletes who
were predominantly leg trained exhibited no changes in basal NO
production (Fig. 3
; left panel; ref 70
). This finding may
reflect differences between cross-sectional (70)
and
longitudinal studies (71)
, the latter being more specific
for exercise, with an alternate explanation being that although NO may
play a role in the short term adaptations to exercise (i.e., over a few
weeks), long-term exercise over a period of years is not associated
with changes. It is possible that adaptations to meet metabolic demands
with training evolve from vasodilation mediated at least in part by NO
in the short term, to longer term adaptations such as metabolic enzyme
changes and vascular restructuring. This is consistent with the
hypothesis advanced by McAllister and Laughlin, who speculated that
vascular endothelial function is enhanced after just a few days of
training and that such adaptation could serve to buffer the increase in
shear stress experienced during exercise. NO may be involved in the
signaling cascade that subsequently triggers the structural changes
(including increased vessel diameter) that minimize or even eliminate
the need for enhanced release of NO (73)
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Whereas basal NO production appears unaffected at rest by long-term
training, acetylcholine-stimulated release is increased, possibly
relating to lower total cholesterol in athletes (70)
. This
effect implies a greater endothelium-dependent vasodilator reserve in
athletes, which would increase capacity to perform localized exercise
not limited by cardiac considerations. In addition, if such adaptations
are present in the coronary circulation, the enhanced dilator reserve
capacity observed in response to nitroglycerin in ultradistance runners
(74)
could be evoked physiologically by endothelial
mechanisms. This may in part underlie the enhanced ischemic threshold
induced by training in the setting of coronary disease. Finally,
enhanced NO-dependent dilator reserve in the aorta may contribute to
improved coronary perfusion and reduced afterload via the increased
aortic compliance we have documented in athletes (75)
and
after 4 wk of moderate intensity cycling in previously sedentary
subjects (76)
Summary
The vast animal literature together with more recent human studies
indicates that endurance exercise training for a period ranging from
days to several weeks enhances basal release of nitric oxide from the
aorta, active and inactive muscle, and coronary arteries. This
adaptation may contribute to the reduction in resting blood pressure
that can be observed after as little as 4 wk of training (77
, 78)
. Increased vascular NO production appears to be a transitory
response to training that progresses to structural and other sustained
adaptations. Training also enhances agonist-induced,
endothelium-dependent dilation in these same vascular beds, but is
associated with training durations ranging from weeks to months. Such
adaptations would be expected to enhance blood and substrate delivery
to cardiac and active skeletal muscle, thus contributing to enhanced
exercise capacity. The effects of training on the other purported
metabolic actions of NO have not been investigated.
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IMPLICATIONS OF IMPAIRED NO FUNCTION FOR EXERCISE CAPACITY |
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There is emerging evidence in humans and more complete data in animals
indicating that endothelial dysfunction limits exercise capacity either
through cardiac or peripheral mechanisms. The ApoE-deficient mouse that
simulates hypercholesterolemia and wild-type mice fed the NOS inhibitor
LNA (NG-nitro-L-arginine) had reduced
postexercise nitrate excretion, aerobic capacity, and peak exercise
redistribution of cardiac output to running muscles (expressed as a
percentage of cardiac output) (79)
. Such findings indicate
that NO contributes significantly to limb blood flow during exercise
and that conditions that reduce NO disturb the hyperemic response to
exercise, resulting in a reduced exercise capacity. In support of this
contention, the forearm blood flow response to handgrip exercise is
diminished in cardiac failure patients. Intra-arterial L-arginine
infusion had no effect on blood flow response in healthy individuals
but restored responses to normal in cardiac failure patients
(80)
. Whereas L-arginine is known to have NO-independent
vasodilatory actions, the lack of effect in the healthy group where
L-arginine is thought to be non rate-limiting to NO production suggests
that the mechanisms for restoration of forearm blood flow responses to
handgrip exercise in the cardiac failure group was NO related.
In patients with hypercholesterolemia and coronary atherosclerosis,
coronary and systemic arteries constrict during exercise
(81
82
83)
, probably reflecting loss of dilator regulation
by the coronary endothelium as a consequence of diminished NO release
or increased degradation. Such effects would also be expected to
augment responsiveness to vasoconstrictors such as norepinephrine and
endothelin. Endothelial dysfunction in the setting of coronary disease
is thus likely to be a major contributor to exertion-induced ischemia
and a limiting factor to exercise capacity. Indeed, Ishibashi and
colleagues have suggested, based on their studies with dogs, that
coronary disease patients with impaired small coronary
endothelium-dependent dilation are more susceptible to hypoperfusion
distal to a coronary artery stenosis, particularly during exertion
(84)
.
NO may also have an important role in pulmonary vasodilation during
exercise. NO is increased in exhaled air during exercise in normal
subjects (85)
; at rest, NO concentration in expired air
was less in congestive heart failure than normal subjects and increased
during exercise by a greater amount in normal subjects
(86)
. This may contribute to blunted pulmonary dilation
and thus an abnormally high ventilatory response, which occurs during
exercise in cardiac failure. Inhalation of NO normalizes this response
and improves exercise capacity in patients with moderate right
ventricular failure (87)
Skeletal muscle
Since the potential role of NO in metabolism and glucose uptake
has emerged only relatively recently, few studies have examined the
effect of cardiovascular disease on skeletal muscle NOS expression or
on functional responses; the link with glucose metabolism has led to a
predominant focus on diabetes. Skeletal muscle NOS activity is reduced
in both obese insulin-resistant Zucker rats (88)
and
humans (89)
. Although no study has examined the question
directly, our findings with regard to the role of NO in glucose uptake
in humans (4)
would suggest that reduced skeletal muscle
nNOS expression may contribute to the impaired exercise capacity in
diabetics (90
, 91)
. However, glucose uptake is often
preserved in diabetics during exercise, and further work is clearly
warranted to directly examine the role of NO in glucose uptake in this
group.
Expression of inducible NOS has also been examined in the setting of
cardiac failure as a possible link between myocardial dysfunction and
reduction in peripheral exercise tolerance (49
, 92)
. Since
there is increased expression of inducible NOS in vastus lateralis
muscle of congestive heart failure patients relative to normal controls
(92)
, exercise capacity may thus be limited via the
inhibitory effects of NO on enzymes of oxidative phosphorylation
(48)
. Furthermore, Haembrecht and colleagues have observed
intracellular NO accumulation in heart failure and an inverse
relationship between skeletal muscle iNOS expression and maximum oxygen
uptake/mitochondrial creatine kinase (49)
. These data
imply that premature muscle fatigue in cardiac failure may be mediated
by both impaired energy production and impaired energy transfer from
the mitochondrion to the cytosol.
Summary
Definitive evidence for a pivotal role of NO in the impaired
response to exercise in cardiovascular conditions is not yet available.
Furthermore, it is difficult to separate the specific limitations of NO
dysfunction on exercise capacity from limitations related to other
aspects of disease; however, the data cited and mechanistic
plausibility support the contention that NO dysfunction limits exercise
capacity. The major mechanism appears to be reduced blood delivery to
active muscle including the pulmonary and coronary circulations. These
limitations may be particularly important in cardiac failure.
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EFFECTS OF EXERCISE TRAINING ON NO FUNCTION IN CARDIOVASCULAR DISEASE |
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.
Hypertension
In genetic models of hypertension, training improves acetylcholine
responses in aortic and mesenteric rings (94)
, decreases
aortic and carotid responsiveness to norepinephrine by increasing NO
release (95)
, and increases plasma nitrate
(96)
. Recent studies in human hypertension have reported
that daily walking for 30 min over a 12 wk period augmented
endothelium-dependent vasorelaxation (97
, 98)
; there was a
negative correlation between the change in forearm reactive hyperemia
and LDL during the intervention. The lipid profile changes in these
studies, however, were more consistent with dietary modification than
exercise training, and since no objective assessment of improved
fitness was presented, it is difficult to attribute the changes in
endothelial function solely to training.
Hypercholesterolemia
In a mouse model, hypercholesterolemia impaired exercise capacity,
possibly due to impaired NO-dependent vasodilatory capacity
(99)
. In this same study, exercise training at 6 days per
week for 4 wk increased vascular reactivity and NO synthesis, which in
turn correlated with improvement in anaerobic threshold.
Hypercholesterolemic patients with impaired forearm reactivity to
acetylcholine participated in a randomized crossover study
incorporating 4 wk of moderate intensity cycling and 4 wk of normal
sedentary activity (100)
. The training intervention had no
effect on lipid profile, although forearm constrictor responses to
L-NMMA were augmented (Fig. 3
, right panel) and forearm production of
the NO metabolites nitrate and nitrite were increased by training,
suggesting greater NO production at rest. Responses to acetylcholine
were unaffected by the training regimen. These data suggest that for
hypercholesterolemic patients, training has benefits in addition to
lipid profile modification and may be considered a useful adjunct to
conventional lipid lowering therapy.
Diabetes
Otsuka Long-Evans Tokushima fatty rats have impaired aortic
dilation to histamine but not sodium nitroprusside. Although exercise
training and food restriction both significantly reduced plasma levels
of glucose and insulin, lowered serum levels of triacylglycerol and
cholesterol, and reduced the accumulation of abdominal fat, only
exercise restored responses to histamine and increased urinary
excretion of nitrite (101)
. Furthermore, 8 wk of treadmill
training increased skeletal muscle expression of neuronal NOS by
fourfold and expression of endothelial NOS by twofold (2)
.
Although there are no human data, the rat studies suggest that
modulation of the NO pathway by exercise training could provide a novel
approach to improving skeletal muscle glucose uptake.
Coronary disease
The effects of training on NO function have been studied only on
an empirical level with regard to coronary disease. A 12 wk cardiac
rehabilitation program was associated with a 150% increase in the
excretion of NO metabolites. The increase in NO metabolite excretion
was in proportion to the increase in functional capacity as a result of
training (102)
.
Cardiac failure
The efficacy of training to restore endothelial dysfunction
associated with cardiac failure is controversial. In a coronary artery
occlusion heart failure model, 6 wk of treadmill training failed to
restore aortic acetylcholine responses (103)
. Similarly, 4
wk of forearm handgrip exercise did not change responses to
acetylcholine, reactive hyperemia, NOS inhibition, or acute forearm
exercise, whereas the same intervention augmented acetylcholine and
reactive hyperemic responses in healthy controls (104)
.
These data contrast with two earlier studies (105
, 106)
.
Hornig and colleagues showed that heart failure patients exhibited
impaired forearm dilation to release of both wrist and upper arm
occlusion for 4 and 8 min. Patients then underwent daily forearm
isometric handgrip training for 4 wk. The training program elevated
flow-mediated dilation in the trained arm to levels observed in
disease-free subjects, although this improvement regressed to baseline
6 wk after cessation of training. Studies performed in the presence of
NOS inhibition with L-NMMA indicated that the restorative effects of
training on flow-mediated dilation were related to endothelial release
of NO. Second, using plethysmography Katz and colleagues observed
augmented responsiveness to acetylcholine after 8 wk of forearm
training (105)
. Training frequency may account for
discrepancies between the human studies, with the latter two positive
studies incorporating daily training sessions and the former only four
sessions per week.
Although the handgrip studies have provided initial support for
training-related adaptations in the NO system, only one study has
examined the effects of large muscle dynamic endurance exercise in
cardiac failure (107)
. Forty minutes of cycling 5 days per
week for 6 months improved femoral blood flow in response to
intra-arterial infusion of acetylcholine but not sodium nitroprusside;
the vasoconstrictor effect of NOS inhibition with L-NMMA also
increased, suggesting enhanced basal release of NO. The increase in
peak oxygen uptake was in proportion to the change in
endothelium-dependent dilation, so that impaired endothelial NO
production may contribute to peripheral exercise limitation and
increased exercise capacity as a result of training may be a
consequence of improved NO production from the endothelium.
Summary
The studies discussed indicate that the role of NO in modulating
vascular tone after training must be defined in terms of type of
training, vascular region, and time course of the training response.
Preliminary data indicate that the NO system is modified by training in
the setting of cardiovascular disease and that these effects may
contribute to increased functional capacity. However, the role of NO in
the coronary circulation and skeletal muscle particularly with regard
to glucose uptake is yet to be established.
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CONCLUSION |
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ACKNOWLEDGMENTS |
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.
B.A.K. is an NH&MRC Research Fellow. This work was also supported by a
block grant from the National Health and Medical Research Council to
The Baker Medical Research Institute. |
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90 min of rest.
Mean ± SE. L-NMMA protocol (filled circles); control
protocol (open circles). L-arginine (L-Arg) was infused during the
final 5 min of both protocols. *P< 0:05 between trials
(4)