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Division of Critical Care and Respiratory Division, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada H3A 1A1
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Hussain, Sabah N. A., Qasim El-Dwairi, Mohammed N. Abdul-Hussain, and Dalia Sakkal. Expression of nitric oxide
synthase isoforms in normal ventilatory and limb muscles.
J. Appl. Physiol. 83(2): 348-353, 1997.
Nitric oxide (NO), an important messenger molecule with
widespread actions, is synthesized by NO synthases (NOS). In this
study, we investigated the correlation between fiber type and NOS
activity among ventilatory and limb muscles of various species. We also
assessed the presence of the three NOS isoforms in normal skeletal
muscles and how various NOS inhibitors influence muscle NOS activity.
NOS activity was detected in various muscles; however, NOS activity in
rabbits and rats varied significantly among different muscles.
Immunoblotting of muscle samples indicated the presence of both the
neuronal NOS and the endothelial NOS isoforms but not the
cytokine-inducible NOS isoform. However, these isoforms were expressed
to different degrees in various muscles. Although the neuronal NOS
isoform was detectable in the canine diaphragm, very weak expression
was detected in rabbit, rat, and mouse diaphragms. The endothelial NOS
isoform was detected in the rat and mouse diaphragms but not in the
canine and rabbit diaphragms. We also found that
NG-nitro-L-arginine methyl ester,
7-nitroindazole, and
S-methylisothiourea were
stronger inhibitors of muscle NOS activity than was aminoguanidine. These results indicate the presence of different degrees of
constitutive NOS expression in normal ventilatory and limb muscles of
various species. Our data also indicate that muscle NOS activity is not determined by fiber type distribution but by other not yet identified factors. The functional significance of this expression remains to be
assessed.
nitric oxide; skeletal muscle; ventilatory muscles; L-arginine
INTRODUCTION NITRIC OXIDE SYNTHASE (NOS) is a flavin- and
heme-containing enzyme that catalyzes the NADPH-dependent conversion of
L-arginine to nitric oxide (NO)
and L-citrulline. Three main NOS
isoforms have been identified thus far, two of which are constitutively expressed and were initially identified in the endothelial cells (ecNOS; type III) and brain cells (bNOS; type I), and the third is a
cytokine-inducible (iNOS; type II) isoform (15).
Under normal conditions, there is strong evidence that NO plays an
important role in the regulation of skeletal muscle vascular tone in
vivo. Scavengers of NO and inhibitors of NOS activity have been shown
to elicit a significant increase in skeletal muscle vascular resistance
and small arteriole tone (25, 30, 35). These results suggest that NO is
an important modulator of skeletal muscle vascular tone. Previous
studies in our laboratory confirmed the significant role
of NO in regulating diaphragmatic blood flow under basal conditions and
in response to brief arterial occlusion (reactive hyperemia), phrenic
nerve stimulation (active hyperemia), and alterations in arterial
pressure (autoregulation) (7, 14, 32, 34).
The exact isoform responsible for NO release in the majority of studies
dealing with the role of NO in muscle blood flow was not identified but
was assumed to be ecNOS. Until recently, this assumption was not
challenged because no information was available regarding the
expression of other NOS isoforms in cardiac and skeletal muscles.
Nakane et al. (23) reported for the first time that bNOS mRNA is
abundant in human skeletal muscle samples. These authors also found a
single 160-kDa protein band that corresponded to bNOS monomer in human
skeletal muscle samples. By comparison, no bNOS mRNA or protein could
be detected in rat skeletal muscle samples. In a subsequent study,
Kobzik et al. (16) reported that bNOS expression in skeletal muscle
fibers is localized to muscle membranes of mainly type II fibers and
that NOS activity, measured as the rate of
L-citrulline production, varies
significantly among rat muscles, with highest activity being in type II
(glycolytic) muscle fibers. These findings suggest that muscle NOS
activity is largely determined by bNOS activity. Kobzik et al. (16)
also proposed that the synthesis of NO by striated muscle fiber exerts a negative influence on muscle force because inhibition of NOS activity
resulted in a shift to the left in force-frequency relationships. In
another study, in vitro incubated rat limb muscles were found to
release NO that rises with increased muscle activity (2). More
recently, Kobzik et al. (17) described the presence of ecNOS isoform in
muscle fibers that have a high abundance of succinate dehydrogenase.
This suggests that ecNOS activity is related to oxidative capacity of
striated muscle fibers. Using immunohistochemistry, these authors
reported that, unlike bNOS, ecNOS staining was more diffuse across the
sarcoplasm. Despite these early reports, many questions regarding the
relationship between muscle fiber type distribution and NOS activity,
the presence or absence of inducible NOS isoform, and selective
inhibition of muscle NOS activity by various NOS inhibitors remain
unanswered. We undertook this study, therefore, to test a main
hypothesis, namely, that skeletal muscle NOS activity correlates with
fiber type distribution, i.e., the higher proportion of fast-twitch
glycolytic fibers, the greater the NOS activity. We also examined
whether total NOS activity is attributable to the constitutive
expression of both neuronal and ecNOS isoforms and not to the
cytokine-inducible NOS isoform. Finally, we assessed the selectivity of
various NOS inhibitors in inhibiting muscle NOS activity.
To achieve our objectives, we measured NOS activity (conversion of
L-arginine to
L-citrulline) in the presence of
various NOS cofactors in limb and ventilatory muscles of various
species. We sampled muscle tissues from rats, dogs, rabbits, and mice
to study the correlation between fiber type and NOS activity over a
wide range of fiber type distribution. We also assessed the effects of
four different NOS inhibitors on muscle NOS activity. Finally, we
performed immunoblotting by using selective antibodies for the three
NOS isoforms to detect the presence of specific NOS isoforms and
the molecular mass of NOS isoforms in various striated muscle
samples.
MATERIALS AND METHODS
-2-ethanesulfonic acid buffer, 0.1 mM EDTA, 1 mM dithiothreitol, 0.32 mM sucrose, 1 mg/ml
phenylmethylsulfonyl fluoride, 10 µg/ml leuopeptin, 10 µg/ml
aprotinin, and 10 µg/ml pepstatin A, pH 7.4). Tissue homogenate (50 µl) was added to 10-ml prewarmed (37°C) tubes containing 100 µl
of reaction buffer of the following composition (in mM): 50 KH2PO4,
60 valine, 1.5 NADPH, 10 FAD, 10 tetrahydrobiopterin
(BH4), 1.2 MgCl2, and 2 CaCl2, as well as 1 mg/ml bovine
serum albumin, 1 µg/ml calmodulin, and 25 µl of 120 µM stock
L-[2,3-3H]arginine
(150-200
counts · min
1 · pmol1). The samples were
incubated for 30 min at 37°C, and the reaction was terminated by
the addition of 500 µl of cold (4°C) stop buffer (100 mM
N-2-hydroxyethylpiperazine-N-2-ethanesulfonic
acid, 12 mM EDTA, pH 5.5). A similar procedure was used to assess
Ca2+/calmodulin-independent NOS
activity, except that Ca2+ and
calmodulin were omitted from the reaction buffer and 1.5 mM of ethylene
glycol-bis(
-aminoethyl
ether)-N,N,N,N-tetraacetic acid and EDTA were added. Background activity was measured by replacing
tissue samples with 50 µl phosphate-buffered solution. This value was
subtracted from tissue sample values to yield actual NOS activity. To
obtain free
L-[2,3-3H]citrulline
for the determination of enzyme activity, 2 ml of Dowex 50w resin (8%
crosslinked, Na+ form) were
added to eliminate excess
L-[2,3-3H]arginine.
The supernatants were removed and examined for the presence of
L-[2,3-3H]citrulline
by liquid scintillation counting. Protein concentration was measured by
using the Bradford technique (Bio-Rad), and the enzyme activity was
expressed in picomoles
L-[2,3-3H]citrulline
produced per minute per milligram protein. In a few experiments, we
assessed the effects of various NOS inhibitors on canine diaphragmatic
NOS activity by adding NOS inhibitors directly to the reaction buffer
at final concentrations of 1, 10, and 100 µM.
Immunoblotting.
Frozen muscle samples were homogenized in 5 vol/wt buffer of the
following composition: 50 mM
tris(hydroxymethyl)aminomethane · HCl (pH 7.5), 1 mM EDTA,
5 mM -mercaptoethanol, 10 µg/ml pepstatin A, 10 µg/ml aprotonin,
10 µg/ml leupeptin, and 100 µg/ml phenylmethylsulfonyl fluoride.
Homogenate proteins (50 µg) were heated at 65°C for 30 min and
then loaded on 8% sodium dodecyl sulfate-polyacrylamide gel
electrophoresis slabs (Novex). Proteins were then
electrically blotted onto polyvinylidene difluoride membrane, blocked
with 5% nonfat dry milk, and subsequently incubated with 1:500 or
1:1,000 dilution of various monoclonal or polyclonal antibodies
selective to various NOS isoforms. Proteins were detected with
horseradish peroxidase-linked anti-mouse or anti-rabbit secondary
antibodies and enhanced chemiluminescence reagents (Amersham).
Pituitary, endothelial cell, and activated macrophage lysates were used
as positive controls for bNOS, ecNOS, and iNOS, respectively. These lysates were supplied by Transduction Laboratories. Predetermined molecular mass standards (Bio-Rad) were used as markers.
Data analysis.
Data are presented as means ± SE. Differences in NOS activity
between muscles or conditions were assessed by using two-way analysis
of variance. P < 0.05 was considered
significant.
RESULTS
To test our main hypothesis, we correlated the proportions of type I and subgroups of type II fibers in various muscles (8, 11, 26) with total NOS activity. Classification of fibers into type I and type II is based on histochemical staining for myosin adenosinetriphosphatase activity, type I being slow-twitch fibers and type II, fast-twitch fibers. Analysis of single muscle flbers demonstrated that specific myosin heavy chains I, IIa, and IIb correspond to histochemical definitions of type I, IIA, and IIB fibers. In addition, histochemically defined type IID/X fibers are known to contain type IId myosin heavy chain. When all muscles of various species were pooled, no significant correlation between fiber type distribution and NOS activity was found (data not shown). The r values for correlation analysis between muscle NOS activity and proportion of type I, IIA, and IIB fibers were 0.24, 0.11, and 0.11, respectively (not significant). However, intraspecies analysis revealed that muscle NOS activity in the rat correlated positively with the proportion of type IID/X fibers and negatively with type I fibers (P < 0.01; Fig. 2)
Immunoblotting. Anti-bNOS and -ecNOS antibodies detected protein bands of 160 and 130 kDa, respectively. The intensity of the bNOS band varied significantly among muscles of different species (Fig. 3A). Canine ventilatory muscles showed relatively high bNOS band intensity, whereas weaker signals were detected in the rat, mouse, and rabbit diaphragms (Fig. 3A). Very weak bNOS signals were detected in rabbit ventilatory muscles. There were also differences in bNOS expression among various muscles within a species. Figure 3B illustrates bNOS expression in rat muscles. Prominent bNOS expression was evident in the intercostal and gastrocnemius muscles, whereas weak bNOS expression was evident in the diaphragm and soleus muscles.
In addition to bNOS, there were differences in ecNOS expression among various muscles. Although rat and mouse diaphragms showed ecNOS expression, neither canine nor rabbit muscles showed any ecNOS expression (Fig. 4A). Less variation in band intensity was detected with anti-ecNOS antibodies in rat muscles (Fig. 4B). We were unable to detect iNOS protein in any of the muscles when a variety of anti-iNOS antibodies were used (data not shown). Inhibition of NOS activity. Diaphragmatic NOS activity was strongly and dose dependently inhibited by 7-NI, L-NAME, or SMT (n = 6, Table 1). Aminoguanidine, on the other hand, was a weak inhibitor of NOS activity (Table 1).
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DISCUSSION
The major finding of this study is that significant differences in mammalian skeletal muscle NOS activity exist within and between species. Analysis of NOS activity within species revealed that in the rat, muscle NOS activity correlated negatively with the proportion of type I fibers and positively with the proportion of type IID/X fibers. We also confirmed previous findings indicating that both ecNOS and bNOS isoforms are present in rat skeletal muscles (16, 17), but canine and rabbit ventilatory muscles appear to lack ecNOS expression (Fig. 4A). We also found that muscle NOS activity is inhibited strongly by L-arginine analogs 7-NI and SMT but weakly by aminoguanidine.
NOS expression in striated muscle fibers. The role of endothelial NO production in the regulation of ventilatory and limb muscle blood flow has been confirmed by numerous investigators (10, 14, 33, 35). In none of these studies was the origin of NO release within skeletal muscles identified, but it was assumed to be the endothelial cell layer. With the most recent discovery of bNOS expression in skeletal muscle fiber, this assumption is being increasingly challenged. Nakane et al. (23) were the first to describe the existence of bNOS mRNA and protein in human skeletal muscle; however, the exact muscle studied in that report was not identified. In a later study, Kobzik et al. (16) demonstrated that rat skeletal muscles express the bNOS isoform, which is located in the sarcolemma of mainly type II fibers. Among the ventilatory muscles, only diaphragmatic NOS activity was measured by these authors. In other studies, in vitro incubated rat limb muscles were found to release NO that was suppressed by NOS inhibitors (2, 16). The major finding of our study is that significant intra- and interspecies differences exist in muscle NOS activity. We would like to point out that we used a single published value of fiber type composition for a given muscle and correlated this value with muscle NOS activity (see RESULTS). One could, therefore, attribute the lack of a relationship between muscle NOS activity and muscle fiber type composition across species to the fact that significant differences in fiber type composition have been reported. However, when the data of Delp and Duan (8) regarding rat limb and ventilatory muscle fiber type composition were replaced by those of either Barnard et al. (3), Brooke and Kaiser (5), Hamalainen and Pette (13), or Green et al. (11), the negative relationship between percentage of type I and muscle NOS activity (Fig. 2) remained highly significant. This finding suggests that muscle fiber composition is an important determinant of muscle NOS activity, at least in the rat. This conclusion supports an earlier one made by Kobzik et a1. (16), who reported that muscle NOS activity in the rat correlated with the percentage of type II muscle fibers. These authors attributed this correlation to a relatively high expression of bNOS in type II fibers and suggested that bNOS activity represents a major part of total muscle NOS activity. Despite the similarity between our findings and those of Kobzik et al. (16) regarding rat muscles, there is a major difference in the experimental approach used in the two studies. While Kobzik et al. studied NOS activity in the particulate fraction of various skeletal muscles, whole cell homogenates were used in our study. The use of whole cell homogenates and the fact that we did not evaluate NOS isoform expression in the cytosolic vs. the particulate fraction of muscle homogenate limited our conclusion regarding the contribution of bNOS expression to total muscle NOS activity and whether bNOS expression correlates with muscle fiber type composition across species. Another factor that might have contributed to interspecies differences in muscle NOS activity is the presence of ecNOS in muscle fibers (17). Our results confirm the presence of this isoform in rat and mouse muscles; however, not all skeletal muscles express ecNOS. We failed to detect ecNOS expression in canine and rabbit muscles (Fig. 4A). This finding was confirmed by using another polyclonal ecNOS antibody (Affinity BioReagents). Despite the observation of prominent ecNOS expression in rat and mouse skeletal muscles, the contribution of this isoform to NOS activity of whole cell homogenate and, by extension, the role of this isoform in determining the relationship between muscle NOS activity and fiber type distribution, remain unclear primarily because we did not identify the localization of ecNOS (particulate vs. cytosolic muscle fractions). It is also likely that differences in NOS activity among various muscles might not be due to diversities in NOS protein expression. This is because the availability of substrates and cofactors such as L-arginine, NADPH, and BH4 is known to play a significant role in NOS activity. Variations in local concentrations of endogenous NOS inhibitors such as NG,NG-dimethylarginine, and NG,NG-dimethylarginine,
which are produced by the endothelium (31), could also explain
differences in basal NOS activity in various muscles. Moreover, the
rate of production of NO and
L-citrulline by NOS is regulated
in part by the local concentration of NO through a process known as
autoinhibition (27). It has also been established that the presence of
NO scavengers such as superoxide anions
(O2·) improves the rate of NO
production by reducing autoinhibition. Conversely, the addition of
superoxide dismutase reduces the rate of NO production by stabilizing
NO and, hence, augmenting autoinhibition (27). It is possible that
inter- and intraspecies differences in local levels of
O2· and superoxide dismutase in
various skeletal muscles may contribute to the diversity in basal NOS
activity. Clearly, more research is needed to elucidate the relevance
of local and systemic factors in modulating muscle NOS activity in
different species.
Inhibition of muscle NOS activity.
L-Arginine analogs, the most
commonly used NOS inhibitors, are known to interfere with
L-arginine binding in the three
NOS isoforms (19). Our results indicate that
L-NAME is capable of dose-dependent inhibition of dia- phragmatic NOS activity. We also found that 7-NI is a potent inhibitor of muscle NOS activity. This
compound is believed to target the heme group of NOS and also
interferes with L-arginine
binding (36). In vivo and in vitro studies in rat tissues suggest that
bNOS, but not ecNOS activity, is inhibited by 7-NI (21, 22). The weak
inhibitory influence of 7-NI on ecNOS activity has been attributed to
poor uptake of this compound by intact endothelial cells (1). Our results also indicate that aminoguanidine, a selective iNOS inhibitor (12, 20), is a weak inhibitor of constitutive NOS activity of the
ventilatory muscles. Only at a concentration of 1 mM (results not
shown) did aminoguanidine partially inhibit muscle NOS activity. We
attribute this partial inhibition to the effect of aminoguanidine on
ecNOS activity (18). Finally, Szabo et al. (29) proposed that SMT is at
least 10- to 30-fold more potent as an iNOS inhibitor than any other
NOS inhibitors. However, SMT is equipotent with methyl-L-arginine in inhibiting
ecNOS activity in vitro and causes an increase in arterial blood
pressure when injected in normal rats (29). We found that SMT is
similar to L-NAME in inhibiting muscle NOS activity.
Physiological implication.
There is increasing evidence indicating that NO regulates diverse
processes in skeletal muscle fibers. For instance, inhibition of muscle
NOS activity has recently been shown to attenuate basal glucose
transport (2). There is also evidence that NO regulates muscle
contractile force through guanosine 3, 5-cyclic
monophosphate (cGMP)-dependent and cGMP-independent processes (16).
Agents that increase intracellular cGMP, such 8-bromo-cGMP, are
known to reverse the influence of NOS inhibitors on muscle force (16). It has also been proposed that NO depresses mitochondrial respiration in skeletal muscles (17), cardiac myocytes (24), hepatocytes (28), and
vascular smooth muscle cells (9). Inhibition of muscle mitochondrial
cytochrome c oxidase by NO, which has
been proposed to be the exact pathway through which NO inhibits
mitochondrial respiration (6), is likely to decrease cellular ATP and
increases ADP, AMP, guanosine 5-diphosphate, and
Pi. These metabolites are known to
regulate diverse cellular processes such as ion transport, protein
synthesis, and muscle contraction. Finally, it has recently been
described (15) that muscle bNOS protein interacts with dystrophin
complex. In dystrophic muscles that lack the dystrophin complex, bNOS
is no longer attached to the sarcolemma, suggesting that the dystrophin
complex is critical for the tethering of bNOS to muscle membrane. These
findings suggest that ecNOS and bNOS target different processes in
skeletal muscle fibers. Whereas ecNOS targets mitochondrial functions,
bNOS is expressed at the sarcolemma in close association with
dystrophin.
Our results confirm that normal skeletal muscles of various species
constitutively express both ecNOS and bNOS isoforms, but the degree of
isoform expression varies significantly among different muscles. We
also found that muscle NOS activity is not always related to the
physiological function of a given muscle (e.g., lung ventilation in the
case of the diaphragm and intercostal muscles), nor is it always
correlated with fiber type composition. The reasons behind these
differences in NOS expression and activity between different muscles
need to be explored.
ACKNOWLEDGEMENTS
The authors thank J. Longo and R. Carin for assistance in preparing the manuscript.
FOOTNOTES
Address for reprint requests: S. Hussain, Rm. L3.05, Royal Victoria Hospital, 687 Pine Av. West, Montreal, Quebec, Canada H3A 1A1 (E-mail: shussain{at}rvhmed.lan.mcgill.ca).
Received 13 May 1996; accepted in final form 25 March 1997.
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  G. D. Wadley, J. Choate, and G. K. McConell NOS isoform-specific regulation of basal but not exercise-induced mitochondrial biogenesis in mouse skeletal muscle J. Physiol., November 15, 2007; 585(1): 253 - 262. [Abstract] [Full Text] [PDF]
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 G. D. Wadley and G. K. McConell Effect of nitric oxide synthase inhibition on mitochondrial biogenesis in rat skeletal muscle J Appl Physiol, January 1, 2007; 102(1): 314 - 320. [Abstract] [Full Text] [PDF]
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 A. Demoule, M. Divangahi, L. Yahiaoui, G. Danialou, D. Gvozdic, K. Labbe, W. Bao, and B. J. Petrof Endotoxin Triggers Nuclear Factor-{kappa}B-dependent Up-regulation of Multiple Proinflammatory Genes in the Diaphragm Am. J. Respir. Crit. Care Med., September 15, 2006; 174(6): 646 - 653. [Abstract] [Full Text] [PDF]
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 T. Vassilakopoulos, G. Deckman, M. Kebbewar, G. Rallis, R. Harfouche, and S. N. A. Hussain Regulation of nitric oxide production in limb and ventilatory muscles during chronic exercise training Am J Physiol Lung Cell Mol Physiol, March 1, 2003; 284(3): L452 - L457. [Abstract] [Full Text] [PDF]
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M. B. Reid Plasticity in Skeletal, Cardiac, and Smooth Muscle: Invited Review: Redox modulation of skeletal muscle contraction: what we know and what we don't J Appl Physiol, February 1, 2001; 90(2): 724 - 731. [Abstract] [Full Text] [PDF]
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D. Javeshghani, D. Sakkal, M. Mori, and S. N. A. Hussain Regulation of diaphragmatic nitric oxide synthase expression during hypobaric hypoxia Am J Physiol Lung Cell Mol Physiol, September 1, 2000; 279(3): L520 - L527. [Abstract] [Full Text] [PDF]
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 N. C. Gocan, J. A. Scott, and K. Tyml Nitric oxide produced via neuronal NOS may impair vasodilatation in septic rat skeletal muscle Am J Physiol Heart Circ Physiol, May 1, 2000; 278(5): H1480 - H1489. [Abstract] [Full Text] [PDF]
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 W. Hirschfield, M. R. Moody, W. E. O'Brien, A. R. Gregg, R. M. Bryan Jr., and M. B. Reid Nitric oxide release and contractile properties of skeletal muscles from mice deficient in type III NOS Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2000; 278(1): R95 - R100. [Abstract] [Full Text] [PDF]
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 U. Förstermann, J.-p. Boissel, and H. Kleinert Expressional control of the `constitutive' isoforms of nitric oxide synthase (NOS I and NOS III) FASEB J, July 1, 1998; 12(10): 773 - 790. [Abstract] [Full Text]
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 Q. El Dwairi, Y. Guo, A. Comtois, E. Zhu, M. T. Greenwood, D. S. Bredt, and S. N. A. Hussain Ontogenesis of Nitric Oxide Synthases in the Ventilatory Muscles Am. J. Respir. Cell Mol. Biol., June 1, 1998; 18(6): 844 - 852. [Abstract] [Full Text]
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 Q. El-Dwairi, A. Comtois, Y. Guo, and S. N. A. Hussain Endotoxin-induced skeletal muscle contractile dysfunction: contribution of nitric oxide synthases Am J Physiol Cell Physiol, March 1, 1998; 274(3): C770 - C779. [Abstract] [Full Text] [PDF]
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