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Departments of Health and Kinesiology and of Medical Physiology, Texas A&M University, College Station, Texas 77843
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The purpose of
the present study was to determine whether hindlimb unloading of rats
alters vasoconstrictor and myogenic responsiveness of skeletal muscle
arterioles. After either 2 wk of hindlimb unloading (HU) or cage
control (C), second-order arterioles were isolated from the white
portion of gastrocnemius (WG; C: n = 9, HU: n = 10) or soleus (Sol; C:
n = 9, HU:
n = 10) muscles and cannulated with
two micropipettes connected to reservoir systems for in vitro study.
Intraluminal pressure was set at 60 cmH2O. The arterioles were exposed
to step changes in intraluminal pressure ranging from 20 to 140 cmH2O to determine myogenic
responsiveness and to KCl (10-100 mM) and norepinephrine
(10
9-104
M) to determine vasoconstrictor responsiveness. Although maximal diameter of WG arterioles was not different between C (185 ± 12 µm) and HU (191 ± 14 µm) rats, WG arterioles from HU rats
developed less spontaneous tone (C: 33 ± 5%, HU 20 ±3%), were
unable to maintain myogenic tone at pressures from 140 to 100 cmH2O, and were less sensitive to
the vasoconstrictor effects of KCl and norepinephrine (as indicated by
a higher agonist concentration that produced 50% of maximal
vasoconstrictor response). In contrast, maximal diameter
of Sol arterioles from HU rats (117 ± 12 µm) was smaller than
that in C rats (148 ± 14 µm). However, the development of
spontaneous tone (C: 30 ± 4%, HU: 36 ± 5%), myogenic
activity, and the responsiveness to vasoconstrictor agonists were not
different between Sol arterioles from C and HU rats. These results
indicate that hindlimb unloading diminishes the myogenic autoregulatory and contractile responsiveness of arterioles from muscle composed of
type IIB fibers and suggest that the compromised ability to elevate
vascular resistance after exposure to microgravity may be related to
these vascular alterations. In addition, hindlimb unloading appears to
induce vascular remodeling of arterioles from muscle composed of type I
fibers, as indicated by the decrease in maximal diameter of arterioles
from Sol muscle.
autoregulation; blood flow; hemodynamics; hindlimb unweighting; morphology; suspension
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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EVIDENCE IS MOUNTING that postflight orthostatic intolerance is not simply a consequence of hypovolemia but results from fundamental alterations in cardiovascular regulation (2, 29). Mulvagh et al. (23) provided early evidence by using echocardiography that inadequate vasoconstrictor responses significantly contributed to the postflight orthostatic intolerance. More recently, Buckey et al. (3) examined a wide range of cardiovascular regulatory mechanisms during a pre- and postflight stand test in crew members having flown 9-14 days. They divided the group into those that could and those that could not finish the stand test. The distinguishing characteristic of the nonfinishers was a compromised ability to vasoconstrict and increase peripheral resistance; venous pooling and stroke volume were similar between the two groups, and heart rate was higher in the nonfinishers. The authors suggested that the degradation of the vasoconstrictor response could occur at several levels, including baroreceptor responsiveness, afferent input, central integration of reflex responses, efferent output, and end-organ (vascular) responsiveness.
With use of hindlimb unloading to model the effects of microgravity in the rat, similar observations of cardiovascular alterations have been made (13, 14, 20-22, 24, 25). For example, in skeletal muscle composed primarily of type IIB fibers, blood flow was found to be higher in the 2-wk hindlimb-unloaded than in control rats under two conditions, during suspension (control animals suspended for 10 min) and during treadmill walking (21). These authors hypothesized that the inability of the vasculature in type IIB skeletal muscle to increase resistance was due to a decreased responsiveness to norepinephrine (NE). To test this hypothesis, Delp et al. (8, 10) examined vasoconstrictor responsiveness of thoracic and abdominal aorta from HU rats. They found that maximal contractile tension evoked by NE and a variety of other vasoconstrictor agonists operating through different mechanisms (i.e., receptor dependent and independent) were diminished by hindlimb unloading. These observations have recently been confirmed in other conduit arteries (26). Collectively, these studies (8, 10, 26) suggest that end-organ responsiveness may be involved in the inability to elevate vascular resistance after exposure to simulated microgravity. However, it remains to be determined whether hindlimb unloading alters intrinsic vasoconstrictor properties of the resistance vasculature. Therefore, the purpose of the present study was to determine whether hindlimb unloading alters vasoconstrictor and myogenic responsiveness of arterioles isolated from muscle composed predominantly of type I [soleus (Sol) muscle] and type IIB [white portion of gastrocnemius muscle (WG)] fibers (9). On the basis of previously observed alterations in muscle blood flow after hindlimb unloading (21), it was hypothesized that constrictor or myogenic responses would be diminished in arterioles from muscle composed of type IIB fibers but not in arterioles from muscle composed of type I fibers.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The methods employed in this study were approved by the Texas A&M University Institutional Animal Care and Use Committee. The investigation conforms with the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals [DHHS Publication No. (NIH) 85-23, Revised 1985, Office of Science and Health Reports, Bethesda, MD 20892].
Animals. Thirty-eight male Sprague-Dawley rats weighing ~350 g were obtained (Charles River) and housed in a temperature-controlled (23 ± 2°C) room with a 12:12-h light-dark cycle. Water and rat chow were provided ad libitum. One week after arrival from the breeder, the rats were randomly assigned to either a hindlimb-unloaded (HU; n = 20) or control (C; n = 18) group. The hindlimbs of the HU rats were partially elevated with a harness attached to the tail as previously performed (8, 10). Briefly, two narrow strips of an adhesive material (moleskin) were placed on the dorsal surface of the tail and positioned to run adjacent and parallel to both sides of the caudal artery to avoid compression of the tail artery. The tail was then wrapped (Co-Flex bandage, Andover), and a previously molded plastic caste (X-lite splint, AOA/Kirschner Medical) was placed around the proximal two-thirds of the tail. A hook was attached to the casted tail harness and then connected by a chain to a swivel apparatus at the top center of the cage. The height of the hindlimb elevation was adjusted to prevent the hindlimbs from touching supportive surfaces, resulting in a suspension angle of ~40-45°. The forelimbs maintained contact with the floor surface, which allowed the animals full range of motion. The hindlimb unloading was maintained for 2 wk, a period previously demonstrated to induce Sol muscle atrophy (28), resting and exercise tachycardia (21), alterations in muscle blood flow (21, 30), and altered aortic vasomotor responses (8, 10). After the 2-wk unloading period, the animals were anesthetized with pentobarbital sodium (35 mg/kg ip) without allowing the hindlimbs to become weight bearing, and the gastrocnemius-plantaris-Sol muscle group was carefully dissected free from the hindlimbs and placed in a chilled (4°C) filtered physiological saline buffer solution (PSS) (pH 7.4).
Microvessel preparation. Under a dissecting microscope, the feed artery leading to the Sol or superficial WG was identified and cut with microscissors. First-order (1A) arterioles were identified at the point where the feed artery entered the muscle. Second-order (2A) arterioles were designated after the bifurcation of the 1A arterioles. 2A arterioles were dissected from the Sol or WG and transferred to a Lucite vessel chamber containing chilled PSS solution. One end of the microvessel was cannulated with a glass micropipette (40-55 µm in tip diameter), filled with filtered PSS-albumin solution (1 g bovine serum albumin/100 ml), and tied securely to the pipette with 11-0 ophthalmic suture. The other end of each vessel was cannulated with a second micropipette and secured with suture. After cannulation, the isolated vessel in the tissue chamber was transferred to the stage of an inverted microscope (Olympus IX70) coupled to a video camera (Panasonic BP310), video micrometer (Microcirculation Research Institute, Texas A&M University), video recorder (Panasonic AG-1300), and a data-acquisition system (Macintosh/MacLab). Vessels were then allowed to equilibrate for 1 h at 37°C and 60 cmH2O intraluminal pressure before myogenic and vasoconstrictor properties were characterized; the bathing solution was replaced every 15 min during the equilibration period. Internal diameters were measured continuously throughout the experiment by videomicroscopic techniques (15, 16).
Experimental design.
To assess active myogenic behavior, the micropipettes cannulating the
arterioles were connected to independent reservoir systems. Intraluminal pressure was measured through sidearms of the two reservoir lines by low-volume-displacement strain-gauge transducers (Electromedics). The isolated vessels were pressurized at 60 cmH2O by setting both reservoirs
at the same hydrostatic level. After the 1-h equilibration period,
intraluminal pressure was increased by increments of 20 cmH2O, i.e., from 60 to 80 to 100 to 120 to 140 cmH2O, by
simultaneously raising both reservoirs in
20-cmH2O increments.
Intraluminal pressure was then lowered from 140 to 20 cmH2O by increments of 20 cmH2O and raised again from 20 to 60 cmH2O. Changes in pressure were
maintained for 3 min, which was sufficient to allow a steady vascular
response to the change in pressure. To determine vascular responses to
vasoconstrictor agonists, concentration-response relationships were
determined by the cumulative addition of KCl (10-100 mM) and NE
(109-104
M) while the arterioles were pressurized at 60 cmH2O. These vasoconstrictors were
selected because they induce constriction through activation of
voltage-gated Ca2+ channels (KCl)
and an 
-receptor mechanism (NE). Finally, a passive pressure-diameter curve was generated by repeating the protocol for
assessing myogenic responsiveness after the arterioles were incubated
in a Ca2+-free PSS buffer for 1 h
(bathing solution was replaced every 15 min). Maximal diameter with an
intraluminal pressure of 60 cmH2O
was determined after the 1-h incubation in
Ca2+-free PSS buffer and before
the second (passive) pressure-response curve.
Solutions and drugs. The PSS buffer contained (in mM) 145 NaCl, 4.7 KCl, 1.2 NaH2PO4, 1.17 MgSO4, 2.0 CaCl2, 5.0 glucose, 2.0 pyruvate, 0.02 EDTA, and 3.0 MOPS with a pH of 7.4. Ca2+-free PSS buffer was similar to the PSS buffer except it contained 2 mM EDTA and CaCl2 was replaced with 2.0 mM NaCl. Concentrated stock solutions of KCl and NE were prepared in PSS buffer.
Statistical analysis.
Intraluminal diameters were measured before and during the myogenic and
vasoconstrictor responses. The development of spontaneous tone was
expressed as the percent constriction relative to maximal diameter and
was calculated as
(Dmax 
DB)/Dmax × 100, where
Dmax is the
maximal diameter determined in
Ca2+-free PSS buffer and
DB is the
starting baseline diameter. The vasoconstrictor data are
presented as a percentage of maximal diameter to normalize for
differences in maximal diameter between groups. These data were
calculated as
D/Dmax × 100, where D is the measured
diameter. Pressure-response and concentration-response curves were
evaluated by using repeated-measures analysis of variance with one
within (intraluminal pressure or agonist concentration) and one between
(experimental groups) factor. Planned contrasts were conducted at each
intraluminal pressure or concentration level to determine whether
differences existed between experimental groups (C vs. HU). The agonist
concentration that produced 50% of the maximal vasoconstrictor
response was designated EC50. All EC50 values were converted to log
values for statistical comparison. Student's unpaired
t-tests were used to determine whether
differences in Sol muscle weight, Sol muscle-to-body weight ratio,
developed spontaneous tone, maximal diameter, and
EC50 values were significant between groups. All values are presented as means ± SE. A value of
P < 0.05 was required for significance.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Sol muscle-to-body weight ratio. Sol muscle weight was 39% lower in HU rats (C: 226 ± 11 mg; HU: 139 ± 11 mg). Similarly, unloading resulted in a 37% reduction in the Sol muscle-to-body weight ratio (C: 0.52 ± 0.02 mg/g; HU: 0.33 ± 0.02 mg/g). Sol muscle atrophy, which is characteristic of reduced skeletal muscle weight-bearing activity (28), confirms the efficacy of the hindlimb unloading treatment.
Vessel characteristics.
The maximal intraluminal diameter (determined in
Ca2+-free solution at 60 cmH2O intraluminal pressure) of
arterioles from WG of HU rats was similar to that of arterioles from C
animals (Fig. 1). However, hindlimb
unloading decreased the maximal diameter of Sol arterioles. All vessels
from C and HU rats exhibited spontaneous tone (Fig.
2). Hindlimb unloading diminished the
development of spontaneous tone in WG arterioles but had no effect on
spontaneous tone developed in Sol arterioles. Differences in the
development of spontaneous tone in arterioles from WG and differences
in the maximal diameter of arterioles from Sol resulted in dissimilar baseline intraluminal diameters between arterioles from C and HU rats.
Baseline diameter, determined at 60 cmH2O intraluminal pressure, of
arterioles from WG was ~124 ± 8 µm in C rats and 153 ± 9 µm in HU rats (P < 0.05),
and baseline diameter of arterioles from Sol was 104 ± 7 µm in C
rats and 75 ± 8 µm in HU animals (P < 0.05).
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Vasoconstrictor responses.
Increases in extracellular KCl produced dose-dependent decreases in
intraluminal diameter in vessels from WG and Sol. In arterioles from
WG, contractile responses evoked by 30-50 mM KCl were lower in HU
rats (Fig. 3). In addition, the sensitivity
of WG arterioles from HU rats to KCl was lower than that from C
animals, as indicated by a higher
EC50 (C: 29 ± 2.4 mM; HU: 43 ± 3.2 mM). Neither contractile responses nor
EC50 values (C: 28 ± 2.7 mM;
HU: 32 ± 2.2 mM) of Sol arterioles to KCl were different between C
and HU rats (Fig. 4).
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8-106
M NE and sensitivity to NE (EC50;
C: 1.5 × 107 ± 2.7 × 108 M; HU: 1.2 × 106 ± 3.1 × 108 M) were lower
in WG arterioles from HU rats (Fig. 5).
There were no differences in contractile responses or
EC50 values (C: 3.9 × 107 ± 1.1 × 107 M; HU: 3.1 × 107 ± 7.2 × 108 M) to NE between Sol
arterioles from C and HU rats (Fig. 6).
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Myogenic responses.
In arterioles from WG of C rats (Fig. 7),
elevations in intraluminal pressure did not alter active vessel
diameter, and the lowering of intraluminal pressure only decreased
active diameter at 20 cmH2O. In
contrast, incremental elevations in intraluminal pressure in WG
arterioles from HU rats increased active vessel diameter from 120 to
140 cmH2O, and active diameter
remained higher during incremental lowering of pressure from 140 to 100 cmH2O. Similar to WG arterioles
from C rats, active diameter was reduced at 20 cmH2O. All active diameters except
that at 20 cmH2O were different
between C and HU rats. Incremental changes in intraluminal pressure did
not alter the passive pressure-diameter response of WG arterioles from
C rats until pressure was lowered to 40 and 20 cmH2O, where passive diameter was
reduced. In WG arterioles from HU rats, pressures of 140 and 120 cmH2O increased passive diameter
and pressures between 40 and 20 cmH2O lowered passive diameter.
There were no differences in passive diameters of WG arterioles from C
and HU animals.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The purpose of this study was to determine whether hindlimb unloading alters vasoconstrictor and myogenic responsiveness of skeletal muscle arterioles. The data indicate that hindlimb unloading diminishes the contractile responsiveness of arterioles isolated from muscle composed of fast-twitch type IIB fibers, as indicated by 1) a diminished development of spontaneous tone (Fig. 2), 2) a decreased sensitivity to vasoconstrictor agonists (Figs. 3 and 5), and 3) a reduced myogenic responsiveness (Fig. 7). Although hindlimb unloading did not affect vasoconstrictor or myogenic responsiveness of arterioles from muscle composed of slow-twitch type I fibers, it did induce decreases in arteriolar maximal diameter (Fig. 1) and baseline diameter at 60 cmH2O (Fig. 8).
The effects of diminished arteriolar contraction could have several functional consequences. A lowering of vasoconstrictor responsiveness and myogenic activity could result in a reduced ability to elevate vascular resistance in vivo. On the basis of the principles of Ohm's law, alterations in the ability to control vascular resistance could subsequently diminish the precision in which arterial pressure and muscle blood flow are regulated. Indeed, previous work has demonstrated that rats having undergone hindlimb unloading experience periods of hypotension when faced with an orthostatic challenge (90° rotation) (20). In addition, McDonald et al. (21) reported that blood flow to muscle composed of type IIB fibers is higher in HU rats when the hindlimbs are suspended and during low-intensity treadmill exercise. The higher blood flow during suspension, where the control animals were acutely suspended for 10 min, indicates that the elevation in muscle blood flow in HU rats was not due to greater muscle metabolite release, because the muscles were unloaded and presumably inactive. Thus the results of the present study, indicating a diminished vasoconstrictor and myogenic responsiveness of arterioles in type IIB muscles, the predominant muscle type in rats (9), are consistent with the observations of a compromised arterial pressure and muscle blood flow regulatory mechanism in HU rats. Furthermore, these results suggest that a diminished capacity of the skeletal muscle resistance vasculature to respond to vasoconstrictor stimuli or to autoregulate may be involved in the etiology of postflight orthostatic intolerance and the inability to elevate vascular resistance (3, 23), given that ~40% of the increase in total peripheral vascular resistance during orthostasis occurs in the skin and skeletal muscles (27).
A second functional consequence resulting from hindlimb unloading-induced alterations in the resistance vasculature could be a loss of aerobic power. With exercise training, for example, maximal oxygen consumption is elevated, and this appears to be due in part to a more precise matching of muscle blood flow and muscle oxidative capacity during exercise (1, 6). In other words, blood flow to muscle composed of high oxidative type I and IIA fibers is elevated and blood flow to muscle composed of low oxidative type IIB fibers is decreased during exercise. The inverse of these cardiovascular adaptations occurs with hindlimb unloading. There is a decrease in maximal oxygen consumption (13, 25) and a less precise matching of blood flow to muscle oxidative capacity (21, 30). As mentioned above, it seems likely that the elevated perfusion of muscle composed of type IIB fibers is related to the diminished arteriolar vasoconstrictor and myogenic function. In contrast, perfusion of muscle composed primarily of high oxidative type I fibers is decreased by hindlimb unloading (21, 30). This decrease in flow does not appear to be due to enhanced myogenic autoregulatory or agonist-induced contractile responsiveness, because these properties were unaltered in arterioles from this muscle type. However, it is possible that the smaller arteriolar baseline (Fig. 8) and maximal diameter (Fig. 1) could function to retard blood flow to muscles having this fiber composition. Thus the vascular alterations described in the present study could serve to elevate blood flow to low oxidative muscles and diminish perfusion of high oxidative muscles, which in turn could diminish efficient oxygen delivery and aerobic power.
It is possible that several factors associated with hindlimb unloading
could initiate the observed alterations in the resistance vasculature,
including changes in blood flow and alterations in transmural pressure
(18). In the antigravity Sol muscle, blood flow is ~100
ml · min1 · 100 g1 throughout the day (12),
but it is reduced to 
10
ml · min1 · 100 g1 by hindlimb unloading
(21). Conversely, blood flow to the WG muscle is <10
ml · min1 · 100 g1, and acute unloading of
the hindlimbs has no effect on perfusion of this muscle type (21). The
hindlimb unloading-induced change in Sol muscle blood flow does not
correspond to a reduced arteriolar contractile responsiveness and thus
does not appear to be the stimulus initiating the alteration in
contractile responsiveness. However, hindlimb unloading-induced
reductions in blood flow could initiate vascular remodeling of Sol
muscle arterioles. For example, reductions in blood flow through rabbit
carotid arteries over a period of days to weeks has been shown to
induce remodeling that results in a smaller maximal diameter and
smaller constricted diameters (19). The reduction in maximal diameter
of Sol muscle arterioles in the present study is therefore consistent
with the hypothesis that decreases in blood flow can induce
modifications in arterial morphology. A similar conclusion was reached
by Chew and Segal (4), who reported hindlimb unloading reduced maximal diameter of femoral arteries.
It appears more likely that the change in arteriolar vasoconstrictor and myogenic properties results from the combined effects of an alteration in the hydrostatic pressure gradient with hindlimb unloading and the tonic state of the arteriolar vasculature before unloading. For example, during normal standing the Sol muscle arteriolar vasculature would be relatively relaxed because of the continuous release of vasodilatory metabolites from the surrounding tonically active muscle fibers (11). When the hindlimbs become unloaded during suspension, these fibers become less active and the release of vasodilatory metabolites diminishes. However, the Sol muscle arterioles may remain in a relatively relaxed state because there is a corresponding reduction in transmural pressure associated with the reduced perfusion pressure in the elevated hindlimbs. Thus the contractile state of smooth muscle cells in Sol muscle arterioles may be relatively unaltered by hindlimb unloading. In contrast, arterioles in the WG have a high degree of tone during standing (7). An acute reduction in transmural pressure via hindlimb unloading would presumably result in relaxation of the resistance vasculature to maintain transmural pressure (5, 17). Thus the contractile state of smooth muscle cells in WG muscle arterioles may be altered by hindlimb unloading, going from a relatively contracted state before unloading to a more relaxed state during unloading. The hindlimb unloading-induced change in the contractile state of the arteriolar smooth muscle over a prolonged period may therefore be the initiating stimulus for the alteration in arteriolar agonist-induced and myogenic contractile responsiveness.
The mechanism responsible for the decrease in arteriolar smooth muscle
myogenic activity could involve alterations in a number of components
comprising the pathway that transduces changes in intravascular
pressure into the development of myogenic tone, such as
stretch-activated channels, G proteins, voltage-dependent Ca2+ channels, protein kinase C,
Ca2+-calmodulin-dependent myosin
light chain kinase, and myofibrillar protein content (5). On the other
hand, the mechanism responsible for the diminished agonist-induced
vasoconstrictor responsiveness does not appear to be related to a
change in a receptor-second-messenger system, because a decrement in
contractile sensitivity was evident with the receptor-mediated agonist
NE (Fig. 5) and the non-receptor-mediated agonist KCl (Fig. 3), which
evokes contractions through voltage-gated Ca2+ channels. We
have previously observed that hindlimb unloading induces similar
changes in abdominal aortas of rats (8, 10). In these arteries,
hindlimb unloading reduced maximal tension in response to NE, the
1-receptor agonist
phenylephrine, the V1-receptor
agonist vasopressin, KCl, and
Ca2+. Collectively,
these studies suggest that agonist-induced contractile responsiveness
may be diminished through a reduction in cellular calmodulin protein
expression, myosin light chain kinase activation or activity, or
myofibrillar protein content. If the diminished myogenic and
agonist-induced vasoconstrictor responses share a common mechanism, and
if the initiating stimulus for adaptation is a reduction in transmural
pressure and the subsequent prolonged relaxation of the resistance
vasculature, then the loss of myofibrillar proteins or smooth muscle
atrophy seems a likely mechanism for the diminished contractile
responsiveness induced by hindlimb unloading. This possibility requires
further investigation.
In conclusion, the present study demonstrates that hindlimb unloading does not uniformly affect the resistance vasculature in skeletal muscle. There was a diminished contractile responsiveness of arterioles isolated from muscle composed of fast-twitch type IIB fibers, as indicated by 1) diminished development of spontaneous tone, 2) a decreased sensitivity to vasoconstrictor agonists, and 3) reduced myogenic responsiveness. In contrast, hindlimb unloading did not affect vasoconstrictor or myogenic responsiveness of arterioles from muscle composed of slow-twitch type I fibers, but unloading did induce arteriolar remodeling in this muscle type resulting in a decreased baseline and maximal diameter.
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ACKNOWLEDGEMENTS |
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This research was supported by National Aeronautics and Space Administration Grants NAGW-4842 and NAG5-3754.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: M. D. Delp, Dept. Health and Kinesiology, Texas A&M Univ., College Station, TX 77843 (E-mail: mdd{at}hlkn.tamu.edu).
Received 2 September 1998; accepted in final form 1 December 1998.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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