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Department of Physiology and Institute for Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611-3008
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Respiratory afferent stimulation can elicit increases in respiratory motor output that outlast the period of stimulation by seconds to minutes [short-term potentiation (STP)]. This study examined the potential contribution of spinal mechanisms to STP in anesthetized, vagotomized, paralyzed rats. After C1 spinal cord transection, stimulus trains (100 Hz, 5-60 s) of the C1-C2 lateral funiculus elicited STP of phrenic nerve activity that peaked several seconds poststimulation. Intracellular recording revealed that individual phrenic motoneurons exhibited one of three different responses to stimulation: 1) depolarization that peaked several seconds poststimulation, 2) depolarization during stimulation and then exponential repolarization after stimulation, and 3) bistable behavior in which motoneurons depolarized to a new, relatively stable level that was maintained after stimulus termination. During the STP, excitatory postsynaptic potentials elicited by single-stimulus pulses were larger and longer. In conclusion, repetitive activation of the descending inputs to phrenic motoneurons causes a short-lasting depolarization of phrenic motoneurons, and augmentation of excitatory postsynaptic potentials, consistent with a contribution to STP.
central control of breathing; short-term potentiation; bistability; bulbospinal pathways
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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IN THE NEURAL CONTROL OF breathing, there are many examples of persistent responses that outlast the presentation of a stimulus (5, 9, 13). Examples include input from receptors located in the carotid body, the walls of the respiratory tract, and the somatic musculature. This short-term respiratory memory or plasticity appears to integrate and smooth responses to various stimuli and prevent large and rapid fluctuations in ventilation (21).
One of the most commonly observed forms of short-term plasticity is the short-term potentiation (STP) of respiratory motor output that follows activation of carotid chemoreceptor afferent pathways by either chemical or electrical stimulation (5, 9, 24). Mifflin (20) has clearly demonstrated that a component of the STP resulting from carotid sinus nerve stimulation occurs within the nucleus of the tractus solitarius. However, a component of this short-term plasticity may also arise at the spinal cord level. Soma of bulbospinal premotor neurons are located primarily in the ventral respiratory group and provide both excitatory and inhibitory descending projections to spinal respiratory motoneurons (6). High-frequency stimulation of descending pathways in the spinal cord, including axons of bulbospinal ventral respiratory group neurons, reveals a STP of phrenic nerve activity (18). Section of the spinal cord rostral to the stimulation site has no effect on the STP, thereby confirming that spinal circuitry is sufficient for its generation. Short-term plasticity of the descending synaptic input to spinal motoneurons controlling muscles involved in expiratory efforts has also recently been demonstrated in turtles (13), although the response consisted primarily of a depression of synaptic efficacy. Taken together, these findings suggest that plasticity at the spinal level may contribute to the short-term plasticity evident in central respiratory networks.
The work of Mifflin (20) is the only study to date directly examining the subthreshold behavior and synaptic responsiveness of central respiratory-related neurons during the induction of STP. Using intracellular recording, he found that, after a period of high-frequency stimulation of the carotid sinus nerve, the primary response of second-order neurons within the nucleus of the solitary tract was an increase in excitatory postsynaptic potential (EPSP) amplitude. This was accompanied in ~60% of the neurons by a modest (3-5 mV) depolarization of the resting membrane potential (MP).
In earlier work (18), our laboratory identified two distinct categories of phrenic motoneurons that could be distinguished on the basis of their synaptic response to stimulation of descending inputs. One group (type A motoneurons) exhibited a very short-latency action potential after each stimulus pulse in a train of stimuli. A second group (type B motoneurons) displayed a longer latency EPSP that summated over three to five stimuli in a high-frequency (100 Hz) train to give rise to an action potential. Temporal summation caused these neurons to depolarize during the train. On the basis of these results and the findings of Mifflin (20) in the nucleus of the solitary tract, we hypothesized that high-frequency stimulation of descending pathways in the spinal cord would result in an augmentation in EPSP amplitude and cause a sustained depolarization in a subset of phrenic motoneurons. These changes would provide an increase in excitability that could contribute to STP elicited by physiological stimuli such as chemoreceptor activation.
In the present study, subthreshold behavior of individual phrenic motoneurons was monitored in response to single-pulse stimulation of descending spinal pathways before and after a period of high-frequency stimulation of these same pathways. We found that phrenic motoneurons exhibit prolonged depolarization consequent to the high-frequency stimulation, with some of these exhibiting bistable behavior. In addition, there is an augmentation of both the amplitude and duration of EPSPs in response to low-frequency test stimuli. These findings are consistent with plasticity at the synapse between bulbospinal respiratory neurons and phrenic motoneurons, contributing to short-term increases in tidal volume after afferent-evoked (e.g., carotid chemoreceptor-induced) increases in breathing.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiments were performed on adult male Sprague-Dawley rats
(300-600 g; vendor: Charles River). Anesthesia was induced with isoflurane and maintained with intraperitoneal or intravenous injection
of urethane (1.5 g/kg) that was supplemented as required (0.15-0.3
g/kg iv). Adequacy of anesthesia was assessed at least every 30 min by
the absence of changes in arterial blood pressure, heart rate, or
respiratory rate in response to a noxious paw pinch. A femoral vein and
artery were cannulated, a tracheotomy and bilateral thoracotomy
performed, and the rats mechanically ventilated. Body temperature was
monitored with a rectal probe and maintained near 37°C by using a
servo-controlled heating pad and lamp. Body fluid content and buffering
were maintained by the continuous infusion of bicarbonate-saline
solution (154 mM Na+; 124 mM Cl
; 30 mM
HCO
The vertebral spines in the lumbar and upper thoracic regions were exposed, and the animal was clamped into a stereotaxic holder. The right phrenic nerve was isolated in the neck by a lateral approach, sectioned, and placed on bipolar silver hook electrodes for stimulation and recording. A laminectomy from C1-7 and an occipital craniotomy were performed. The spinal cord was transected at C1 with the use of forceps in most rats (27 of 37). Completeness of the transection was assessed visually after removal of tissue over a 1- to 2-mm rostrocaudal extent. Care was taken to preserve the anterior spinal artery. The exposed surface of the brain stem and cord was then covered with warmed mineral oil, and at least 1 h elapsed after spinalization before an experiment was begun.
Stimulation and Recording
The experimental paradigm is illustrated in Fig. 1. The lateral funiculus was stimulated with a concentric bipolar electrode (SNE-100, David Kopf Instruments) lowered into the C1-C2 spinal cord ~3 mm caudal to the transection and at the point of dorsal root entry. The depth of the electrode was adjusted to give the maximum orthodromic monosynaptic response in the phrenic nerve. Single pulses (0.5-1 Hz, 0.1-ms duration, 50-400 µA) or trains of stimuli (100 Hz, 0.1-ms pulse duration, 5-60 s) were delivered through an optically coupled stimulus isolation unit. Stimulus intensity was adjusted to three times the threshold for orthodromic activation of phrenic motoneurons, unless otherwise indicated. In spinal cord-intact animals, stimulation was confined to the inspiratory or expiratory phases with the use of a logic circuit (17) and laboratory computer. Phrenic nerve activity was amplified, filtered (3 Hz to 10 kHz), and integrated (Paynter filter, 15-ms time constant).
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Filtered (0-10 kHz) intracellular recordings were made with glass
micropipettes (6-40 M
) filled with 3 M potassium acetate containing 10 mM potassium chloride. Phrenic motoneurons were identified by antidromic activation of the ipsilateral phrenic nerve.
The response of phrenic motoneurons to orthodromic stimulation of
bulbospinal pathways was determined. All signals were displayed on a
storage oscilloscope and recorded directly on computer as well as on
videotape and a chart recorder. MP was measured, and any offset was
corrected by subtracting the offset voltage measured after removal of
the electrode from the neuron.
Values are expressed as means ± SE. The statistical significance
(P < 0.05) of changes was ascertained by Student's
t-test for paired comparisons with the Bonferroni
(26) correction for multiple comparisons. The time course
of the decay of integrated phrenic nerve (
Phr) activity or the
repolarization of MP after stimulation was analyzed by using the
following equation: %change in Phr (or MP) = A · e
t + B, where 
is the reciprocal of the time
constant and A and B are constants. Least squares
regression was used to estimate the relationship between ln(Phr 
B) and time t when B was iterated in increments of 0.5 to maximize r2. Logarithm
A was the y-intercept, and was
the slope of this regression line. Time 0 was chosen at the
peak Phr or at the peak depolarization of individual motoneurons.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Spinalization abolished all respiratory-related phasic activity on the phrenic nerve, even during marked hypercapnia (alveolar PCO2 > 70 Torr) obtained by increasing inspired CO2 fraction (0.05) and lowering the ventilator frequency (<60 breaths/min). Mean arterial pressure in spinalized animals averaged 89 ± 6 mmHg, which was lower than that in unspinalized animals (103 ± 4 mmHg; P < 0.05).
Effect of Repetitive Spinal Cord Stimulation on Phrenic Nerve Discharge
Repetitive stimulation (100 Hz; 15-60 s) caused a sustained increase in discharge of the ipsilateral phrenic nerve that outlasted the period of stimulation (Fig. 2). The magnitude of integrated nerve activity increased in the immediate poststimulation period, reaching a peak at 7.8 ± 1.2 s after stimulus termination (n = 12; Fig. 2). Activity then decayed with a time constant of 49.3 ± 8.7 s. A few units continued to fire tonically for 119 ± 14 s. This overall pattern of phrenic response was reproducible within individual animals and was independent of the duration (15-60 s) of stimulation.
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Effect of Repetitive Spinal Cord Stimulation on Phrenic Motoneurons
Twenty-four phrenic motoneurons were tested for their response to 100-Hz stimulation. Three qualitatively different response patterns were observed. However, within a given neuron, the response pattern was independent of the duration of stimulation (2-5 trials per neuron, 5- to 30-s duration stimulus trains).Depolarizing response.
As shown in the example in Fig. 3,
neurons exhibiting this pattern of response (10 of 24) underwent a
progressive membrane depolarization during stimulation to a new
plateau, followed by a brief repolarization at the termination of
stimulation (note the repolarization following termination of the
stimulus train in Fig. 3C) and then a second depolarization
(Fig. 3, top, between C and D;
n = 10 of 24). As mentioned above, the overall pattern of potentiation did not vary for depolarizing neurons exposed to
different stimulus durations. The neuron illustrated with a depolarizing response to a 5-s period of high-frequency stimulation in
Fig. 3 also exhibits a depolarizing response to either 15- or 30-s
stimulation periods (Fig. 4). The general
pattern of the response (i.e., depolarization) remains the same,
despite subjecting the neuron to a full range of stimulus periods.
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Repolarizing response.
One-third of the tested motoneurons (8 of 24) exhibited the response
pattern illustrated in Fig. 6. This
consisted of a progressive depolarization to a new MP during
stimulation, followed by an exponential return toward the
prestimulus MP immediately poststimulation without a secondary
depolarization.
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Bistable response.
The final response pattern consisted of a bistable behavior that was
observed in 25% of neurons tested (6 of 24). As shown in Figs.
7 and 8, these neurons depolarized during
stimulation to a new steady level that
was maintained for ~1 min after stimulation (bistable behavior).
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5 nA; 2 s; n = 2) restored these neurons
to their prestimulus MP (Fig. 8B).
Effect of Repetitive Spinal Cord Stimulation on EPSP Waveform
As indicated above for depolarizing (Fig. 3) and repolarizing (Fig. 6) neurons, a period of 100-Hz spinal cord stimulation led to a short-term increase in the amplitude and duration of EPSPs evoked by low-frequency (0.5-1 Hz) test pulses in neurons exhibiting any of the three response patterns to high-frequency stimulation (depolarizing, n = 7; repolarizing, n = 5; bistable, n = 1). The average response for all neurons is shown in Fig. 9. Five seconds poststimulation, the EPSP amplitude had increased 76.1 ± 10.1% above a control of 4.1 ± 0.3 mV (P < 0.01; n = 10). EPSP slope (measured as the rise time from 20 to 80% of the peak) increased an average of 84.6 ± 30.9% (n = 12; P < 0.01) above control (4.13 ± 0.48 mV/ms), then decayed toward control, but remained elevated (35.1 ± 7.1%; n = 10; P < 0.01) 1 min poststimulation.
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Presence of Interneurons Proximal to the Phrenic Nucleus
Probable interneurons in the vicinity of the phrenic nucleus (n = 10 in spinal cord intact, n = 2 in spinalized rats; Fig. 10) were identified by using four criteria: 1) the presence of respiratory modulated activity but differing from that of the whole phrenic nerve in spinal cord-intact animals; 2) neurons not antidromically activated from the ipsilateral phrenic nerve at stimulus intensities supermaximal for eliciting a maximal antidromic field potential; 3) neurons orthodromically activated by phrenic nerve stimulation; and 4) neurons located within the region from which the phrenic nerve antidromic field potential could be recorded (i.e., within or proximal to the phrenic nucleus). Figure 10 shows an extracellular recording of an interneuron exhibiting tonic activity with a superimposed phasic inspiratory pattern that was orthodromically activated during spinal cord stimulation.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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A STP in phrenic nerve activity followed high-frequency stimulation of the ipsilateral lateral funiculus. As previously shown (18), STP of phrenic nerve activity was unaffected by section of the spinal cord, thereby confirming that supraspinal circuitry is not required. Short-term plasticity of the descending synaptic input to spinal motoneurons controlling muscles involved in expiratory efforts has also been recently shown in turtles (13), although, in the turtle, the response consisted of a depression of synaptic efficacy with little effect on motor output to inspiratory muscles. It is also clear that the spinal cord is not uniquely responsible for STP, and other pathways can make a significant contribution. Mifflin (20), for example, noted that the STP in respiratory motor output resulting from carotid sinus nerve stimulation occurs within the nucleus of the solitary tract. Taken together, these findings suggest that both excitatory and inhibitory short-term plasticity of breathing may occur at several locations within the respiratory control system, including brain stem and spinal cord circuitry.
Comparison of STP Elicited by Spinal Cord vs. Primary Afferent Stimulation
Poststimulation STP of phrenic nerve activity in anesthetized rats or cats has virtually identical time courses, whether it is evoked by carotid sinus nerve stimulation (9, 25) or spinal cord stimulation. The similarity of these response patterns is consistent with a common, spinal mechanism contributing to both responses. However, marked differences in both the magnitude and time course of STP on respiratory motor output have been reported. These differences can arise in response to activation of a number of different afferent inputs or even with stimulation of the same afferent pathway but under different experimental conditions (see Ref. 24). For example, STP of hypoglossal nerve activity elicited by stimulation of the superior larygneal nerve in anesthetized cats decays with a slower time constant than STP of the same nerve elicited by carotid sinus nerve stimulation (12). Because stimulation of either the superior laryngeal or the carotid sinus nerves elicits similar increases in the hypoglossal motor output, it is difficult to explain the difference in STP solely on the basis of a change in the interaction between premotor and motoneurons. A more attractive explanation is that the differences depend on processing of afferent information upstream from the premotor neurons. Differential processing within the nucleus of the solitary tract is one upstream candidate and is consistent with the demonstration that STP occurs in at least some second-order neurons within the nucleus of the solitary tract in response to stimulation of the carotid sinus nerve (20).Nevertheless, plasticity in the interaction between premotor and motor circuitry provides a simple mechanism to explain marked differences in the pattern of plasticity on different respiratory motor outputs. This is consistent with the demonstration of Jiang et al. (12) that superior laryngeal nerve stimulation elicits a substantial increase in activity and STP on hypoglossal nerve activity. In contrast, superior laryngeal nerve stimulation inhibits phrenic nerve activity, and there is no poststimulus STP of phrenic nerve activity. A STP mechanism that is activity dependent and located within the premotor and motor circuitry would readily explain this independence of STP observed on the hypoglossal and phrenic nerves. Thus it seems likely that there are multiple nodes of plasticity in the central respiratory control system, with different sites participating to a greater or lesser extent, depending on the physiological circumstances.
Patterns of Phrenic Motoneuron Response Underlying STP
Three distinct response patterns of phrenic motoneuron response were observed in response to high-frequency stimulation of descending pathways. One of these, the repolarizing response, decayed with a relatively short time constant (14 s). Motoneurons with this brief time course could only contribute to the early component of STP (overall time constant = 49 s). The twofold longer time constant of the depolarizing response (33 s) plus the 5-s delay while these neurons undergo a secondary depolarization suggest that these neurons contribute to the population STP over a much longer interval. This poststimulation depolarization is likely to contribute to the delayed increase in phrenic nerve activity, which occurs with a comparable time course. Motoneurons exhibiting bistable behavior (duration 45 s) could contribute to the entire envelope of STP. Although the
bistable response of individual motoneurons has an on-off (binary)
pattern, the staggering of off-times in different neurons could
contribute to the appearance of a gradual decay in activity of the
whole phrenic nerve.
Experimental determination of the mechanisms contributing to the stimulation-induced progressive depolarization of phrenic motoneurons was beyond the scope of this study, but these could involve several nonmutually exclusive processes. Both pre- (see below) and postsynaptic events could contribute. Postsynaptic changes could include temporal summation of EPSPs, a fading of inhibitory postsynaptic potentials (IPSPs) due to shifts in chloride potential, accumulation of extracellular potassium, or a G-protein-mediated process such as potassium channel closure (2). N-methyl-D-aspartate (NMDA) receptor activation could also contribute to the increased activity. NMDA receptors could be located either directly on motoneurons or on interneurons interposed in the descending pathway. This possibility is consistent with the previous observation that ketamine and MK-801 markedly reduce a long-latency excitation of phrenic motoneurons during paired pulse stimulation of bulbospinal pathways (18). STP could also result from excitation of phrenic motoneurons by a pool of recurrently activated spinal interneurons, as has been described in another region involved in cardiorespiratory control, the nucleus of the solitary tract (8). Recurrent excitation between synaptically coupled phrenic motoneurons (i.e., without incorporating interneurons) is unlikely to provide a major contribution to STP, because high-frequency antidromic stimulation of phrenic motoneurons in the present study, or in previous work in cats (14), resulted in hyperpolarization of phrenic motoneurons rather than sustained activation. Finally, a variety of neuromodulators (e.g., serotonin, norepinephrine, and substance P; Ref. 7) or their receptors have been identified in the phrenic nucleus. Neuromodulators could be released in response to activation of sensory afferent inputs or in response to high-frequency discharge rates and, consequently, contribute to the development of STP.
The poststimulation secondary depolarization in motoneurons exhibiting the depolarizing response could be the result of two parallel processes. For example, temporal summation of fast EPSPs could combine with a slow membrane depolarization. In this instance, termination of the stimulus would result in a rapid decay of the temporally summed fast EPSPs, whereas a slower process mediating membrane depolarization extends beyond this period. Thus a brief repolarization would be produced. The same mechanism that produces the slow response may also modulate the amplitude of the EPSPs (see below). Alternatively, the poststimulus depolarization could represent a balance between changes in both inward and outward currents. After stimulus termination, outward currents could initially dominate, tending to repolarize the membrane, but a more rapid decline in net outward current could result in the secondary depolarization.
To our knowledge, this is the first description of bistable behavior in a subset of phrenic motoneurons and is similar to previous descriptions in which a relatively brief excitatory input caused a sustained increase in the excitability of other spinal motoneurons (1, 3, 15). Because the intracellular injection of a hyperpolarizing current reset the MP to the prestimulus control, it indicates that this behavior was likely to arise from a change in the motoneuron property rather than as the result of increased activity in their presynaptic neurons. A serotonin-dependent, calcium-mediated plateau potential is one mechanism that can cause bistable behavior (11). A serotonergic contribution to the STP in the present paradigm could be argued, if descending serotonergic pathways were activated by the spinal stimulation. Alternatively, the plateau depolarization could arise from a persistent inward dendritic current (15). In the case of phrenic motoneurons, this would imply that dendrites possess active mechanisms for differential control of their response to, for example, descending respiratory inputs vs. nonbreathing behaviors, such as coughing or emesis.
In the present study, an increase in EPSP amplitude also contributed to the increase in motoneuron excitability. The increased EPSP amplitude and slope could result from either an increase in transmitter release or an increase in the postsynaptic response. An increase in transmitter release could result from an accumulation of calcium in presynaptic terminals (27). It is also conceivable that high-frequency stimulation resulted in recruitment of interneurons interposed between the bulbospinal and the motoneurons. Once recruited, these neurons could act as an amplifier to increase the gain of synaptic input to phrenic motoneurons.
The relative contribution of mono- vs. polysynaptic pathways to the EPSPs observed in phrenic motoneurons is not clear, but the response latencies are consistent with a paucisynaptic pathway. In a previous study (18), the EPSP latency in phrenic motoneurons after stimulation of the descending pathways was used to divide phrenic motoneurons into two distinct groups. In one, the latency to EPSP onset was too short (<1 ms) to be resolvable from the stimulus artifact. This was almost certainly a monosynaptic input. In the second group of motoneurons, the EPSP onset latency was ~1.1 ms, and time to EPSP peak averaged 2.4 ms. This latency is at least consistent with the inclusion of an interposed interneuron (18). Interestingly, paired-pulse potentiation was evident in the form of temporal summation of EPSPs only in the motoneurons with longer latency synaptic responses. This suggests a possible role for interneurons in mediating at least some of the changes underlying STP. Interneurons within the immediate vicinity of phrenic motoneurons were identified in the present study, as well as in previous work in the rat (10). Their location is consistent with a role in descending polysynaptic pathways. At least in cats, a polysynaptic pathway contributes to the descending respiratory drive to phrenic motoneurons (see Ref. 22). In the present study, lengthening of the EPSP duration (see Fig. 3F) is consistent with the recruitment of a polysynaptic pathway that contributes to the later components of the compound EPSP.
Postsynaptic changes in phrenic motoneurons could also contribute to EPSP augmentation. For example, motoneuron depolarization could result in activation (or inactivation) of voltage-dependent conductances that alter the motoneuron's current-voltage relationship (27). In similar fashion, depolarization could reduce the voltage-dependent block of NMDA receptors and result in an increased contribution from these receptors that contribute currents with slower kinetics.
In many motoneurons, an IPSP preceded the EPSP, although the duration of the IPSP was masked by the EPSP (e.g., Fig. 6E; and see Fig. 9 in Ref. 18). The short latency of this IPSP suggests a monosynaptic input, and a monosynaptic inhibitory pathway originating in the Bötzinger complex has been confirmed in cats (19). Alternatively, the inhibition may be mediated via interneurons located in the rostral cervical spinal cord. Neurons within the rostral spinal cord could have been activated in the present study either directly by current spread or via synaptic inputs. However, few connections have been described between these neurons and phrenic motoneurons (4, 16, 23).
In summary, a significant finding of this study was that repetitive activation of descending inputs to phrenic motoneurons causes STP, resulting from a short-term increase in their excitability. Each phrenic motoneuron exhibits one of three different patterns of depolarization and an increase in the amplitude of evoked EPSPs. The overall time course of increased excitability is similar to that of the decay of the STP recorded on the whole phrenic nerve. This short-term plasticity of respiratory motor output is likely to contribute to the short-term increases in breathing that follow activation of a variety of respiratory afferent pathways.
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ACKNOWLEDGEMENTS |
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We thank Dr. George Alheid for helpful comments and discussion.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute/National Institute of Neurological Disorders and Stroke Grants HL/NS-40336 and HL/NS-60097 and the National Sudden Infant Death Research Foundation of Australia.
Present address of C. F. L. Hinrichsen: Dept. of Anatomy and Physiology, University of Tasmania, Hobart, Tasmania 7001, Australia.
Address for reprint requests and other correspondence: D. R. McCrimmon, Dept. Physiology-M211, Feinberg School of Medicine, Northwestern Univ., 303 E. Chicago Ave., Chicago, IL 60611-3008 (E-mail: dm{at}northwestern.edu).
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. Section 1734 solely to indicate this fact.
First published December 13, 2002;10.1152/japplphysiol.00599.2002
Received 8 July 2002; accepted in final form 7 December 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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