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J Appl Physiol 100: 1563-1568, 2006. First published January 12, 2006; doi:10.1152/japplphysiol.01035.2005
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{alpha}-Adrenergic receptor-mediated restraint of skeletal muscle blood flow during prolonged exercise

Darren S. DeLorey, Jason J. Hamann, Heidi A. Kluess, Philip S. Clifford, and John B. Buckwalter

Departments of Anesthesiology and Physiology, Medical College of Wisconsin, and Veterans Affairs Medical Center, Milwaukee, Wisconsin

Submitted 24 August 2005 ; accepted in final form 10 January 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Sympathetic nervous system restraint of skeletal muscle blood flow during dynamic exercise has been well documented. However, whether sympathetic restraint of muscle blood flow persists and is constant throughout prolonged exercise has not been established. We hypothesized that both {alpha}1- and {alpha}2-adrenergic receptors would restrain skeletal muscle blood flow throughout prolonged constant-load exercise and that the restraint would increase as a function of exercise duration. Mongrel dogs were instrumented chronically with transit-time flow probes on the external iliac arteries and an indwelling catheter in a branch of the femoral artery. Flow-adjusted doses of selective {alpha}1- (prazosin) and {alpha}2-adrenergic receptor (rauwolscine) antagonists were infused after 5, 30, and 50 min of treadmill exercise at 3 and 6 miles/h. During mild-intensity exercise (3 miles/h), prazosin infusion resulted in a greater (P < 0.05) increase in vascular conductance (VC) after 5 [42% (SD 6)], compared with 30 [28% (SD 6)] and 50 [28% (SD 8)] min of running. In contrast, prazosin resulted in a similar increase in VC after 5 [29% (SD 10)], 30 [24% (SD 9)], and 50 [22% (SD 9)] min of moderate-intensity (6 miles/h) exercise. Rauwolscine infusion resulted in a greater (P < 0.05) increase in VC after 5 [39% (SD 14)] compared with 30 [26% (SD 9)] and 50 [22% (SD 4)] min of exercise at 3 miles/h. Rauwolscine infusion produced a similar increase in VC after 5 [19% (SD 3)], 30 [15% (SD 6)], and 50 [16% (SD 2)] min of exercise at 6 miles/h. These results suggest that the ability of {alpha}1- and {alpha}2-adrenergic receptors to produce vasoconstriction and restrain blood flow to active muscles may be influenced by both the intensity and duration of exercise.

vascular conductance; sympathetic nervous system; sympatholysis

SKELETAL MUSCLE VASCULAR TONE represents a dynamic balance between sympathetic nervous system (SNS) vasoconstriction and locally released vasoactive substances. During dynamic exercise, skeletal muscle vascular conductance (VC) increases in an exercise intensity-dependent manner. Measurement of lumbar sympathetic nerve activity during exercise suggests that muscle sympathetic nerve activity (MSNA) also increases (11) in an exercise intensity-dependent manner. It is currently believed that local vasodilator responses outweigh sympathetic vasoconstrictor tone and shift the balance between these two competing influences in favor of vasodilation (2). Whereas locally produced metabolic chemicals may attenuate SNS-mediated vasoconstriction, a process termed functional sympatholysis (26), several studies have demonstrated that the SNS continues to produce vasoconstriction and restrain skeletal muscle blood flow during dynamic exercise (3, 5, 15, 22). Furthermore, Buckwalter et al. (3, 5) have demonstrated that both {alpha}1- and {alpha}2-adrenergic receptors restrain skeletal muscle blood flow, even during intense exercise. Although these studies have documented sympathetic restraint of muscle blood flow at rest and during exercise, they have largely focused on the relationship between exercise intensity and the magnitude of sympathetic restraint. As a result, relatively little is known about the temporal aspects of SNS-mediated restraint of skeletal muscle blood flow during prolonged constant-load exercise. Specifically, whether sympathetic restraint of muscle blood flow persists throughout prolonged constant-load exercise and whether the magnitude of restraint is influenced by exercise duration have not been established.

Several previous studies have reported a progressive increase in sympathetic efferent nerve activity to muscle throughout prolonged constant-load exercise (1, 18, 31), suggesting that vasoconstriction in the skeletal muscle vasculature may increase throughout prolonged exercise. However, {alpha}1- and {alpha}2-adrenergic receptor responsiveness has been shown to be sensitive to local temperature (9, 13, 14, 19), hydrogen ion concentration (20, 21, 34), and locally released vasoactive substances, including nitric oxide (7, 8, 23, 36–38), all of which may increase during prolonged exercise and reduce receptor responsiveness. A decrease in receptor responsiveness could potentially result in a decline in SNS restraint of skeletal muscle blood flow over time. Despite the potential for a decline in {alpha}-adrenergic receptor responsiveness during prolonged exercise, Rowlands and Donald (28) reported that vasoconstriction to sympathetic nerve stimulation increased over time in anesthetized dogs. Studies by Peterson et al. (24) and Joyner et al. (16) also suggest that sympathetic vasoconstriction in skeletal muscle may increase over time during exercise. Therefore, the purpose of this study was to investigate the effect of exercise duration on {alpha}1- and {alpha}2-adrenergic receptor-mediated restraint of skeletal muscle blood flow during prolonged constant-load exercise. We hypothesized that {alpha}-adrenergic receptor-mediated restraint of skeletal muscle blood flow would be present throughout prolonged exercise and that the magnitude of restraint would progressively increase throughout prolonged constant-load exercise.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
All experimental procedures were approved by the Institutional Animal Care and Use Committee and were conducted in accordance with the American Physiological Society's Guiding Principles in the Care and Use of Animals. Thirteen mongrel dogs (18–23 kg) were selected for their willingness to run on a motorized treadmill and were chronically instrumented in a series of three sterile surgeries. For each surgery, anesthesia was induced with thiopental sodium (25 mg/kg; Gensia Pharmaceuticals, Irvine, CA). Animals were then intubated with a cuffed endotracheal tube, and a surgical level of anesthesia was maintained through mechanical ventilation with 1.5% halothane (Halocarbon Laboratories, River Edge, NJ) and 98.5% O2. Animals were given an analgesic for pain management (buprenorphrine hydrochloride, 0.3 mg; Reckitt and Coleman, Kingston-upon-Hull, UK) and antibiotics for 10 days (cefazolin sodium, 500 mg twice a day; Apothecon, Princeton, NJ) postoperatively. In the initial surgery, the carotid arteries were externalized and placed in neck skin tubes for measurement of arterial blood pressure via percutaneous cannulation. After a 1-wk recovery, animals were instrumented with ultrasonic transit-time flow probes (4–6 mm; Transonic Systems, Ithaca, NY) around the external iliac of each hindlimb for measurement of skeletal muscle blood flow. Cables were tunneled under the skin to the back and externalized. After a 2-wk recovery, a heparinized catheter (0.045 in. OD, 0.015 in. ID, 60 cm long, Data Science International, St. Paul, MN) was implanted in a side branch and advanced into the femoral artery of one hindlimb in the final surgery. The catheter was tunneled under the skin to the back, externalized, and used for infusion of experimental drugs. To maintain patency, the catheter was flushed daily with saline and filled with a heparin lock (100 IU heparin/ml in 50% dextrose solution). Dogs were given 2 days to recover from the final surgery before any experimental procedures were performed.

To minimize changes in body temperature during the exercise sessions, laboratory temperature was maintained below 20°C for all experiments. For each experiment, the dog was brought to the laboratory and rested in a sling while the flow probes were connected to a flowmeter (Transonic Systems), and a 20-gauge intravascular catheter (Insyte, Becton-Dickinson, Sandy, UT) was inserted retrogradely into the lumen of the carotid artery and attached to a solid-state pressure transducer (Abbott, North Chicago, IL) for measurement of arterial pressure. After calibration of the pressure transducer and flow probes, the dog was transferred to the treadmill.

Experiments were conducted during treadmill running at mild (3 miles/h) and moderate (6 miles/h) exercise intensities. Flow-adjusted doses of either a selective {alpha}1-adrenergic receptor (prazosin, Pfizer, Exton, PA; 0.25 µg/ml of experimental hindlimb flow; series 1) or {alpha}2-adrenergic receptor (rauwolscine, RBI, Natick, MA; 1.25 µg/ml of experimental hindlimb flow; series 2) antagonist was infused after 5, 30, and 50 min of exercise while the animal continued to run on the treadmill for an additional 5 min. Each combination of treadmill speed and exercise duration was performed on a separate day for each antagonist; thus each dog completed a total of 12 experiments.

On separate days, arterial blood was collected after 5, 30, and 50 min of exercise at 3 and 6 miles/h for measurement of plasma norepinephrine (NE) concentration by high-pressure liquid chromatography.

Arterial blood pressure and external iliac blood flow were recorded at 100 Hz directly to a computer with a Powerlab data-acquisition system (ADInstruments, Castle Hill, Australia). Data were analyzed offline to calculate the absolute and relative change in mean arterial pressure (MAP), heart rate (HR), right and left limb iliac blood flow, and iliac vascular conductance (iliac blood flow/MAP) in response to intra-arterial infusion of selective antagonists. Values were averaged over 30 s before and after antagonist infusion for comparison.

Data for each receptor type were analyzed separately; a three-way ANOVA (exercise intensity x duration x drug) was used to analyze data expressed in absolute terms, whereas data expressed as a percent change in response to antagonist infusion were analyzed by two-way ANOVA (exercise intensity x duration). Where significant F ratios were found, a Tukey's post hoc test was performed. All data are presented as means (SD). A P value of <0.05 was considered statistically significant.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Intra-arterial infusion of the selective {alpha}1- and {alpha}2-adrenergic receptor antagonists, prazosin and rauwolscine, increased experimental limb blood flow and VC after 5, 30, and 50 min of exercise at both 3 and 6 miles/h. Figure 1 is an original tracing and demonstrates that the increases in experimental limb blood flow and VC in response to drug infusion occurred without changes in contralateral limb blood flow and vascular conductance and MAP.


Figure 1
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  		Fig. 1. Original data tracing from a dog exercising on a treadmill at 3 miles/h. Arrow indicates intra-arterial infusion of the selective {alpha}2-adrenergic receptor antagonist, rauwolscine, into the femoral artery of the experimental hindlimb. Note that there were no changes in mean arterial pressure, blood flow, or vascular conductance in the control (contralateral) limb.

 
Series 1: {alpha}1-mediated restraint.

Six mongrel dogs completed series 1. Baseline hemodynamics and MAP, experimental and control limb blood flow, and VC responses to intra-arterial infusions of prazosin are presented in Table 1. Control and experimental limb blood flow and VC increased (P < 0.05) in an exercise-intensity dependent manner, whereas MAP was not different during exercise at 3 and 6 miles/h. However, at both 3 and 6 miles/h, MAP was greater (P < 0.01) after 5 compared with 30 and 50 min of treadmill running. HR increased (P < 0.01) in an intensity-dependent manner; however, HR was not different over time at 3 miles/h [5 min: 153 beats/min (SD 25); 30 min: 147 beats/min (SD 22) 50 min: 148 beats/min (SD 18)] or 6 miles/h [5 min: 184 beats/min (SD 13); 30 min: 181 beats/min (SD 18); 50 min: 190 beats/min (SD 18)]. Control and experimental limb blood flow and VC increased rapidly at the onset of exercise, and despite some fluctuation throughout the 50-min exercise bout, mean blood flow and VC were not different before the infusion of prazosin at 5, 30, and 50 min of exercise at both 3 and 6 miles/h (Table 1). Intra-arterial infusions of prazosin caused an increase in experimental limb VC at all exercise durations at both 3 and 6 miles/h. During exercise at 3 miles/h, the increase in VC, expressed as a percent change from preinfusion VC, was greater (P < 0.01) after 5 [42% (SD 6)] compared with 30 [28% (SD 6)] and 50 [28% (SD 8)] min of exercise (Fig. 2). A similar pattern was observed for the absolute change in VC with the largest increase (P < 0.05) in response to prazosin being after 5 min [1.3 ml·min–1·mmHg–1 (SD 0.3)], whereas similar smaller increases occurred after 30 [1.0 ml·min–1·mmHg–1 (SD 0.4)] and 50 min [1.0 ml·min–1·mmHg–1 (SD 0.4)] of running. At 6 miles/h, infusion of prazosin resulted in similar percent increases in VC after 5 [29% (SD 10)], 30 [24% (SD 9)], and 50 min [22% (SD 9)] of exercise (Fig. 2). The absolute increase in VC in response to prazosin was not different after 5 [1.2 ml·min–1·mmHg–1 (SD 0.4)], 30 [1.1 ml·min–mmHg–1 (SD 0.3)], and 50 [1.0 ml·min–1·mmHg–1 (SD 0.3)] min of exercise.


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  		Table 1. Baseline hemodynamics and response to intra-arterial infusion of prazosin

 

Figure 2
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  		Fig. 2. Percent change in iliac vascular conductance in response to intra-arterial infusion of the selective {alpha}1-adrenergic receptor antagonist, prazosin, into the femoral artery of the experimental hindlimb. Values are means (SD). mph, Miles/h. *P < 0.05, significantly different from 30- and 50-min time points.

 
Series 2: {alpha}2-mediated restraint.

Six mongrel dogs completed series 2. Baseline hemodynamics and MAP, experimental and control limb blood flow, and VC responses to intra-arterial infusions of rauwolscine are presented in Table 2. As in series 1, control and experimental limb blood flow and VC increased (P < 0.05) in an exercise intensity-dependent manner. MAP was not different during exercise at 3 and 6 miles/h. However, MAP was greater (P < 0.05) after 5 compared with 30 and 50 min of exercise during both the 3 and 6 miles/h exercise bouts. HR increased (P < 0.01) in an intensity-dependent manner; however, HR was not different over time at 3 miles/h [5 min: 156 beats/min (SD 26); 30 min: 149 beats/min (SD 26); 50 min: 144 beats/min (SD 22)] or 6 miles/h [5 min: 187 beats/min (SD 32); 30 min: 182 beats/min (SD 28); 50 min: 184 beats/min (SD 24)]. Control and experimental limb blood flow and VC increased rapidly at the onset of exercise, and, despite some fluctuation throughout the 50-min exercise bout, mean blood flow and VC were not different after 5, 30, and 50 min of exercise at both 3 and 6 miles/h (Table 2). Intra-arterial infusion of rauwolscine resulted in an increase in experimental limb VC at all exercise durations at both 3 and 6 miles/h. During exercise at 3 miles/h, the increase in VC, expressed as a percent change from preinfusion VC, was greater (P < 0.01) after 5 [39% (SD 14)] compared with 30 [26% (SD 9)] and 50 min [22% (SD 4)] of exercise (Fig. 3). A similar pattern was observed for the absolute change in VC [5 min: 1.2 ml·min–1·mmHg–1 (SD 0.4); 30 min: 0.9 ml·min–1·mmHg–1 (SD 0.4); 50 min: 0.8 ml·min–1·mmHg–1 (SD 0.2)]. At 6 miles/h, a similar percent increase in VC was observed at all exercise durations [5 min: 19% (SD 3); 30 min: 15% (SD 6); 50 min: 16% (SD 2)] in response to infusion of rauwolscine (Fig. 3). Similar increases in absolute VC were observed at all exercise durations [5 min: 0.9 ml·min–1·mmHg–1 (SD 0.4); 30 min: 0.7 ml·min–1·mmHg–1 (SD 0.2); 50 min: 0.8 ml·min–1·mmHg–1 (SD 0.3)].


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  		Table 2. Baseline hemodynamics and response to intra-arterial infusion of rauwolscine

 

Figure 3
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  		Fig. 3. Percent change in iliac vascular conductance in response to intra-arterial infusion of the selective {alpha}2-adrenergic receptor antagonist, rauwolscine, into the femoral artery of the experimental hindlimb. Values are means (SD). *P < 0.05, significantly different from 30- and 50-min time points.

 
Plasma NE concentration tended to be higher during exercise at 6 compared with 3 miles/h, and there was also a tendency for plasma NE to increase over time at 3 [n = 7; 5 min: 279 pg/ml (SD 86); 30 min: 285 pg/ml (SD 181); 50 min: 341 pg/ml (SD 179)] and 6 miles/h [n = 4; 5: 322 pg/ml (SD 234); 30: 339 pg/ml (SD 120); 50: 396 pg/ml (SD 135)]; however, a main effect for exercise intensity (P = 0.17) or duration (P = 0.28) was not observed.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The purpose of this study was to investigate the sympathetic restraint of skeletal muscle blood flow during prolonged constant-load exercise. The main findings of this study were the following: 1) {alpha}1- and {alpha}2-adrenergic receptors restrain blood flow to active skeletal muscle throughout prolonged mild- (3 miles/h) and moderate-intensity (6 miles/h) exercise, 2) {alpha}1- and {alpha}2-adrenergic receptor-mediated restraint of blood flow declined over time during mild-intensity (3 miles/h) exercise, and 3) {alpha}1- and {alpha}2-adrenergic receptor-mediated restraint was attenuated during moderate compared with mild-intensity exercise; however, sympathetic restraint remained relatively constant throughout moderate-intensity (6 miles/h) exercise. These results demonstrate that {alpha}1- and {alpha}2-adrenergic receptor-mediated restraint of skeletal muscle blood flow may be modulated by both the intensity and duration of exercise.

Consistent with previous reports from our laboratory (3, 5, 15) and others (22), both {alpha}1- and {alpha}2-adrenergic receptors restrained blood flow to active skeletal muscle in the present study. To our knowledge, this is the first study to report {alpha}1- and {alpha}2-adrenergic receptor-mediated restraint of blood flow throughout prolonged mild- (3 miles/h) and moderate-intensity (6 miles/h) exercise. Also consistent with previous work from our laboratory, {alpha}1- and {alpha}2-adrenergic receptor-mediated restraint was attenuated in an exercise intensity-dependent manner in the present study (3, 5). However, contrary to our hypothesis, sympathetic vasoconstriction decreased over time during prolonged mild-intensity exercise and was relatively constant throughout prolonged moderate-intensity exercise.

The pattern of greater sympathetic restraint during the initial 5 min of mild-intensity exercise compared with all other time points during both mild- and moderate-intensity exercise suggests an interplay between exercise duration and intensity that may modulate the ability of the sympathetic nervous system to produce vasoconstriction. Additionally, this pattern of response suggests that the first several minutes of exercise represent a transitional phase where the competing influences of sympathetic vasoconstrictor tone and locally produced vasoactive substances seek to adjust vascular tone from a relatively vasoconstricted state at rest to a more vasodilated state during exercise. At some point, an equilibrium blood flow is established that ensures both adequate muscle O2 delivery and maintenance of MAP. The precise time point at which this new balance is achieved during mild-intensity exercise, or why this transition appears to occur earlier during moderate-intensity exercise, cannot be discerned from the present data. It is recognized that there are other factors that regulate muscle blood flow, including endothelial, myogenic, and humoral mechanisms. How these factors change over time and influence vascular tone has not been investigated and deserves further attention.

The pattern of increase in MSNA is influenced by exercise duration and intensity. Several studies have reported a progressive increase in MSNA throughout prolonged exercise (1, 31), whereas a single study reported a decline (25). Additionally, Kozlowski et al. (18) reported a progressive increase in NE spillover in dogs during prolonged moderate-intensity exercise, suggestive of a progressive increase in MSNA. The accumulated evidence from these studies, although not conclusive, suggests that MSNA progressively increases throughout prolonged exercise. In the present study, there was a trend for increased arterial plasma NE concentrations over time during exercise at both 3 and 6 miles/h. Importantly, the arterial plasma NE data suggest that sympathetic outflow did not decline over time and that the exercise duration-dependent decline in {alpha}-adrenergic-mediated restraint of skeletal muscle blood flow was not due to a decline in sympathetic outflow. Thus the greater sympathetic restraint after 5 compared with 30 and 50 min of treadmill running at 3 miles/h suggests that the SNS became less effective at producing vasoconstriction as exercise continued, despite constant or increasing MSNA.

Functional sympatholysis, defined as an attenuated vascular responsiveness to sympathetic stimulation (26), may explain the reduction of sympathetic restraint of skeletal muscle blood flow during prolonged exercise in the present study. Several metabolites and ions extruded from muscle during contraction and vasoactive agents released from the vascular endothelium have been proposed as potential mediators of sympatholysis. However, to date no substance has been shown to be obligatory for sympatholysis. The pattern of response in the present study suggests that any potential mediator(s) of sympatholysis may require a longer period of time to reach an effective concentration during exercise at a mild intensity, compared with a higher intensity (i.e., a threshold exists). Alternatively, other vascular control mechanisms may assume a larger role in the control of vascular tone during prolonged exercise. For example, Shipley et al. (32) recently demonstrated that differential mechanisms were responsible for the immediate and sustained vasodilation of isolated skeletal muscle arterioles in response to a prolonged step increase in flow.

Presynaptic inhibition of neurotransmitter release from nerve endings may explain a decline in sympathetic restraint over time despite increasing MSNA. For example, adenosine, which is released from exercising muscle, has been shown to inhibit NE release from nerve terminals (33, 39). In the present study, there was a tendency for arterial plasma NE to increase throughout exercise, suggesting that NE release was not attenuated over time. Additionally, the demonstration of increased NE spillover during prolonged exercise in dogs in the study of Kozlowski et al. (18) suggests that NE was being released in increasing quantities throughout prolonged exercise. These data argue against presynaptic inhibition of neurotransmitter release being responsible for the decline in sympathetic restraint in the present study.

A number of studies in both animals (4, 6, 29, 30, 35) and humans (12, 27, 40) have reported attenuated {alpha}-adrenergic receptor responsiveness during exercise, and a decline in receptor responsiveness may explain the reduced sympathetic restraint over time in the present study. The preponderance of evidence in the literature suggests that the {alpha}2-receptor is more sensitive to changes in the interstitial environment than the {alpha}1-receptor (6, 29, 30, 35). Interestingly, the magnitude and pattern of response to infused selective antagonists was nearly identical for {alpha}1- and {alpha}2-adrenergic receptors during prolonged exercise in the present study. This unexpected finding suggests that the potential mediator(s) of the response affects both receptors similarly.

{alpha}-Adrenergic receptor function has also been shown to be sensitive to changes in pH (20, 21, 34). Acidosis has been shown repeatedly to decrease the sensitivity of {alpha}2-adrenergic receptors, whereas {alpha}1-receptor responsiveness appears to be less sensitive to modulation by changes in pH (20, 21, 34). Whether pH changed throughout prolonged exercise in the present study was not examined. The relatively low exercise loads and the ability of the animals to maintain both exercise intensities for ~1 h suggest that a large decrease in pH was not experienced during either exercise bout. Additionally, attenuation of {alpha}-adrenergic receptor responsiveness typically occurs at higher exercise intensities (and presumably more acidic pH values) than those utilized in the present study (6, 29, 30). Given the different sensitivities of the receptors to changes in pH, the similar magnitude and pattern of the response of both receptors suggest that factors other than changes in pH may be involved.

Heat production and muscle temperatures presumably increased as a function of both exercise intensity and duration in the present study. Several previous studies have demonstrated that temperature influences vasoconstrictor responsiveness (9, 13, 14, 19). Prolonged exercise may result in a cardiovascular drift (increase in HR over time), which is often associated with an increase in core temperature and dehydration (10). In the present study, HR did not increase over time at either exercise intensity, suggesting that any increase in temperature throughout exercise was modest. Furthermore, an increase in temperature primarily attenuates {alpha}2-adrenergic receptor responsiveness, whereas {alpha}1-receptor responsiveness remains unchanged (17, 19). Thus the similar response of {alpha}1- and {alpha}2-receptors in the present study is not consistent with an increase in temperature mediating the response.

In conclusion, this study demonstrated a decline in the sympathetic restraint of skeletal muscle blood flow during prolonged mild-intensity exercise. These results suggest that a dynamic relationship exists between the duration and intensity of exercise and the ability of the SNS to produce vasoconstriction. Further investigation will be required to identify the mechanism(s) involved.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This project was supported by the National Heart, Lung, and Blood Institute and the Medical Research Service of the Department of Veteran Affairs. D. S. DeLorey was supported by a postdoctoral research fellowship from the Natural Sciences and Engineering Research Council of Canada.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
The authors acknowledge the expert technical assistance of Paul Kovac throughout this project.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. B. Buckwalter, Anesthesia Research 151, VA Medical Center, Milwaukee, WI 53295 (e-mail: jbuckwal{at}mcw.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.


   REFERENCES
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 DISCUSSION
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 ACKNOWLEDGMENTS
 REFERENCES
 

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D. S. DeLorey, J. J. Hamann, Z. Valic, H. A. Kluess, P. S. Clifford, and J. B. Buckwalter
{alpha}-Adrenergic receptor responsiveness is preserved during prolonged exercise
Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H392 - H398.
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