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Am J Physiol Heart Circ Physiol 292: H392-H398, 2007. First published September 1, 2006; doi:10.1152/ajpheart.00787.2006
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{alpha}-Adrenergic receptor responsiveness is preserved during prolonged exercise

Darren S. DeLorey, Jason J. Hamann, Zoran Valic, 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 23 July 2006 ; accepted in final form 29 August 2006


   ABSTRACT
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 ABSTRACT
METHODS
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 DISCUSSION
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Our laboratory has previously reported a decline in sympathetic nervous system restraint of skeletal muscle blood flow during prolonged mild-intensity exercise. This decline may be explained by a decrease in {alpha}1- and {alpha}2-adrenergic receptor responsiveness over time. Thus the purpose of the present study was to investigate the effect of exercise duration on {alpha}1- and {alpha}2-adrenergic receptor responsiveness during prolonged constant-load exercise. Mongrel dogs (n = 6) were instrumented chronically with transit-time flow probes on the external iliac arteries and an indwelling catheter in a branch of the femoral artery. On separate days, flow-adjusted doses of selective {alpha}1- (phenylephrine) {alpha}2-adrenergic-receptor (clonidine) agonists, and tyramine (to evoke endogenous norepinephrine release) were infused following 5, 30 and 50 min of mild-intensity treadmill exercise (3 miles/h), with hindlimb blood flow (HBF) and mean arterial pressure (MAP) monitored continuously. Vascular conductance (VC) was calculated as HBF/MAP. While the dogs ran on the treadmill at 3 miles/h, infusion of phenylephrine resulted in similar decreases in VC after 5 [73% (SD 10)], 30 [76% (SD 9)], and 50 [73% (SD 10)] min of exercise. Infusion of the {alpha}2-agonist clonidine also produced similar decreases in VC after 5 [58% (SD 10)], 30 [58% (SD 11)], and 50 [53% (SD 12)] min of exercise. Infusion of tyramine resulted in similar decreases in VC after 5 [55% (SD 15)], 30 [51% (SD 10)], and 50 [50% (SD 7)] min of exercise. These results demonstrate that {alpha}1- and {alpha}2-adrenergic receptor responsiveness to infusion of selective {alpha}1- and {alpha}2-adrenergic-receptor agonists and endogenous norepinephrine release (tyramine) does not decline during prolonged mild-intensity exercise. Thus a decrease in {alpha}-adrenergic receptor responsiveness over time does not appear to be responsible for the decrease in sympathetic restraint of muscle blood flow during prolonged exercise.

vascular conductance; sympathetic nervous system; skeletal muscle; blood flow; functional sympatholysis

SKELETAL MUSCLE VASCULAR TONE reflects a dynamic balance among intrinsic myogenic tone, sympathetic vasoconstriction, and local vasodilation. During a transition from rest to exercise or with an increase in exercise intensity, skeletal muscle blood vessels dilate. Although somewhat counterintuitive, the sympathetic nervous system continues to produce vasoconstriction that opposes local vasodilation and restrains skeletal muscle blood flow both at the onset of exercise and during the steady state of dynamic exercise (4, 6, 14, 21). A number of investigations have reported that the ability of the sympathetic nervous system to produce vasoconstriction and oppose local vasodilation declines as a function of exercise intensity, a process known as functional sympatholysis (22).

When compared with the effect of exercise intensity, the influence of exercise duration on the ability of the sympathetic nervous system to produce vasoconstriction has received little attention. In the hindlimb of anesthetized dogs, the vasoconstrictor response to lumbar sympathetic nerve stimulation increased over time during electrically stimulated muscle contractions (3, 24). Additionally, augmented sympathetic outflow did not attenuate muscle blood flow during the first 5 min of rhythmic handgrip exercise but did so for the remainder of a 20-min exercise bout (15). One potential mechanism to explain the above results is a progressive increase in {alpha}-adrenergic receptor responsiveness during prolonged exercise/muscle contraction, which can be studied by examining the response to exogenous infusion of {alpha}-adrenergic agonists. Beaty and Donald (3) reported a progressive increase in vascular responsiveness to norepinephrine infusion over time in the contracting hindlimb, whereas Rowlands and Donald (24) documented that exercise duration did not affect vasoconstrictor responsiveness to norepinephrine. In conscious dogs, Buckwalter et al. (5) demonstrated unchanged vascular responsiveness to phenylephrine (a selective {alpha}1-adrenergic receptor agonist) over the first 15 min of treadmill exercise. Given these contrasting results, it is difficult to arrive at a consensus regarding the effect of exercise duration on {alpha}-adrenergic receptor responsiveness of the skeletal muscle vasculature.

A recent study (10) from our laboratory suggests that further investigation into the effect of exercise duration on {alpha}-adrenergic receptor responsiveness may be warranted. We investigated the sympathetic restraint of skeletal muscle blood flow by administering selective {alpha}1- and {alpha}2-adrenergic receptor antagonists during prolonged exercise. During mild intensity exercise, the magnitude of {alpha}1- and {alpha}2-adrenergic receptor-mediated restraint was greater during the initial adjustment to exercise (~5 min) compared with the "steady state" (30 and 50 min) (10). The level of tonic vasoconstriction reflects the net effect of sympathetic nerve activity, neurotransmitter release for a given nerve activity, and the responsiveness of the postsynaptic receptor. Which of these factors were altered by exercise duration could not be discerned in our previous study. However, the fact that circulating catecholamines remained relatively constant argues against a diminution in sympathetic nerve activity as exercise continued, thus emphasizing the need to investigate the question of {alpha}-adrenergic responsiveness during prolonged exercise.

Therefore, the purpose of this study was to investigate the effect of exercise duration on {alpha}1- and {alpha}2-adrenergic receptor responsiveness to the infusion of selective {alpha}1- and {alpha}2-adrenergic receptor agonists and endogenously released norepinephrine during prolonged constant-load exercise. On the basis of the previous findings from our laboratory, we hypothesized that {alpha}1- and {alpha}2-adrenergic receptor responsiveness would decline over time in response to both the infusion of selective {alpha}-adrenergic agonists and endogenously released norepinephrine during prolonged constant-load exercise.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
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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." Six 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% isoflurane (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 period, animals were instrumented with ultrasonic transit-time flow probes (4–6 mm Transonic Systems, Ithica, 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 period, a heparinized catheter (0.045 in. OD, 0.015 in. ID, 60 cm length, Data Science International, St. Paul, MN) was implanted in a side branch and advanced into the femoral artery of one hindlimb. 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, Ithica, NY), and a 20-gauge intravascular catheter (Insyte, Becton-Dickinson, Sandy, UT) was inserted retrogradely into the lumen of one 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 a mild (3 miles/h) exercise intensity. We previously demonstrated that the magnitude of tonic {alpha}-adrenergic vasoconstriction varied over time during mild-intensity exercise (3 miles/h), whereas no effect of exercise duration was observed at a moderate intensity (6 miles/h). Therefore, in the present study we chose to investigate the potential mechanism(s) for the exercise duration-dependent decline in {alpha}-adrenergic receptor-mediated tonic vasoconstriction during mild-intensity exercise. On three separate days, vasoactive drugs were infused into the experimental hindlimb while the dog continued to run on the treadmill. On days 1 and 2 the selective {alpha}1- and {alpha}2-adrenergic receptor agonists phenylephrine (0.05 µg/ml of experimental hindlimb flow; series 1; Pfizer, Exton, PA), and clonidine (0.1 µg/ml of experimental hindlimb flow; series 2; RBI, Natick, MA) were administered at 5, 30, and 50 min of exercise. On experimental day 3, we investigated receptor responsiveness to endogenous norepinephrine by evoking the release of norepinephrine via tyramine (3 µg/ml of experimental hindlimb flow; series 3; Sigma Chemical) infusion at 5, 30, and 50 min of exercise.

To investigate potential influences of temperature and pH on receptor responsiveness, rectal temperature and arterial blood gases were determined in a fourth experimental session. Rectal temperature was measured continuously (Electromedics, Parker, CO), and arterial blood samples were drawn anaerobically in heparinized syringes (Vital Signs, Engelwood, CO) at 5, 30, and 50 min of exercise and were analyzed with a blood-gas analyzer (ABL 520, Radiometer, Copenhagen, Denmark).

Arterial blood pressure, external iliac blood flow, and rectal temperature were recorded at 100 Hz directly to a computer with a Powerlab data acquisition system (ADInstruments, Castle Hill, Australia). Data were analyzed off-line to calculate the absolute and relative change in mean arterial pressure (MAP), experimental and contralateral (control) limb iliac blood flow, and iliac vascular conductance (VC) (iliac blood flow/MAP) in response to intra-arterial infusions. A 30-s average immediately before each drug infusion was used as the baseline for each variable. After drug infusion, all variables were averaged over 1-s intervals, and the nadir 1-s average for VC was chosen as the peak response.

Data for each drug were analyzed separately. Comparisons at different exercise durations were made by repeated measures ANOVA. Where significant F ratios were found, Tukey's post hoc analysis 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
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 RESULTS
DISCUSSION
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Intra-arterial infusion of the selective {alpha}1- and {alpha}2-adrenergic receptor agonists phenylephrine and clonidine and release of endogenous norepineprine from nerve terminals evoked by tyramine infusion produced robust vasoconstriction after 5, 30, and 50 min of exercise at 3 miles/h. Figure 1 is a raw data tracing for the infusion of tyramine demonstrating that the decrease in experimental limb blood flow and VC in response to drug infusion was not accompanied by changes in contralateral limb blood flow or MAP. Similar responses were observed for phenylephrine and clonidine.


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 tyramine 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-adrenergic receptor responsiveness. Baseline hemodynamics and vascular responses to intra-arterial infusions of phenylephrine are presented in Table 1. MAP increased following the onset of exercise and then gradually declined over time, such that MAP was greater (P < 0.05) after 5 [117 mmHg (SD 13)] compared with 30 [106 mmHg (SD 12)] and 50 [105 mmHg (SD 12)] min of exercise. Control and experimental limb blood flow and VC were not different (P > 0.05) before the infusion of phenylephrine at 5, 30, and 50 min of exercise at 3 miles/h (Table 1). Intra-arterial infusions of phenylephrine caused a decrease in experimental limb blood flow and VC at all exercise durations at 3 miles/h. The decrease in experimental limb blood flow was similar (P > 0.05) after 5 [315 ml/min (SD 122)], 30 [307 ml/min (SD 86)], and 50 [273 ml/min (SD 101)] min of exercise. The decrease in experimental limb blood flow expressed as a percentagechange from preinfusion blood flow was also similar (P > 0.05) after 5 [72% (SD 11)], 30 [75% (SD 9)], and 50 [71% (SD 11)] min of exercise. Consistent with the blood flow response, the decrease in experimental VC was not different (P > 0.05) after 5 [2.8 ml·min–1·mmHg–1 (SD 1.2)], 30 [3.0 ml·min–1·mmHg–1 (SD 0.9)], and 50 [2.7 ml·min–1·mmHg–1 (SD 1.1)] min of exercise (Fig. 2A). The decrease in experimental VC, expressed as a percentage change from preinfusion VC, was also similar (P > 0.05) after 5 [73% (SD 10)], 30 [76% (SD 9)], and 50 [73% (SD 11)] min of exercise (Fig. 2B).


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

 

Figure 2
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  		Fig. 2. Absolute (A) and percent (B) change in experimental limb iliac vascular conductance in response to intra-arterial infusion of the selective {alpha}1-adrenergic receptor agonist phenylephrine. Values are means (SD).

 
Series 2: {alpha}2-adrenergic receptor responsiveness. Baseline hemodynamics and vascular responses to intra-arterial infusions of clonidine are presented in Table 2. MAP increased following the onset of exercise and then gradually declined throughout the exercise bout, such that MAP was greater (P < 0.05) after 5 [121 mmHg (SD 15)] compared with 30 [106 mmHg (SD 8)] and 50 [99 mmHg (SD 7)] min of exercise. Control and experimental limb blood flow and VC were not different (P > 0.05) before the infusion of clonidine at 5, 30, and 50 min of exercise at 3 miles/h (Table 2). Intra-arterial infusions of clonidine caused a decrease in experimental limb blood flow and VC at all exercise durations at 3 miles/h. The decrease in experimental limb blood flow was similar (P > 0.05) after 5 [242 ml/min (SD 115)], 30 [229 ml/min (SD 96)], and 50 [200 ml/min (SD 67)] min of exercise. The decrease in experimental limb blood flow expressed as a percentage change from preinfusion blood flow was also similar (P > 0.05) after 5 [57% (SD 12)], 30 [57% (SD 11)], and 50 [52% (SD 11)] min of exercise. Consistent with the blood flow response, the decrease in experimental VC was not different (P > 0.05) after 5 [2.1 ml·min–1·mmHg–1 (SD 1.0)], 30 [2.3 ml·min–1·mmHg–1 (SD 0.8)], and 50 [2.1 ml·min–1·mmHg–1 (SD 0.7)] min of exercise (Fig. 3A). The decrease in experimental VC expressed as a percentage change from preinfusion VC was also similar (P > 0.05) after 5 [58% (SD 10)], 30 [58% (SD 11)], and 50 [53% (SD 13)] min of exercise (Fig. 3B).


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

 

Figure 3
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  		Fig. 3. Absolute (A) and percent (B) change in experimental limb iliac vascular conductance in response to intra-arterial infusion of the selective {alpha}2-adrenergic receptor agonist clonidine. Values are means (SD).

 
Series 3: vasoconstriction to endogenously released norepinephrine. Baseline hemodynamics and vascular responses to intra-arterial infusions of tyramine are presented in Table 3. Before the infusion of tyramine, MAP was greater (P < 0.05) after 5 [122 mmHg (SD 16)] min compared with 30 [106 mmHg (SD 16)] and 50 [102 mmHg (SD 16)] min of exercise. Control and experimental limb blood flow and VC were not different (P > 0.05) before the infusion of tyramine at 5, 30, and 50 min of exercise at 3 miles/h (Table 3). Intra-arterial infusions of tyramine caused a decrease in experimental limb blood flow and VC at all exercise durations at 3 miles/h. The decrease in experimental limb blood flow was similar (P > 0.05) after 5 [271 ml/min (SD 96)], 30 [222 ml/min (SD 65)], and 50 [219 ml/min (SD 65)] min of exercise. The decrease in experimental limb blood flow expressed as a percentage change from preinfusion blood flow was also similar (P > 0.05) after 5 [55% (SD 15)], 30 [49% (SD 12)], and 50 [48% (SD 7)] min of exercise. Consistent with the blood flow response, the decrease in experimental VC was not different (P > 0.05) after 5 [2.3 ml·min–1·mmHg–1 (SD 0.9)], 30 [2.3 ml·min–1·mmHg–1 (SD 0.8)], and 50 [2.3 ml·min–1·mmHg–1 (SD 0.7)] min of exercise (Fig. 4A). The decrease in experimental VC expressed as a percentage change from preinfusion VC was also similar (P > 0.05) after 5 [55% (SD 15)], 30 [51% (SD 10)], and 50 [50% (SD 7)] min of exercise (Fig. 4B).


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  		Table 3. Baseline hemodynamics and response to intra-arterial infusion of tyramine

 

Figure 4
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  		Fig. 4. Absolute (A) and percent (B) change in experimental limb iliac vascular conductance in response to intra-arterial infusion of tyramine. Values are means (SD).

 
Rectal temperature (n = 3) was not different at 5 [39.9°C (SD 0.4)], 30 [40.4°C (SD 0.9)], and 50 [40.4°C (SD 1.0)] min of exercise. Arterial blood pH (n = 4) was also not different over time [5 min: 7.49 (SD 0.04); 30 min: 7.49 (SD 0.07); 50 min: 7.49 (SD 0.04)].


   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The main finding of the present study is that {alpha}-adrenergic receptor responsiveness was preserved during prolonged exercise. These results demonstrate that the ability of {alpha}1- and {alpha}2-adrenergic receptors to produce vasoconstriction was unchanged over time during prolonged constant-load exercise.

Previous investigations of the effect of exercise duration on vasoconstrictor responsiveness have yielded conflicting results. Rowlands and Donald (24) demonstrated that in response to electrical stimulation of the lumbar sympathetic nerves during electrically stimulated muscle contractions, skeletal muscle vasoconstriction progressively increased over time (~65 min), suggesting that {alpha}-adrenergic receptor responsiveness may increase over time. Interestingly, there were no time-dependent changes in vasoconstrictor responsiveness to the intra-arterial infusion of norepinephrine in the same study (24), whereas Beaty and Donald (3) reported a progressive increase in vasoconstriction over time (~35 min) in response to the infusion of norepinephrine. Additionally, unchanged {alpha}1-adrenergic receptor responsiveness during the initial 15 min of mild and moderate intensity dynamic exercise has been reported (5).

Our laboratory recently demonstrated that {alpha}-adrenergic receptor-mediated restraint of skeletal muscle blood flow declined over time (~50 min) during a prolonged bout of constant-load, mild-intensity exercise (10). This finding combined with the relatively constant plasma norepinephrine concentrations suggested that {alpha}-adrenergic receptor responsiveness may decline during prolonged exercise.

The reason for the apparent difference in receptor responsiveness among the above studies is not clear. However, differences may be related to: 1) the use of anesthetized preparations (3, 24) compared with a conscious dynamically exercising dog in the present study and others (5, 10); and 2) the use of selective {alpha}-adrenergic agonists to directly address receptor responsiveness compared with the vascular response to electrical stimulation, which reflects the sum effect of neurotransmitter release and the receptor response. Additionally, electrically stimulated muscle contractions elicit a considerably different fiber recruitment pattern than voluntary running. In large part, the control of exercise hyperemia is believed to be a local phenomenon (18, 23), and the distribution of blood flow between (1, 2, 16) and within (23) muscles is not uniform during voluntary exercise. Electrically stimulated contractions may produce a considerably different pattern of muscle perfusion, which would be expected to alter the production (timing and magnitude) of metabolic by-products and other vasoactive substances, thus potentially influencing receptor responsiveness.

To ensure that the unchanged {alpha}-adrenergic receptor responsiveness over time was not limited to the binding of exogenously administered {alpha}1- and {alpha}2-agonists in the present study, we also examined receptor responsiveness to endogenously released norepinephrine evoked by tyramine infusion. Consistent with the results from selective agonist infusions, {alpha}-adrenergic receptor responsiveness to endogenous norepinephrine did not decline over time during prolonged constant-load exercise. The unchanged response to tyramine suggests that there was little or no presynaptic inhibition of neurotransmitter release and no decline in neurotransmitter availability during prolonged constant-load exercise.

Several previous studies have demonstrated an exercise intensity-dependent decline in {alpha}-adrenergic receptor responsiveness (7, 25, 26, 29–31). However, the mechanism(s) responsible for the decline in {alpha}-adrenergic receptor responsiveness has not been elucidated. The association between attenuated receptor responsiveness and increasing exercise intensity in human and animal studies suggests that the mechanism may be related to muscle metabolism, [H+], or muscle temperature.

Some studies have demonstrated that {alpha}-adrenergic receptor responsiveness can be modulated by infusing or blocking the production of various metabolic by-products, including nitric oxide and prostaglandins (8, 11). Whereas the concentration of a number of metabolic byproducts may increase during prolonged constant-load exercise, the preserved receptor responsiveness over time in the present study suggests that: 1) the concentration of specific substances that are capable of attenuating {alpha}-adrenergic receptor responsiveness did not increase above the concentration achieved by minute 5 of exercise or 2) the ability of these substances to influence postsynaptic receptor responsiveness was not altered during prolonged constant-load exercise.

Temperature is known to influence vasoconstrictor responsiveness (9, 12, 13, 17, 19) with increasing temperature resulting in an attenuation of {alpha}-adrenergic receptor responsiveness. In the present study, rectal temperature was used as an index of muscle temperature (27). Rectal temperature did not change significantly over time in the present study. The unchanged {alpha}-adrenergic receptor responsiveness over time in the present study may be related to the lack of change in temperature.

{alpha}-Adrenergic receptor function has also been shown to be sensitive to changes in pH (20, 28). 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, 28). Arterial blood pH did not decrease over time in the present study, thus the preserved {alpha}-adrenergic receptor responsiveness may be a function of the unchanged blood pH.

The lack of change in {alpha}-adrenergic receptor responsiveness over time in the present study suggests that a mechanism other than reduced {alpha}-adrenergic receptor responsiveness was responsible for the exercise duration-dependent decline in {alpha}-adrenergic-mediated restraint of skeletal muscle blood flow previously reported by our laboratory (10). In the prior study, we utilized plasma catecholamine measurements as an index of muscle sympathetic nerve activity. Despite evidence of a constant or modestly increasing level of circulating catecholamines over time (10), it remains possible that efferent sympathetic nerve activity directed toward the vasculature of exercising skeletal muscle declined. Additionally, other factors that regulate skeletal muscle blood flow, including endothelial, myogenic, and humoral mechanisms, may exert an increasing effect on the regulation of vascular tone throughout a prolonged bout of constant-load exercise.

In conclusion, this study demonstrated preserved {alpha}-adrenergic receptor responsiveness to infusion of selective {alpha}1- and {alpha}2-agonists and endogenous norepinephrine release during prolonged constant-load exercise. These results suggest that the ability of {alpha}1- and {alpha}2-adrenergic receptors to produce vasoconstriction is not diminished during prolonged constant-load exercise. Furthermore, a decline in {alpha}-adrenergic receptor responsiveness does not explain the previously reported exercise duration-dependent decline in {alpha}-adrenergic receptor-mediated restraint of skeletal muscle blood flow (10).


   GRANTS
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 ABSTRACT
 METHODS
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 DISCUSSION
 GRANTS
REFERENCES
 
Support for this project was provided 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
 
The authors acknowledge the expert technical assistance of Paul Kovac throughout this project and Julie Benning for assistance with the preparation of this manuscript.


   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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