AJP - Heart Fuel your research with LabChart
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 283: H2038-H2044, 2002. First published July 26, 2002; doi:10.1152/ajpheart.00412.2001
0363-6135/02 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
283/5/H2038    most recent
00412.2001v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Khan, M. H.
Right arrow Articles by MacLean, D. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Khan, M. H.
Right arrow Articles by MacLean, D. A.
Vol. 283, Issue 5, H2038-H2044, November 2002

Effects of graded LBNP on MSNA and interstitial norepinephrine

Mazhar H. Khan1, Lawrence I. Sinoway1,2, and David A. MacLean3

1 Division of Cardiology, The Pennsylvania State University College of Medicine and The Milton S. Hershey Medical Center, Hershey 17033; 2 Lebanon Veterans Affairs Medical Center, Lebanon, Pennsylvania 17042; and 3 Exercise Science Laboratory, Kent State University, Kent, Ohio 44242


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Exposure to lower body negative pressure (LBNP) leads to an increased activation of the sympathetic nervous system (SNS) and an increase in muscle sympathetic nerve activity (MSNA). In this study, we examined the relationship between MSNA and interstitial norepinephrine (NEi) concentrations during LBNP. Twelve healthy volunteers were studied (26 ± 6 yr). Simultaneous MSNA and microdialysis data were collected in six of these subjects. Measurements of MSNA (microneurography) and NEi (microdialysis, vastus lateralis) were performed at rest and then during an incremental LBNP paradigm (-10, -30, and -50 mmHg). MSNA rose as a function of LBNP (P < 0.001, n = 12). The plasma norepinephrine (NEp) concentration was 0.9 ± 0.1 nmol/l at rest (n = 12). NEi measured in six subjects rose from 5.2 ± 0.8 nmol/l at rest to 17.0 ± 1.7 nmol/l at -50 mmHg (P < 0.001). Of note, the rise in NEp with LBNP was considerably less compared with the changes in NEi (Delta 21 ± 6% vs. Delta 197 ± 52%, n = 6, P < 0.015). MSNA and NEi showed a significant linear relationship (r = 0.721, P < 0.004). Activation of the SNS increased MSNA and NEi levels. The magnitude of the NEi increase was far greater than that seen for NEp suggesting that NE movement into the circulation decreases with baroreceptor unloading.

baroreceptors; nervous system; sympathetic; microdialysis; microneurography


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

THE SYMPATHETIC NERVOUS SYSTEM (SNS) plays an important role in the regulation of skeletal muscle blood flow. Activation of the SNS leads to an increase in muscle sympathetic nerve activity (MSNA) resulting in vasoconstriction and a decrease in muscle blood flow (13, 24). In response to the firing of sympathetic nerves, norepinephrine (NE) is released into the synaptic cleft from presynaptic storage vesicles. Once in the neurovascular cleft, NE interacts directly with the receptors on the vessels producing its biological effects.

After synaptic release, NE undergoes metabolism and uptake by both neuronal and non-neuronal tissues. The neuronal uptake process, termed uptake 1, is the predominant process by which NE is cleared from the synaptic cleft (8, 22). A smaller percentage is taken up by non-neuronal tissues (uptake 2), whereas the remainder of the released NE escapes these processes and enters the general circulation, a process known as "NE spillover" (12).

Previous reports have tried to understand neurovascular physiology during sympathetic activation by measuring plasma NE (NEp) and NE spillover. This latter method has generally employed radiotracer techniques (7, 16). However, based on the above discussion, it is clear that NEp and/or NE spillover may not provide a true reflection of events occurring within the synaptic cleft. Compared with these measurements, interstitial NE (NEi) at rest and in response to SNS activation is likely to be more reflective of neurovascular NE concentrations-its main site of action (10). Because of methodological limitations, it has been extremely difficult in humans to directly access the interstitial space for measurements of NE concentrations.

The microdialysis technique allows the measurement and quantification of various substances within the interstitial space of human subjects. The purpose of the present study was to utilize this powerful method to measure skeletal muscle NEi while simultaneously measuring MSNA during sympathoexcitation. To engage the autonomic nervous system, a graded lower body negative pressure (LBNP) paradigm was used. The combination of these techniques allowed the investigators to examine 1) whether differences exist in NE concentrations between the interstitial space and the plasma compartment and 2) the effects of LBNP and MSNA on NEi versus NEp levels (Fig. 1).


View larger version (19K):
[in this window]
[in a new window]
  		Fig. 1.   Schematic representations of the generation of sympathetic traffic evaluated with microneurography (top). This is followed by a view of the events that determine norepinephrine (NE) release at the neuroeffector junction (bottom). RVLM, rostral ventral lateral medulla; CVLM, caudal ventral lateral medulla; NTS, nucleus tractus solitarius; IML, intermediolateral gray.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

We studied a total of 12 healthy subjects, 7 men and 5 women, with a mean age of 26 ± 6 yr. We obtained nerve data in 12 subjects, and in 6 of these subjects we simultaneously obtained microdialysis data. All volunteers were nonsmokers and in good health as assessed by a prestudy history and physical examination. All subjects provided an informed consent approved by the Institutional Review Board of The Milton S. Hershey Medical Center.

Experimental paradigm. Subjects reported to the General Clinical Research Center in the morning after an overnight fast. They were instructed to refrain from caffeine intake for 24 h before the experiment. Subjects were placed on a padded table with their lower body (up to the level of the umbilicus) positioned inside a LBNP chamber. An IV was placed in an antecubital vein. To perform vastus lateralis muscle microdialysis, a LBNP chamber was constructed in which only the left leg and pelvis were placed within the tank and exposed to LBNP. The right leg from the level of upper thigh down remained outside the tank and readily accessible for the performance of microdialysis and microneurography. Continuous monitoring of the heart rate (HR) was performed with ECG, and arterial blood pressure (BP) was measured using the volume-clamp method (Finapres, Ohmeda; Madison, WI). Microdialysis probes and the peroneal nerve electrodes were then placed (see below for details).

After instrumentation and a 90-min "equalization period," baseline MSNA, BP, and HR were recorded and microdialysate and blood samples were collected. After 10 min of baseline, LBNP was initiated. The negative pressure was applied in a graded incremental manner beginning with -10 mmHg, proceeding to -30 mmHg, and then to -50 mmHg. All stages were 10 min in length, and BP and HR were closely monitored during this time. The experiment was terminated when the paradigm was completed or if any of the following occurred: 1) volunteers developed presyncopal symptoms such as lightheadedness, dizziness, nausea, cold sweats, yawning, or visual disturbances, 2) volunteers developed a sudden fall in systolic BP of >35 mmHg, and/or 3) volunteers developed a fall in systolic BP to <85 mmHg.

Microdialysis. The microdialysis probes were inserted in the vastus lateralis muscle of the subject's right leg. This muscle was chosen because there are no important nerves or vessels passing through it and thus the risk of neurovascular damage to the lower extremity was extremely small. An area measuring ~25 × 20 cm over the subject's thigh was shaved, prepped with povidone-iodine solution, and then draped using sterile sheets. A skin marker was used to mark the probe insertion sites, which were ~2-3 cm apart. With the use of strict aseptic techniques, the skin and subcutaneous sites at the probe entry and exit sites were anesthetized with a local injection of lidocaine (0.5-1.0 ml). The probes, four to six in number (depending on the muscle size and orientation), were inserted into the muscle via a 20-gauge cannula. After insertion, the microdialysis probes were attached to a perfusion pump (CMA model 102) and perfused at a rate of 5 µl/min with a saline solution containing 3.0 mM glucose and 0.5 mM lactate.

Microdialysis probes. The semipermeable fibers (GFS Plus 12, Gambro) used to construct the microdialysis probes had a molecular mass cutoff of 3,000 kDa [0.20 mm inner diameter (ID), 0.22 mm outer diameter (OD)]. Briefly, each end of a single fiber was inserted ~1 cm into a hollow polyamide tube (0.25 mm ID, 0.36 mm OD) and glued, and the actual diffusible portion (distance between the two polyamide tubes) was 4 cm. A complete description of microdialysis probe construction can be reviewed in MacLean et al. (19).

Determination of probe recovery. To fully utilize the microdialysis technique, an estimate of the extraction fraction of the compound being measured in the interstitial space needs to be made, which is defined as "probe recovery." This determination is necessary to calculate actual interstitial concentrations and to document any possible changes that may occur to probe recovery during the course of the experiment. To achieve this, a small amount of radioactive tracer, in the form of compound being investigated, is added to the microdialysis perfusate. It has been suggested that the relative loss of the isotope from the perfusate into the interstitial space represents probe recovery for that compound. This was confirmed in vitro by Kurosawa et al. (15), where the simultaneous measurement of tracer loss and compound recovery proved to be similar. The major advantage of this method is that probe recovery can be determined in vivo for each collected sample allowing continuous monitoring of probe recovery over time.

To determine the probe recovery of NE in this study, a small amount of [3H]NE (0.1 µCi/ml) was added to the perfusate. Probe recovery was calculated from the loss of radioactive tracer, and the actual interstitial concentration of NE was calculated from the probe recovery values and dialysate NE concentrations (18).

Microneurography. This technique provides direct recordings of sympathetic nerve activity directed to blood vessels in skeletal muscle. MSNA was our primary index of sympathoexcitation. External mapping of the peroneal nerve course (40-100 V, 0.2 ms, 1 Hz) was performed just behind the fibular head of the right leg. A reference electrode was placed subcutaneously ~2-3 cm away from the recording site. Multiunit recordings of MSNA in the leg were obtained by transcutaneous placement of a tungsten microelectrode (insulated 200 µm diameter with a tapered uninsulated 1- to 5-µm tip) into a C-fiber-containing fascicle in the nerve. The electrode was manipulated to yield a neurogram with characteristic bursts of MSNA. The signals thus obtained represent postganglionic vasoconstrictor nerve traffic. The signals were amplified 1,000 times by a preamplifier and 50-100 times by an amplifier. The signals were filtered (bandwidth of 700-2,000 Hz), rectified, and integrated to obtain a mean voltage neurogram. The neurograms were analyzed and expressed as bursts per minute. MSNA was also analyzed by signal averaging. For each subject, four 10-min segments of MSNA data were selected, representing signals recorded during baseline and at each level of LBNP. A signal-averaged MSNA waveform was produced for each segment using the signal-averaged ECG (SAECG) extension within the PowerLab v.4.1 software package (ADInstruments). SAECG used the ECG to parse the MSNA signal into packets spanning individual cardiac cycles and summed all MSNA cycles into a composite waveform whether the cycle contained a burst or not. It then divided this composite by the number of cycles in the original data segment to yield the average MSNA signal per cycle, which was then numerically integrated to determine the area under the curve.

Blood and dialysate samples. A Teflon intravenous catheter was placed in a forearm vein and attached to a saline lock to ensure patency. Approximately 3 ml of blood were drawn during baseline and then during minute 9 of each level of LBNP. Blood samples were placed in prechilled tubes containing EDTA and glutathione and immediately centrifuged, and the plasma was separated and frozen at -80°C until analyzed. One milliliter of plasma was used for the determination of NE concentrations (100 µl injection volume) using HPLC and electrochemical detection (26).

The specific activity of [3H]NE in 5 µl of collected dialysate was determined using traditional liquid scintillation counting techniques. Dialysate samples were collected with 2 µl of a 3 mM sodium metabisulfite solution and did not require any further processing due to the highly filtered nature of the samples. Forty microliters of dialysate were combined with 60 µl of 0.1 M glacial acetic acid (75 µl injection volume), and NE concentrations were determined by HPLC in a similar fashion to the plasma samples.

MSNA was analyzed as bursts. It was measured during baseline and at minute 9 of each 10-min level of LBNP (-10, -30, and -50 mmHg). HR and mean arterial pressure (MAP) were also used for comparison of the different LBNP stages (see below).

Signal-averaged MSNA was measured each minute for every level of LBNP. With the use of a paired t-test, we found that for each level of LBNP, minute 9 was not statistically different than any other minute. HR and MAP values at minute 9 were also compared with each other minute. We found that at -30 and -50 mmHg, HR took 4 and 3 min, respectively, to reach a steady-state value. At -50 mmHg, the minute 2 value for MAP was 3.3 mmHg higher than the minute 9 value (91.9 ± 3.9 mmHg at minute 9 and 95.2 ± 3.9 mmHg at minute 2, P < 0.036). Thus all values reached a steady state by minute 9.

Microdialysate was collected over the entire 10-min baseline and LBNP periods to obtain a sufficient volume for NE analysis. The signals for BP, ECG, and MSNA were sampled at 100 Hz and stored on a computer using a commercially available data-acquisition system (PowerLab, ADInstruments).

Statistical analysis. We analyzed MAP, HR, MSNA, and NEp using a two-way ANOVA. Two main effects were examined: LBNP (a within-subject variable with 4 levels: baseline, -10, -30, and -50 mmHg) and probe placement (a between-subject variable with 2 levels: subjects with and without microdialysis probes). This approach allowed us to determine whether 1) the one-legged LBNP tank that was specially designed for these experiments evoked graded autonomic responses and 2) microdialysis probe placement altered the autonomic responses. NEi was analyzed with a one-way ANOVA with repeated measures for the four levels of LBNP. All post hoc analyses were performed using Dunnett's test to compare all values to baseline.

To test the relationship between NE and MSNA, we performed a Pearson's partial correlation, which was adjusted for the paradigm (1). This approach was used to account for the fours levels of LBNP.

NEi data were collected from a total of 15 microdialysis probes in 6 subjects; however, before statistical analysis, these data were averaged within each subject so that each subject had only one NEi value for each level of LBNP. All data are expressed as means ± SE. P < 0.05 was considered statistically significant.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Effects of microdialysis probe insertion on measured hemodynamic variables. As can be seen in Table 1 (n = 12), there was no effect of probe insertion on HR, MAP, NEp, or MSNA ("probe" main effects were not significant for all 4 variables). Thus the act of measuring NEi did not in itself systematically alter the study of LBNP effects on hemodynamics.

                              
View this table:
[in this window]
[in a new window]
  		Table 1.   Data from all levels of the LBNP protocol

Effects of one-legged LBNP on HR, MAP, NEp, and MSNA. As expected, LBNP led to an increase in HR (main effect P < 0.031) and MAP (main effect P < 0.046). Of note, both NEp and MSNA bursts rose with LBNP (main effects P < 0.025 and P < 0.001, respectively). Pointwise comparisons demonstrated statistically significant differences between baseline and LBNP -50 mmHg values for all four parameters.

Effects of one-legged LBNP on NEi. The number of probes used for the determination of NEi at baseline and during -10, -30, and -50 mmHg LBNP were 15, 15, 14, and 10, respectively. The reasons for this difference in the number of probes at different levels of LBNP were as follows: 1) As LBNP increased, some probes ceased to function. LBNP induced leg movement, which caused some probes to kink. This resulted in a reduced volume of perfusate, which was assessed by weighing the sample tubes after collection, and 2) the development of presyncope, which resulted in insufficient dialysate to measure NEi.

The coefficient of variation for the four subjects in whom multiple probes were used to measure NEi was 24.2% for all levels of LBNP. In vivo probe recovery for NE remained unchanged throughout the experiment. Probe recovery during baseline and -10, -30, and -50 mmHg LBNP was 25.1 ± 0.6%, 24.0 ± 0.6%, 24.7 ± 0.6%, and 23.8 ± 0.7%, respectively. LBNP led to a large increase in NEi. The values were 5.2 ± 0.8 nM at rest, 8.4 ± 0.9 nM at -10 mmHg, 11.7 ± 1.5 nM at -30 mmHg, and 17.0 ± 1.7 nM at -50 mmHg (P < 0.001).

Comparative effects of LBNP on NEp and NEi. The percent increase from baseline to the maximum level of LBNP was much greater for NEi than for NEp (n = 6, 197 ± 52% vs. 21 ± 6%, P < 0.015, paired t-test). This led to a progressive NEi-to-NEp gradient (Fig. 2).


View larger version (27K):
[in this window]
[in a new window]
  		Fig. 2.   A: interstitial NE (NEi) and plasma NE (NEp) values during the stages of the lower body negative pressure (LBNP) paradigm (baseline, -10, -30, and -50 mmHg of negative pressure). NEp and NEi values were obtained from the same 6 subjects. B: the NE gradient (NEi to NEp) at the different levels of the LBNP paradigm. NEi data from multiple probes were meaned; thus each subject contributed no more than 1 data point for each level of LBNP. As this figure illustrates, a large NE gradient exists at rest and rises as LBNP increased.

MSNA bursts correlated with NEi (Fig. 3; r = 0.721, P < 0.004, n = 6). Similar relationships were noted when signal-averaged MSNA was used (r = 0.675, P < 0.011, n = 6). A relationship between MSNA bursts and NEp was also noted (r = 0.319, P = 0.05, n = 12 subjects).


View larger version (11K):
[in this window]
[in a new window]
  		Fig. 3.   Adjusted NEi values over the 4 levels of the LBNP paradigm are plotted versus adjusted muscle sympathetic nervous activity (MSNA; in bursts/min) in the same 6 subjects. Each NEi value represents the mean of all functioning probes within a given subject at a given level of LBNP. The number of probes used for each NEi value varied from 1 to 4 (1 probe for 5 data points, 3 probes for 8 data points, and 4 probes for 4 data points). Data were adjusted for the paradigm using Pearson's partial correlation to account for repeated measures. If data were collected at all levels in all subjects, there would be 24 data points. However, only 17 data points are present because 3 were lost to probe failure, 3 to lost MSNA sites, and 1 to orthostasis.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The main findings of the study are as follows: 1) one-legged LBNP led to a rise in MSNA, NEi, and NEp at -50 mmHg; 2) MSNA correlated with both NEi and NEp; and 3) the rate of rise of NEp as LBNP increased was much less than the rate of increase in NEi. The results of our study suggest that NEi concentrations are reflective of changes in SNS activity seen during baroreceptor unloading. Furthermore, we believe that NE concentrations at the neurovascular junction are better reflected by NEi than by NEp. Finally, the large gradient in NEi and NEp, which increases as a function of LBNP, suggests that the capillary barrier and the level of blood flow contributes importantly to the NEp level.

Assessment of autonomic function. Because of the significance of the SNS in circulatory control, numerous methodologies have been employed to understand its functioning under various physiological conditions. These include plasma measurements of NE kinetics and the measurement of MSNA using microneurography. NE kinetics have been studied extensively using compartmental and noncompartmental techniques developed by Linares, Esler, and others (3, 7, 10, 17). The steady-state [3H]NE technique is the most commonly used method to measure NE spillover. The major drawback of this technique is that the rate of entry of NE into the circulation during "stress" may or may not represent the same percentage of released NE that is seen under resting conditions. It must be emphasized that aside from NE release, many local and systemic factors can influence NE spillover. The local factors include NE uptake and metabolism, the width of the neuronal cleft, and conductivity of the capillary bed (6). Systemic factors include the level of cardiac output as well as regional blood flow (2, 4). These additional factors render NE spillover an imprecise index of NE released from sympathetic nerve terminals.

Microneurographic recordings of sympathetic nerve traffic represent another method that has been utilized to increase our understanding of autonomic control in human subjects. This technique provides a measure of sympathetic nerve traffic; however, it does not provide direct information regarding the events taking place at the neuroeffector junction. Moreover, it can be argued that with microneurography, sympathetic "activity" is measured in a nerve fascicle that is proximal to the sympathetic nerve ending. Accordingly, it is unclear whether all nerve impulses translate into electrochemical coupling and the release of NE at the neurovascular junction.

Despite these caveats, important information has been gathered by measuring MSNA and NE spillover. For example, in studies conducted by Wallin et al. (25), a positive correlation between MSNA and total body NE spillover and NEp concentration at rest and during isometric hand grip exercise has been shown. Kingwell et al. (14) demonstrated a positive correlation between MSNA and cardiac NE spillover at rest. Thus NE spillover under the appropriate circumstance may be reflective of increased SNS activity. We suggest that this relationship may be greatly dependent on the level of regional blood flow as well as the diffusion capacity of NE from the interstitium into the vascular space.

Study findings and their implications. In the present report, we used the microdialysis technique to directly determine NEi concentrations at rest and during LBNP. With the application of LBNP, the SNS is activated through unloading of baroreceptors leading to an increase in the MSNA (23). In addition, LBNP can be employed in a graded and incremental fashion, leading to graded levels of sympathetic activation (3).

In the present study, LBNP resulted in an increase in MSNA associated with a corresponding increase in NEi. MSNA correlated with both NEi and NEp. However, the rate of rise in NEp was much less than that noted for MSNA vs. NEi (Fig. 2). At rest, the NEp concentration was ~18% of the NEi concentration; at -50 mmHg LBNP, NEp was only 7% of NEi.

Parenthetically, the increase in NEp compared with baseline is smaller than the increases seen in previous reports. We suspect that the magnitude of the increase was less in this report because we used the less vigorous one-legged LBNP as the stimulus and not two-legged LBNP as the stimulus to increase sympathetic outflow (11).

What mechanisms might explain these findings? Previous studies have suggested that the endothelium serves as a barrier to NE diffusion from the interstitium into the circulation (21). We suggest that this barrier accounts for the NEi-to-NE blood concentration gradient seen at rest. Furthermore, a decrease in local blood flow can alter the gradient for diffusion, which could increase the NEi-to-NEp gradient (9). In our studies, LBNP led to an increase in MSNA and NEi and presumably to a greater level alpha -receptor stimulation by NE. These alpha -receptors are located at the metarteriole and precapillary levels. We speculate that this process led to a reduction in the intracapillary pressure, which was already compromised by low limb flows as a result of the diminished cardiac output seen with LBNP. These processes may have even produced a collapse of some capillary beds, which would have resulted in an even greater gradient between NEi and NEp (5, 20). We hypothesize that this effect reduced the area available for diffusion and limited the rate of NE diffusion into the general circulation (Fig. 2). Further work will be necessary to test this line of reasoning.

It should be noted that a possible limitation to the findings is the different anatomic location from where each of the variables was measured. For example, NEp was measured from an antecubital vein, NEi was measured from the vastus lateralis muscle, and MSNA was measured from the peroneal nerve. It is possible that the degree of sympathetic outflow at the recording site differed from that at the site of NEi measurement. Moreover, it is possible that there was somewhat less release in NE from the nerves in the arm than in the leg for a given level of MSNA. Future studies comparing NEi in the leg and arm will be necessary to further explore this issue. Despite these potential drawbacks, the magnitude of change in NEi compared with NEp was so substantial that any influence of regional MSNA or NE release differences are unlikely to explain the observed findings.

In conclusion, activation of the SNS with LBNP leads to increases in MSNA, NEi, and NEp. Both NEi and NEp correlate with MSNA. At rest, a large concentration gradient exists between NEi and NEp. This gradient increases with LBNP. We believe that our findings suggest that 1) NEi is a better reflection of NE release than NEp, and 2) the capillary diffusion barrier as well as the level of regional blood flow importantly contribute to this gradient.


    ACKNOWLEDGEMENTS

The authors are grateful to Kristen S. Gray, Michael Herr, Cynthia Hogeman, Teresa Markle, and Jason Neil for excellent technical support, Allen Kunselman for statistical expertise, and Jennifer Stoner for excellent secretarial skills.


    FOOTNOTES

This project was supported by a Pennsylvania State University Dean's Feasibility Grant (to D. A. MacLean and M. H. Khan), a Veterans Administration Merit Review Award (to L. I. Sinoway), National Aeronautics and Space Administration Grants NAG-9-1259-01 (to D. A. MacLean) and NAGW-4400 (to L. I. Sinoway), and National Institutes of Health (NIH) Grants R01 AG-12227 and R01 HL-60800 (to L. I. Sinoway) and a NIH-sponsored General Clinical Research Center grant with National Center for Research Resources grant M01 RR-10732. L. I. Sinoway was the recipient of a NIH K24 HL-04011 Midcareer Investigator Award in Patient-Oriented Research.

Address for reprint requests and other correspondence: L. I. Sinoway, Div. of Cardiology, MC H047, The Pennsylvania State Univ. College of Medicine, The Milton S. Hershey Medical Center, PO Box 850, Hershey, PA 17033 (E-mail: lsinoway{at}psu.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.

July 26, 2002;10.1152/ajpheart.00412.2001

Received 17 May 2001; accepted in final form 18 July 2002.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Altman, DG. Practical Statistics for Medical Research. London: Chapman and Hall, 1991, p. 288-299.

2.   Baily, RG, Leuenberger U, Leaman G, Silber D, and Sinoway LI. Norepinephrine kinetics and cardiac output during nonhypotensive lower body negative pressure. Am J Physiol Heart Circ Physiol 260: H1708-H1712, 1991[Abstract/Free Full Text].

3.   Baily, RG, Prophet SA, Shenberger JS, Zelis R, and Sinoway LI. Direct neurohumoral evidence for isolated sympathetic nervous system activation to skeletal muscle in response to cardiopulmonary baroreceptor unloading. Circ Res 66: 1720-1728, 1990[Abstract/Free Full Text].

4.   Davis, D, Sinoway LI, Robison J, Minotti JR, Day FP, Baily R, and Zelis R. Norepinephrine kinetics during orthostatic stress in congestive heart failure. Circ Res 61, SupplI: I87-I90, 1987[Medline].

5.   Dietrich, HH, and Tyml K. Microvascular flow response to localized application of norepinephrine on capillaries in rat and frog skeletal muscle. Microvasc Res 43: 73-86, 1992[ISI][Medline].

6.   Esler, M. Clinical application of noradrenaline spillover methodology: delineation of regional human sympathetic nervous responses. Pharmacol Toxicol 73: 243-253, 1993[ISI][Medline].

7.   Esler, M, Jennings G, Korner P, Blombery P, Sacharias N, and Leonard P. Measurement of total and organ-specific norepinephrine kinetics in humans. Am J Physiol Endocrinol Metab 247: E21-E28, 1984[Abstract/Free Full Text].

8.   Esler, M, Jennings G, Lambert G, Meredith I, Horne M, and Eisenhofer G. Overflow of catecholamine neurotransmitters to the circulation: source, fate and functions. Physiol Rev 70: 963-985, 1990[Free Full Text].

9.   Ganong, WF. Dynamics of blood and lymph flow. In: Review of Medical Physiology (18th ed.). Stamford, CT: Appleton and Lange, 1997, chapt. 30, p. 536-552.

10.   Goldstein, DS. Clinical pharmacology of the autonomic nervous system. In: Handbook of Clinical Neurology (74 Revised Series 30): The Autonomic Nervous System Part 1, edited by Vinken PJ, and Bruyn GW.. Amsterdam: Elsevier, 1999, chapt. 4, p. 135-179.

11.   Greenleaf, JE, Petersen TW, Gabrielsen A, Pump B, Bie P, Christensen NJ, Warberg J, Videbaek R, Simonson SR, and Norsk P. Low LBNP tolerance in men is associated with attenuated activation of the renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol 279: R822-R829, 2000[Abstract/Free Full Text].

12.   Hoffman, BB, Lefkowitz RL, and Taylor P. Neurotransmission: the autonomic and somatic motor nervous systems. In: Goodman and Gilman's The Pharmacological Basis of Therapeutics (9th ed.), edited by Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, and Gilman AG.. New York: McGraw-Hill, 1996, sect. II, chapt. 6, p. 105-139.

13.   Johnson, JM, Rowell LB, Niederberger M, and Eisman MM. Human splanchnic and forearm vasoconstrictor responses to reductions of right atrial and aortic pressures. Circ Res 34: 515-524, 1974[Abstract/Free Full Text].

14.   Kingwell, BA, Thompson JM, Kaye DM, McPherson GA, Jennings GL, and Esler MD. Heart rate spectral analysis, cardiac norepinephrine spillover, and muscle sympathetic nerve activity during human sympathetic nervous activation and failure. Circulation 90: 234-240, 1994[Abstract/Free Full Text].

15.   Kurosawa, M, Hallström A, and Ungerstedt U. Changes in cerebral blood flow do not directly affect in vivo recovery of extracellular lactate through microdialysis probe. Neurosci Lett 126: 123-126, 1991[ISI][Medline].

16.   Leuenberger, U, Sinoway L, Gubin S, Gaul L, Davis D, and Zelis R. Effects of exercise intensity and duration on norepinephrine spillover and clearance in humans. J Appl Physiol 75: 668-674, 1993[Abstract/Free Full Text].

17.   Linares, OA, Jacquez JA, Zech LA, Smith MJ, Sanfield JA, Morrow LA, Rosen SG, and Halter JB. Norepinephrine metabolism in humans. Kinetic analysis and model. J Clin Invest 80: 1332-1341, 1987[ISI][Medline].

18.   MacLean, DA, Bangsbo J, and Saltin B. Muscle interstitial glucose and lactate levels during dynamic exercise in humans determined by microdialysis. J Appl Physiol 87: 1483-1490, 1999[Abstract/Free Full Text].

19.   MacLean, DA, Imadojemu VA, and Sinoway LI. Interstitial pH, K+, lactate and phosphate determined with MSNA during exercise in humans. Am J Physiol Regul Integr Comp Physiol 278: R563-R571, 2000[Abstract/Free Full Text].

20.   Mitchell, D, Yu J, and Tyml K. Comparable effects of arteriolar and capillary stimuli on blood flow in rat skeletal muscle. Microvasc Res 53: 22-32, 1997[ISI][Medline].

21.   Rose, CP, and Goresky CA. Interactions between capillary exchange, cellular entry and metabolic sequestration processes in the heart. In: Handbook of Physiology. The Cardiovascular System. Microcirculation. Bethesda, MD: Am. Physiol. Soc, 1984, sect. 2, vol. IV, chapt. 16, p. 781-798.

22.   Shannon, JR, Flattem NL, Jordan J, Jacob G, Black BK, Biaggioni I, Blakely RD, and Robertson D. Orthostatic intolerance and tachycardia associated with norepinephrine- transporter deficiency. N Engl J Med 342: 541-549, 2000[Abstract/Free Full Text].

23.   Sundlöf, G, and Wallin BG. Effect of lower body negative pressure on human muscle nerve sympathetic activity. J Physiol 278: 525-532, 1978[Abstract/Free Full Text].

24.   Victor, RG, and Leimbach WN, Jr. Effects of lower body negative pressure on sympathetic discharge to leg muscles in humans. J Appl Physiol 63: 2558-2562, 1987[Abstract/Free Full Text].

25.   Wallin, BG, Esler M, Dorward P, Eisenhofer G, Ferrier C, Westerman R, and Jennings G. Simultaneous measurements of cardiac noradrenaline spillover and sympathetic outflow to skeletal muscle in humans. J Physiol 453: 45-58, 1992[Abstract/Free Full Text].

26.   Weicker, H. Determination of free and sulfoconjugated catecholamines in plasma and urine by high-performance liquid chromatography. Int J Sports Med 9, Suppl2: S68-S74, 1988.

Am J Physiol Heart Circ Physiol 283(5):H2038-H2044


This article has been cited by other articles:


Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
J. Sugawara, H. Komine, K. Hayashi, M. Yoshizawa, T. Otsuki, N. Shimojo, T. Miyauchi, T. Yokoi, S. Maeda, and H. Tanaka
Systemic {alpha}-adrenergic and nitric oxide inhibition on basal limb blood flow: effects of endurance training in middle-aged and older adults
Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1466 - H1472.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
J. Xing, S. Koba, V. Kehoe, Z. Gao, K. Rice, N. King, L. Sinoway, and J. Li
Interstitial norepinephrine concentrations in skeletal muscle of ischemic heart failure
Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1190 - H1195.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
A. Momen, K. Thomas, C. Blaha, A. Gahremanpour, A. Mansoor, U. A. Leuenberger, and L. I. Sinoway
Renal vasoconstrictor responses to static exercise during orthostatic stress in humans: effects of the muscle mechano- and the baroreflexes
J. Physiol., June 15, 2006; 573(3): 819 - 825.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
H. Guo, F. Schaller, N. Tierney, S. A. Smith, and X. Shi
New Insight into the Mechanism of Cardiovascular Dysfunction in the Elderly: Transfer Function Analysis
Experimental Biology and Medicine, September 1, 2005; 230(8): 549 - 557.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
T. E. Wilson, K. D. Monahan, D. S. Short, and C. A. Ray
Effect of age on cutaneous vasoconstrictor responses to norepinephrine in humans
Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2004; 287(5): R1230 - R1234.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
M. Ichinose, M. Saito, T. Ogawa, K. Hayashi, N. Kondo, and T. Nishiyasu
Modulation of control of muscle sympathetic nerve activity during orthostatic stress in humans
Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2147 - H2153.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
K. D. Monahan, T. E. Wilson, and C. A. Ray
Omega-3 Fatty Acid Supplementation Augments Sympathetic Nerve Activity Responses to Physiological Stressors in Humans
Hypertension, November 1, 2004; 44(5): 732 - 738.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
K. D. Monahan and C. A. Ray
Gender affects calf venous compliance at rest and during baroreceptor unloading in humans
Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H895 - H901.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
T. A. Markel, J. C. Daley III, C. S. Hogeman, M. D. Herr, M. H. Khan, K. S. Gray, A. R. Kunselman, and L. I. Sinoway
Aging and the Exercise Pressor Reflex in Humans
Circulation, February 11, 2003; 107(5): 675 - 678.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
283/5/H2038    most recent
00412.2001v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Khan, M. H.
Right arrow Articles by MacLean, D. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Khan, M. H.
Right arrow Articles by MacLean, D. A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online