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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 7 3218-3226
Copyright © 2003 by The Endocrine Society

Effect of Cortisol on Muscle Sympathetic Nerve Activity in Pima Indians and Caucasians

Barbora Vozarova, Christian Weyer, Soren Snitker, Jean-Francois Gautier, Giovanni Cizza, George Chrousos, Eric Ravussin and P. Antonio Tataranni

Clinical Diabetes and Nutrition Section (B.V., C.W., P.A.T.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Human Services, Phoenix, Arizona 85016; University of Maryland School of Medicine (S.S.), Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, Baltimore, Maryland 21210; Service de Diabetologie (J.-F.G.), Hôpital Saint-Louis, 75010 Paris, France; National Institute of Mental Health (G.C.), National Institutes of Health, Bethesda, Maryland; Pediatric and Reproductive Endocrinology Branch (G.C.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 70808; and Pennington Medical Research Center (E.R.), Louisiana State University, Baton Rouge, Louisiana 20892

Address all correspondence to: Barbora Vozarova, M.D., Ph.D., Clinical Diabetes and Nutrition Section, National Institutes of Health, 4212 North 16th Street, Room 5-41, Phoenix, Arizona 85016. E-mail: bvozarov{at}mail.nih.gov.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The hypothalamo-pituitary-adrenal axis and sympathetic nervous system (SNS) interact to maintain cardiovascular and metabolic homeostasis, especially during stress. Pima Indians have a low SNS activity, which may contribute to both their increased risk of obesity and reduced risk of hypertension. Although glucocorticoids inhibit SNS activity, Pima Indians are not hypercortisolemic compared with Caucasians. This does not exclude the possibility that the SNS is more responsive to an inhibitory effect of cortisol in the former than in the latter group.

We measured fasting plasma ACTH and cortisol and muscle SNS activity [muscle sympathetic nervous system activity (MSNA), microneurography] in 58 males [27 Pimas/31 Caucasians]. Seven Pimas and 12 Caucasians were randomized to a double-blind, placebo-controlled, cross-over study to examine the effect of overnight partial chemical adrenalectomy (metyrapone) followed by cortisol replacement (hydrocortisone) on plasma ACTH, cortisol, and MSNA.

There were no ethnic differences in fasting plasma ACTH or cortisol, but MSNA adjusted for percent body fat was lower in Pimas than in Caucasians (P < 0.006). No correlation was found between fasting cortisol and basal MSNA. Administration of metyrapone did not lead to significant changes in MSNA. In response to a hydrocortisone infusion, MSNA decreased in Pima Indians (P = 0.03) but not in Caucasians (P = 0.7).

Our data indicate that the low SNS activity that predisposes Pima Indians to obesity is not due to a tonic inhibitory effect of cortisol. However, an acute release of cortisol is likely to more effectively contain sympathoexcitation during stress in Pima Indians than in Caucasians, which may be an important mechanism of cardioprotection in this Native American population.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE PIMA INDIANS living in Southwestern Arizona are one of the most obese populations in the world (1). While the exact etiology of their obesity remains unclear, we have previously found that the risk of gaining weight is increased in adult Pimas with a relatively low resting metabolic rate (2) and a high energy intake (3). Several animal models of obesity (4) indicate that low energy expenditure and a high energy intake are markers of a blunted sympathetic nervous system (SNS) activity. Interestingly, in Pima Indians basal muscle SNS activity (MSNA) is 20–30% lower compared with weight-matched Caucasians (5, 6, 7), SNS reactivity to both stimulatory and inhibitory stimuli is blunted (6) and, most importantly, a low sympathoadrenal activity is associated with future weight gain (8). We have also shown that a blunted SNS activity may contribute to the low prevalence of hypertension despite high prevalence of obesity in this population (5, 9, 10). The underlying cause of the low SNS activity in the Pimas remains unknown.

The peripheral (11) and central (12) effects of glucocorticoids and their role in metabolic and cardiovascular homeostasis continue to be actively investigated. We (13) and others (14) have been exploring the interaction between the hypothalamo-pituitary-adrenal (HPA) axis and the SNS. There is now evidence that cortisol may have an inhibitory effect on SNS activity (15, 16, 17, 18, 19, 20). This inhibition appears to be mediated by both indirect suppression of hypothalamic CRH [which when centrally administered, increases the firing rate of sympathetic nerves (15)] and direct inhibitory effects of cortisol on noradrenergic neurons in the locus ceruleus and other brain stem noradrenergic nuclei (Fig. 1AGo). Frank hypercortisolism, however, is not present in Pima Indians and is therefore not the explanation for the low SNS activity in this Native American population (13). Nevertheless, our previous observation does not rule out the possibility of ethnic differences in the responsiveness of the SNS to the inhibitory effect of cortisol.



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  		FIG. 1. Schematic diagram of the interrelation between HPA axis and SNS system under physiologic conditions (A) after administration of metyrapone (B) and after administration of hydrocortisone infusion (C) (full lines, positive feedback; dashed line, negative feedback).

 
The aim of the present study was to extend our previous findings on the interaction between the HPA axis and the SNS and to examine the effect of pharmacological manipulation of the HPA axis on muscle SNS activity (MSNA) in Pima Indians and Caucasians. We hypothesized that a partial chemical adrenalectomy induced by a single overnight dose of metyrapone (which inhibits 11ß-hydroxylase and, therefore, the conversion of 11-deoxycortisol to cortisol) followed by cortisol replacement (Fig. 1Go, B and C) would cause larger changes in MSNA in Pima Indians compared with Caucasians. This would indicate that the responsiveness of the SNS to the inhibitory effect of cortisol is higher in Pima Indians than in Caucasians.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Twenty-seven Pima Indian males and 31 Caucasian males were admitted for 6–10 d to the metabolic ward of the Clinical Diabetes and Nutrition Section of the National Institutes of Health (Phoenix, AZ). Data from some of these individuals were included in an earlier report (13). Women were not studied to avoid the confounding effects of hormonal changes during the menstrual cycle. All subjects were in good health as determined by physical examination and routine blood and urine tests, and all had normal thyroid function. None were taking medications at the time of entry into the study. All subjects were nondiabetic (21) and normotensive (blood pressure, <140/90 mm Hg).

Upon admission, all subjects were fed a weight-maintaining diet (50%, 30%, and 20% of daily calories provided as carbohydrate, fat, and protein, respectively) calculated on the basis of body weight and adjusted to maintain body weight to within ± 1%. Sodium intake was 4–6 g/d depending on weight maintenance caloric requirement. Body composition was estimated by total body dual energy x-ray absorptiometry (Lunar Radiation Corp., Madison, WI) with calculations of percent body fat, fat mass and fat-free mass as previously described (22). Waist and thigh circumferences were measured at the umbilicus in the supine and the gluteal fold in the standing positions and waist-to-thigh ratio calculated as an index of body fat distribution. The protocol was approved by the Institutional Review Board of the National Institute of Diabetes and Digestive and Kidney Diseases and Indian Health Service. All subjects gave written consent before participation.

Experimental protocol

After admission, all subjects spent their time on the metabolic ward and their physical activity was limited to ambulation in the hallways, playing pool or table tennis and an occasional outing to a park adjacent to the hospital. At least 3 d after admission and after an overnight fast, subjects underwent an oral glucose tolerance test.

On the following day, MSNA was measured by microneurography and blood samples were collected for measurement of plasma concentrations of ACTH, cortisol, catecholamines and their metabolites. Briefly, an iv plastic catheter was inserted in the antecubital vein at least 1 h before the first blood draws and kept patent by saline solution (<500 ml over 2 h). Then, a tungsten microelectrode (200 µm shaft diameter, 1- to 5-µm noninsulated tip) was inserted into the peroneal nerve posterior to the fibular head. A reference electrode was inserted sc 1–3 cm from the recording electrode. The search for a satisfactory recording site was limited to 1 h. The electrical signal was amplified, filtered, integrated, and recorded. MSNA was identified visually and expressed as the mean number of bursts per minute over a 10-min period (23).

Metyrapone/hydrocortisone study. Seven Pima Indians and 12 Caucasians who entered the main study were randomized [Latin square (24)] to a double-blind, placebo-controlled, cross-over study designed to test the effect of an overnight partial chemical adrenalectomy followed by cortisol replacement on SNS activity (Fig. 2Go). At 2300 h the day before the MSNA assessment, placebo or metyrapone (30 mg/kg) was administered. Metyrapone inhibits cortisol synthesis, thereby stimulating hypothalamic CRH and increasing pituitary secretion of ACTH into the circulation (Fig. 1BGo). Metyrapone administration was always followed the next day by an infusion of hydrocortisone (prepared from hydrocortisone sodium succinate) and placebo administration by an infusion of saline (infusion volume <250 cc). The next morning after an overnight fast, baseline blood samples were collected for assessment of plasma ACTH, cortisol, catecholamine concentrations, and their metabolites. After obtaining the 20-min baseline MSNA recording as described above, an infusion of hydrocortisone (1 µg/kg·min) or saline was started and continued for 60 min and blood samples for ACTH and cortisol were collected every 15 min during this time. If a successful MSNA study was completed, subjects were then crossed over to the other arm of the study after a washout of at least 2 d (with subjects remaining in the hospital). Four subjects (1 Pima and 3 Caucasians), had to be rescheduled for a second hospital admission (within 3 months) due to an unsuccessful second MSNA study. The MSNA studies before and after the cross-over were conducted on different legs.



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  		FIG. 2. Schematic diagram of the experimental design. Seven Pima Indians and 12 Caucasians who entered the main study were randomized to a double-blind, placebo-controlled, cross-over study designed to test the effect of an overnight partial chemical adrenalectomy followed by cortisol replacement on SNS activity. At 2300 h the day before the MSNA assessment, placebo or metyrapone was administered. Metyrapone administration was always followed the next day by an infusion of hydrocortisone and placebo administration by an infusion of saline. The next morning after an overnight fast, baseline blood samples were collected for assessment of plasma ACTH and cortisol. After obtaining the baseline MSNA recording, an infusion of hydrocortisone or saline was started and continued for 60 min and blood samples for ACTH and cortisol were collected every 15 min during this time. If a successful MSNA study was completed, subjects were then crossed over to the other arm of the study after a washout of at least 2 d. DXA, Dual energy x-ray absorptiometry.

 
Analytical measurements

Plasma glucose concentrations were determined by the glucose oxidase method (Beckman Instruments, Fullerton, CA) and plasma insulin concentrations by an automated immunoassay (Access, Beckman Instruments).

Plasma ACTH and cortisol were measured by a RIA (25). Plasma epinephrine (EPI), norepinephrine (NE), dihydroxyphenylalanine (DOPA), dihydroxyphenyl acetic acid (DOPAC), and dihydroxyphenylglycol (DHPG) concentrations were measured by reversed phase liquid chromatography with electrochemical detection.

Statistical analyses

Statistical analyses were performed using the software of the SAS Institute (Cary, NC). Results are given as mean ± SD (unless indicated otherwise). The values for MSNA, ACTH, cortisol, and catecholamines were logarithmically transformed before analysis to approximate normal distributions.

Ethnic differences in anthropometric and metabolic variables were assessed by unpaired Student’s t test. The relationships between MSNA, ACTH, and cortisol concentrations were examined by calculating Pearson correlation coefficients and multiple linear regression models were used to examine these relationships after adjusting for covariates. For those variables measured twice in response to the oral administration of either placebo or metyrapone, the changes were calculated as the {Delta}s (metyrapone-placebo) and the treatment effect was assessed by paired t test, whereas the treatment of race interaction was assessed by comparing the deltas in Pimas and Caucasians by unpaired t test. Percent changes were calculated as {Delta}s (metyrapone-placebo), divided by the value of the variable during the placebo [(metyrapone-placebo)/placebo]. For those variables measured more than twice in response to either placebo or hydrocortisone infusion, the time, treatment, and race effects and their interactions were assessed by ANOVA for repeated measures.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The anthropometric and metabolic characteristics of the whole study population and of the subgroup of individuals who underwent the overnight partial chemical adrenalectomy and subsequent cortisol replacement are summarized in Table 1Go.


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  		TABLE 1. Physical and metabolic characteristics of the study population

 
Baseline assessments of HPA axis and SNS activity

In the entire study group, there were no ethnic differences in fasting plasma ACTH, cortisol, NE, and EPI concentrations. However, Pima Indians had lower fasting plasma concentrations of catecholamine metabolites (DOPAC, DHPG) compared with Caucasians. When expressed in absolute values, baseline MSNA was similar in Pima Indians and Caucasians (Table 1Go). However, after adjustment for percent body fat, MSNA was lower in Pima Indians than in Caucasians (18 ± 12 vs. 30 ± 11 bursts/min, P = 0.006, respectively).

Fasting plasma ACTH concentrations were positively correlated with fasting plasma cortisol concentrations in Caucasians but not Pima Indians (Fig. 3AGo). In contrast, MSNA was positively correlated with fasting plasma ACTH concentrations in Pima Indians but not Caucasians (Fig. 3BGo). The relationship between MSNA and ACTH in Pima Indians remained significant after adjustment for age and percent body fat (P = 0.003). MSNA was not correlated with cortisol in either ethnic group (Fig. 3CGo). In multivariate analyses, plasma ACTH (P = 0.009) but not cortisol (P = 0.4) concentrations was an independent determinant of MSNA after adjustment for age, percent body fat, and race. In both of these models, MSNA remained lower in Pima Indians compared with Caucasians (P = 0.01).



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  		FIG. 3. Relationships between morning fasting ACTH and cortisol (A), MSNA and ACTH (B), and MSNA and cortisol concentrations (C) in 27 Pima Indian ({blacktriangleup}) and 31 Caucasian (*) participants in metyrapone/hydrocortisone study.

 
Metyrapone/hydrocortisone study

1) Changes in HPA axis and SNS activities after administration of metyrapone. Administration of metyrapone resulted in a significant decrease in cortisol (64%, P = 0.0001 and 44%, P = 0.0001, respectively) and increase in ACTH concentrations (11-fold, P = 0.0001; and 8-fold, P = 0.0001, respectively) compared with placebo in both Pimas and Caucasians (Fig. 4Go, A and B). There were no ethnic differences in the metyrapone-induced changes in cortisol and ACTH (P = 0.07, P = 0.3, respectively). The metyrapone-induced suppression of plasma cortisol was only weakly associated with the increase in plasma ACTH concentrations (r = 0.26, P = 0.1). Compared with placebo, metyrapone administration induced a 17% increase in MSNA in the Pimas and 1% decrease in the Caucasians, but neither of these changes were significant and there was no race effect (Fig. 4Go, E and F). In Pimas, but not in Caucasians, a negative correlation between metyrapone-induced changes in plasma cortisol concentrations and MSNA was observed (r = -0.61, P = 0.02) (Fig. 5Go, A and B). No correlations between changes in ACTH and MSNA were observed in either ethnic group (r = -0.14, P = 0.6, r = 0.19, P = 0.4, in Pima Indians and Caucasians, respectively). Fasting plasma catecholamine concentrations were not significantly affected by the administration of metyrapone (data not shown). Metyrapone had no effect on either mean the blood pressure (P = 0.6 and P = 0.7, for Pima Indians and Caucasians, respectively) or on the heart rate (P = 0.9 and P = 0.7).



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  		FIG. 4. Comparison of cortisol (A and B), ACTH (C and D), and muscle SNS activity (MSNA) (E and F) after placebo or metyrapone administration in 12 Caucasians and 7 Pima Indians. P value indicates differences due to intervention. Muscle SNS activity (MSNA) after administration of metyrapone/hydrocortisone and infusion vs. placebo/saline solution in 12 Caucasians and 7 Pima Indians (G and H). 0 min, Values after administration of placebo or metyrapone. Subsequent values represent values during administration of saline (dashed lines) or hydrocortisone (full line). p, Time x intervention effect in each ethnic group separately.

 


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  		FIG. 5. Relationship between change in plasma cortisol concentrations and change in MSNA (metyrapone-placebo) in 12 Caucasians (triangles) and 7 Pima Indians (circles).

 
2) Changes in HPA axis and SNS activities after infusion of hydrocortisone. The 60-min saline infusion resulted in no changes in plasma cortisol (P = 0.2 for time effect) or ACTH concentrations (P = 0.4), but a significant increase over time in MSNA (P = 0.0004) was observed. In contrast, the 60-min hydrocortisone infusion resulted in a significant increase in cortisol (P = 0.0001), which had been suppressed by the administration of metyrapone the night before. The resulting elevated plasma ACTH concentrations started to decrease 30 min after the start of the hydrocortisone infusion (P = 0.002). There was no change in MSNA.

The effects of the saline or hydrocortisone infusions on MSNA in Pimas and Caucasians are shown in Fig. 4Go, G and H. Because there was an increase of MSNA during the administration of saline but none during hydrocortisone infusion, we detected a time x intervention effect (P = 0.001), which suggests that the increase in MSNA observed during saline infusion was prevented by hydrocortisone. This time x intervention effect was dissimilar in the 2 races (P = 0.04, for time x intervention x race effect) such that MSNA after hydrocortisone was significantly lower compared with saline in Pimas (P = 0.03), but not in Caucasians (P = 0.7).

Mean blood pressure and heart rate both increased significantly during the infusions (both P < 0.001) but there was no difference between the interventions (P = 0.4 and 0.9, for time x intervention effect, for blood pressure and heart rate, respectively) or between the races (P = 0.6 and P = 0.2, for time x intervention x race effect, for blood pressure and heart rate, respectively).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The main aim of the study was to test if the lower SNS activity of Pima Indians than in Caucasians is due to a greater responsiveness of the SNS to the inhibitory effect of cortisol in the former group. Two of our main findings refute this hypothesis.

As in a previous study (13), Pima Indians were found to have lower resting SNS activity, but similar fasting plasma ACTH and cortisol concentrations compared with Caucasians. However, we did not observe a correlation between fasting cortisol and basal MSNA, which is at variance with a previous report of weak positive correlation between these two variables in a smaller group of individuals (13). The difference between the two studies, which is most likely attributable to differences in samples size, is relatively unimportant because neither a positive correlation nor the lack thereof support the hypothesis that cortisol is tonically involved in the suppression of basal SNS activity.

Because we hypothesized that the lower SNS activity of Pima Indians compared with Caucasians is due to a greater responsiveness of the SNS to the inhibitory effect of cortisol in the former group, we had anticipated to observe a greater increase in MSNA in the Pimas following chemical adrenalectomy. We observed a stronger relationship between suppression of cortisol and changes in MSNA in Pimas compared with Caucasians. Furthermore, we observed a 17% increase in MSNA in Pimas compared with the 1% decrease in Caucasians after metyrapone administration. However, this difference was not statistically significant. Thus, the direction but not the magnitude of the MSNA change was consistent with our hypothesis, which leads us to conclude that acute suppression of the HPA axis was not sufficient to overcome the ethnic difference in SNS activity. This finding does not exclude the possibility that a more pronounced and/or protracted suppression of cortisol concentration could have resulted in the expected outcome (16, 17). However, it does indicate that suppression of cortisol is not likely to be a clinically viable option for correcting the low SNS observed in the Pimas and its pathophysiological contribution to obesity.

Notwithstanding the above considerations, several findings from this study indicate that the relationship between the HPA axis and the SNS may differ between Pima Indians and Caucasians. These include the positive relationship between ACTH and MSNA and the significant suppression of MSNA following hydrocortisone administration in Pimas but not in Caucasians.

The positive correlation between MSNA and ACTH in the Pima Indians was unexpected and especially striking. While it is tempting to speculate that circulating ACTH, the secretion of which is centrally controlled by CRH as well as several other secretagogues (26), may be a better marker of central CRH concentration and its effects on SNS in Pima Indians than Caucasians, this cannot be resolved in our study. Interestingly, Dodt et al. (27) have shown that acute administration of ACTH enhances sympathetic outflow to the muscle and that this effect is most likely mediated via central nervous system autonomic centers. If this is the mechanism underlying the observation in Pima Indians, we do not have an explanation for why the stimulatory effect of ACTH on MSNA was not equally apparent in Caucasians.

As previously observed (27), the infusion of saline was associated with an increase in MSNA in our study, which is most likely due to increasing discomfort/stress as the study progressed (27, 28). Interestingly, the placebo-associated increase in MSNA was prevented by hydrocortisone infusion to a greater extent in the Pimas than in Caucasians. A suppression of MSNA in response an infusion of hydrocortisone has been reported previously in Caucasians, but the onset of this response was only evident starting 60–80 min after the onset of the infusion (27). Dodt et al. and others (27, 29) have suggested that cortisol-mediated inhibition of SNS could be an important mechanism in cardiovascular adaptation to stress and that a chronic disturbance of this mechanism could contribute to sympathetic hyper-reactivity in stressful situations in subjects who are likely to develop primary hypertension. Because suppression of MSNA in response to hydrocortisone was evident as early as 15 min after the initiation of the infusion in the Pimas from our study, we preliminarily conclude that acute release of cortisol is likely to be more effective at limiting sympathoexcitation during stress in Pima Indians compared with Caucasians. This could be an important mechanism of cardioprotection in this Native American population, which is extremely prone to obesity, but less susceptible to hypertension (5, 9, 10).

Even though ethnic differences in hypothalamic CRH levels, pulsatility of ACTH and diurnal variation of ACTH and cortisol were not assessed in this study, our data indicate that the activity of the HPA axis at baseline and after pharmacologic manipulation was not different between Pimas and Caucasians. Thus, it may not be immediately apparent how similar changes in cortisol exert different effects on the SNS system, but not HPA axis in the two ethnic groups.

To explain this possibility, we would like to propose two main arguments. Tissue-specific differences in glucocorticoid action may be mediated by factors affecting prereceptor glucocorticoid metabolism (11) as well as glucocorticoid hormone binding to GR, translocation efficiency of the ligand/receptor complex to the nucleus, and pleiotropic modulation of the expression of glucocorticoid-responsive genes (30). It is possible that one or several such mechanisms may differentially modulate the central effects of cortisol in Pimas and Caucasians. Second, glucocorticoids inhibit the activity of central noradrenergic neurons in a complex manner (31, 32). Because there are distinct populations of CRH neurons that control the HPA axis and the noradrenergic neurons in the locus ceruleus (33), it is possible that the effects observed in our study are due to differential responsiveness of these two distinct populations of CRH-containing neurons to cortisol. Alternatively, a selective difference in the responsiveness of central noradrenergic neurons to the direct effect of cortisol (Fig. 1CGo) may exist between Pimas and Caucasians.

A potential shortcoming of this investigation is represented by the inconsistencies in some of the ethnic comparisons in the larger group and in the subgroup enrolled in the metyrapone/hydrocortisone study. These inconsistencies may arise doubts about the generalizability of the findings from the latter group. However, we submit that these concerns are somewhat diminished by the following considerations. Mean plasma cortisol concentrations, the hormone that was central to our hypothesis, did not depend on ethnicity in either the whole group or the subgroup participating to the metyrapone/hydrocortisone study. In the presence of similar concentrations of cortisol, Pima Indians participating in metyrapone/hydrocortisone study had lower MSNA than Caucasians or even Pimas Indians in the general group. Thus, the lack of the effect of metyrapone on MSNA in this very group of Pima Indians could be interpreted as especially strong evidence to refute the hypothesis of greater responsiveness of the SNS to the inhibitory effect of cortisol in people with low MSNA. Nevertheless, because of the above mentioned differences between the whole group and the group participating in the metyrapone/hydrocortisone study and the small number of subjects in the latter, we invite caution in the interpretation the results.

In conclusion, our data indicate that the abnormally low SNS activity that predisposes Pima Indians to develop obesity is not due to a tonic inhibitory effect of cortisol. However, our findings also suggest that an acute release of cortisol is likely to more effectively contain sympathoexcitation during stress in Pima Indians compared with Caucasians. This may be an important mechanism of cardioprotection in this Native American population.


   Acknowledgments
 
The authors are grateful to Drs. James B. Young and Jack Yanowski for helpful comments and suggestions during the design of the study and interpretation of the results. We wish to thank members of the Gila River Indian Community for their participation. We also gratefully acknowledge the nurses of the Clinical Research Unit, as well as the staff of the metabolic kitchen for their care of the volunteers in these studies.


   Footnotes
 
Abbreviations: DHPG, Dihydroxyphenylglycol; DOPA, dihydroxyphenylalanine; DOPAC, dihydroxyphenyl acetic acid; EPI, epinephrine; HPA, hypothalamo-pituitary adrenal; MSNA, muscle sympathetic nervous system activity; NE, norepinephrine; SNS, sympathetic nervous system.

Received November 19, 2002.

Accepted March 12, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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