Plasma Norepinephrine Appearance Research Articles

Is obstructive sleep apnea the cause of sympathetic nervous activation in human obesity?

based on findings in experimental models of obesity, the sympathetic nervous system has commonly been assumed to have a determining role in obesity development through its influence on the regulation of energy expenditure. An earlier hypothesis was that sympathetic nervous activity was low in

SERTRALINE SUPPRESSES SYMPATHETIC NERVOUS SYSTEM ACTIVITY

The purpose of this study was to determine if short-term treatment with sertraline in healthy volunteers effects sympathetic nervous system (SNS) activity. SNS activity is increased in patients with major depression and in normal aging. This increase in SNS activity in depression and in aging may exacerbate comorbid medical conditions, such as cardiac disease, in which depression is a significant risk factor for mortality. Thirteen healthy volunteers were given either placebo or sertraline 50–100 mg for 2 days and then 1 week later underwent the same protocol with the other drug. The sequence of drug or placebo was randomized. After an overnight fast, intravenous lines were placed in the antecubital vein for infusion of tritiated norepinephrine (3H-NE) and in the dorsal vein of the hand, which was then placed in a heated box (60° C), to obtain arterialized plasma samples. After a 30-minute stabilization period, baseline samples were obtained for plasma norepinephrine (NE) and epinephrine. 3H-NE was administered in a 15 μCi/m2 bolus followed immediately by a constant infusion at the rate of 0.35 μCi/m2/min for a period of 30 minutes. Three sets of blood samples were obtained at 5-minute intervals to determine steady state NE and 3H-NE. Plasma NE concentrations were slightly lower in the sertraline compared to the placebo condition (212 + 77 vs. 254 + 102 pg/ml; P=0.10). By single compartmental analysis, plasma NE appearance rates were significantly lower in the sertraline compared to the placebo condition (0.26 + 0.10 vs. 0.39 + 0.23 μCi/m2/min; P=0.03). A decrease in plasma NE clearance in the sertraline condition also occurred (1.20 + 0.16 vs. 1.45 + 0.34 L/m2/min; P=0.007), which would be expected to increase rather than decrease plasma NE. These preliminary findings that short-term sertraline significantly decreases the plasma NE appearance rate demonstrate that sertraline suppresses systemic SNS activity in healthy control subjects. These results could have significant therapeutic relevance for treating elderly patients with depression and cardiac disease, in which elevated SNS activity could significantly exacerbate underlying cardiac illness. P27

Norepinephrine kinetics in older women: relationship to physical activity and blood pressure.

The sympathetic nervous system participates in the regulation of carbohydrate, lipid, and energy metabolism, and has been implicated in the pathogenesis of hypertension and obesity. Increased sympathetic nervous system activity with age may alter disease risk and contribute to the development of certain chronic diseases. Thus, we examined possible determinants of sympathetic nervous system activity in older normotensive women from infusions of tritiated norepinephrine (NE) to estimate rates of norepinephrine appearance and clearance. A secondary aim was to examine the association between norepinephrine kinetics and mean supine arterial blood pressure. Twenty-two older women (65.7 +/- 5.7 years) were characterized for resting NE kinetics, body composition, body fat distribution, peak aerobic capacity, leisure time physical activity energy expenditure (LTA), dietary carbohydrates, and daily energy intake. Analysis of univariate correlations revealed that only the LTA was significantly correlated with plasma NE appearance (r = 0.54, p < 0.01). Stepwise regression analysis identified LTA as the only significant predictor of plasma NE appearance rate with a total R2 = 0.29. The waist-to-hip ratio was selected as the only significant predictor of mean arterial blood pressure with an R2 = 0.30. When forced into the model, plasma NE appearance explained only 1% of the unique variance in mean arterial blood pressure. In summary, we found that: (1) higher levels of physical activity are related to higher plasma NE appearance in older women; (2) greater central body fatness is an independent predictor of mean arterial blood pressure; and (3) plasma NE appearance rate is a minor contributor to variation in mean arterial blood pressure in older, normotensive women.

NOREPINEPHRINE KINETICS IN OLDER WOMEN: RELATIONSHIP TO PHYSICAL ACTIVITY AND BLOOD PRESSURE

1552 The sympathetic nervous system (SNS) participates in the regulation of carbohydrate, lipid, and energy metabolism, and has been implicated in the pathogenesis of hypertension and obesity. Increased SNS activity with age may alter disease risk and contribute to the development of certain chronic diseases. Thus, we examined possible determinants of SNS activity in older normotensive women from infusions of tritiated norepinephrine (NE) to estimate rates of plasma NE appearance and clearance. A secondary aim was to examine the association between NE kinetics and mean supine arterial blood pressure. Twenty-two older women (65.7 ± 5.7 y) were characterized for resting NE kinetics, body composition, body fat distribution, peak aerobic capacity, leisure time physical activity energy expenditure (LTA), dietary carbohydrates, and daily energy intake. Analysis of univariate correlations revealed that only the LTA was significantly correlated with plasma NE appearance (r = 0.54, p <.01). Stepwise regression analysis identified LTA as the only significant predictor of plasma NE appearance rate with a total R2 = 0.30. Waist-to-hip ratio was selected as the only significant predictor of mean arterial blood pressure with an R2 = 0.29. When forced into the model, plasma NE appearance explained only 1% of the unique variance in mean arterial blood pressure. In summary, we found that: 1) higher levels of physical activity are related to higher plasma NE appearance in older women; 2) greater central body fatness is an independent predictor of mean arterial blood pressure; and 3) plasma NE appearance rate is a minor contributor to variation in mean arterial blood pressure in older, normotensive women.

Measurement and prediction of sympathetic nervous system activity in humans

The measurement of norepinephrine (NE) kinetics has broadened our understanding of sympathetic nervous system activity involvement in energy expenditure, blood pressure regulation and substrate utilization. This methodology, however, has several disadvantages that include administration of radioactivity to volunteers, its expense, and time consuming laboratory analyses. Thus, we developed an equation to predict plasma NE appearance rate (NEAP) derived from infusions of tritiated norepinephrine performed in 113 healthy men (18–78 yr.). The accuracy of the equation was tested using cross-validation procedures. Age, fat mass, plasma [NE], waist circumference, and body weight (BW) correlated significantly with plasma NE appearance rate. The resulting prediction equation in the validation group was: NEAP = 0.00003148 BW [NE], with R 2 = 0.76 and was successfully cross-validated. Using pooled data from both groups the prediction equation was: NEAP (gm/min) = 0.00003108 x [NE (pg/ml)]x[Body weight (kg)] with an R 2 = 0.70 and SEE = 0.096 gm/min. The magnitude of error associated with this equation allows for detection of ageassociated, exercise-induced changes and blood pressure-related differences in plasma NE appearance rate published in the literature. We provide an equation that offers a relatively simple and accurate alternative to estimate plasma NE appearance from the measurement of arterialized plasma [NE] and body weight.

Norepinephrine turnover and energy expenditure in Pima Indian and white men

There is growing evidence of the involvement of sympathetic nervous system (SNS) activity in determining metabolic rate. Whole-body plasma norepinephrine turnover and its relationship to resting metabolic rate (RMR) and 24-hour energy expenditure (24EE) were compared in 14 Pima Indian men (25 ± 4 years, 96 ± 33 kg, 25% ± 9% fat) and nine white men (25 ± 3 years, 88 ± 43 kg, 17% ± 13% fat). Plasma norepinephrine turnover rate correlated strongly with body surface area ( r = .76 and .54 for clearance and appearance, respectively) and fat-free mass ( r = .74 and .52, respectively). However, independent of body size, there was no difference in either norepinephrine clearance or appearance rates between Pima Indian and white men. Norepinephrine appearance rate correlated positively with absolute values of 24EE and RMR, but not when adjusted for differences in body surface area or fat-free mass. However, norepinephrine appearance rate adjusted for differences in body size correlated with spontaneous physical activity. The results indicate that Pima Indian and white men have similar plasma norepinephrine appearance rates, but Pima Indians tend to be more resistant β-adrenergic stimulation. Although energy expenditure and SNS activity were not directly related, a higher SNS tone may either promote or reflect elevated levels of spontaneous physical activity and therefore influence both energy balance and body composition.

Effects of age and level of physical activity on plasma norepinephrine kinetics

We examined the effects of age and physical activity on plasma norepinephrine (NE) kinetics in active and inactive older and younger men. NE kinetics were estimated by calculation of the rates of NE appearance and clearance during infusion of tritiated norepinephrine [( 3H]-NE). Older active men had the highest level of plasma NE (pg/ml) and NE appearance (microgram.min-1.FFW-1, where FFW is fat-free weight) relative to younger men and inactive older men. NE clearance (l.min-1.FFW-1) was not influenced by age or physical activity. No significant associations were noted between percent body fat, supine blood pressure with resting levels of NE, NE appearance, and NE clearance. We concluded that 1) chronic participation in physical activity by older men, but not younger men, is associated with higher resting levels of plasma NE and NE appearance and 2) the degree of adiposity does not influence plasma NE kinetics in healthy younger and older men. The level of physical activity is an influencing factor on plasma NE and NE appearance into circulation in healthy older men.

Preliminary evidence of benzodiazepine subsensitivity in panic disorder

Benzodiazepine receptors appear to mediate both the anxiolytic effects of benzodiazepine drugs and the anxiogenic effects of several benzodiazepine inverse agonists (Tallman and Gallagher 1985). Evidence that brain benzodiazepine receptor density is decreased in genetically fearful strains of rats (Robertson et al. 1978) suggests that human anxiety states might be associated with decreased functioning of the benzodiazepine system. This hypothesis has not been tested in humans. Recently, using a tritiated norepinephrine (NE) isotope dilution technique, we showed that a single oral dose of 15 mg of diazepam suppresses sympathetic nervous system (SNS) outflow as reflected by a fall in plasma NE appearance rate (NEA) and plasma epinephrine (EPI) (Roy-Byrne et al. 1988). This suggests that central nervous system (CNS) benzodiazepine pathways play a role in the regulation of

Suppression of norepinephrine appearance rate in plasma by diazepam in humans

Studies demonstrating benzodiazepine-induced reductions in plasma norepinephrine (NE) have assumed that changes in circulating plasma NE closely parallel changes in sympathetic nervous system (SNS) activity and that benzodiazepines suppress SNS outflow. However, decreases in plasma NE could also result from increased removal of NE from plasma via neuronal uptake or tissue metabolism. This study used a tritiated norepinephrine ([3H] NE) isotope dilution technique for measurement of plasma NE kinetics to determine if the fall in plasma NE induced by a single dose of diazepam orally administered to eight psychiatrically-healthy volunteers was due to a fall in plasma NE appearance rate or an increase in plasma NE removal. Diazepam decreased plasma NE appearance, but not clearance, and also decreased plasma epinephrine and mean arterial pressure, memory performance and alertness. Plasma levels of diazepam were correlated with drug effects on memory and alertness but not cardiovascular or SNS effects.

The importance of body composition to the increase in plasma norepinephrine appearance rate in elderly men.

Several studies have documented an increase in sympathetic nervous system (SNS) activity, as reflected by either plasma norepinephrine (NE) concentration or NE appearance rate, with aging. Because similar increases have been noted in young obese persons, and because adiposity increases with age, we hypothesized that body composition might be an important determinant of heightened SNS activity. Baseline SNS activity, energy expenditure, and responses to a standard formula "meal" were compared in 11 young (31.1 +/- 5 years) (m +/- SD) and 9 old (64.9 +/- 6.3 years) persons. Both baseline NE concentration, p less than .05, and the NE appearance rate, p less than .05, were increased in the elderly group. The percentage of body fat, p = .004, and age, p less than .02, were correlated independently with NE appearance rate but not with NE concentration. Although plasma NE increased after the meal in both groups, NE appearance increased in the young group only. We conclude that NE appearance rate is a better reflection of SNS activity than NE concentration. We also found that the percentage of body fat and age are independent determinants of baseline SNS activity, which together account for 52% of the variability in SNS activity, as reflected by NE appearance rate.

Age Differences in the Plasma Clearance Mechanisms for Epinephrine and Norepinephrine in Humans*

There is an age-related increase in plasma norepinephrine (NE) in humans that is due to both an increase in NE appearance into plasma and a decrease in plasma NE clearance. However, previous studies demonstrated no difference in plasma epinephrine (EPI) in young and old subjects, and the effect of aging on plasma EPI appearance and clearance is unclear. To study age differences in basal NE and EPI metabolism we infused eight young (aged 19-26 yr) and eight old (aged 64-74 yr) normal subjects with [3H]NE or [3H]EPI (15 microCi/m2 bolus dose plus 0.35 microCi/m2/min for 50 min) to achieve steady state conditions on separate days. The old subjects had higher arterialized plasma NE levels [mean, 217 +/- 13 (+/- SE) vs. 149 +/- 12 pg/mL; P less than 0.005] and plasma NE appearance. In contrast, neither plasma EPI levels (98 +/- 8 vs. 104 +/- 10 pg/mL; P = NS) nor EPI appearance rates were different in the old and young subjects. The plasma clearance rates of EPI and NE were nearly identical in the young subjects (1.63 +/- 0.14 vs. 166 +/- 0.09 L/min X m2; P = NS). Plasma NE clearance was lower in the old compared to the young subjects (1.38 +/- 0.06 vs. 1.64 +/- 0.10 L/min X m2; P less than 0.05) and was lower than EPI plasma clearance in the same subjects. Although NE and EPI can be removed by both neuronal and nonneuronal uptake mechanisms, and mean plasma clearance values for NE and EPI are the same in the young, the age-related decline in catecholamine clearance is specific for NE. This finding implies a differential effect of age on a catecholamine removal mechanism that is specific for NE.

Sympathetic nervous system activity in panic disorder

To assess sympathetic nervous system (SNS) activity in panic disorder, arterialized venous norepinephrine (NE) and epinephrine (EPI) were measured in 10 patients and 10 age- and weight-matched controls. In addition, arterialized plasma NE kinetics were determined using a tritiated NE isotope dilution technique. There were no significant differences between patients and controls for resting, supine plasma NE levels, plasma NE appearance rate, plasma NE clearance, or plasma cortisol. However, plasma EPI levels were significantly higher in panic patients (103 ± 23 vs. 33 ± 16 pg/ml). Furthermore, there was a significant correlation between anxiety ratings and plasma EPI levels in panic disorder patients. These findings suggest that during the resting state, panic disorder is associated with a selective activation of the adrenomedullary component of the SNS.

Age and alpha-2 adrenergic regulation of plasma norepinephrine kinetics in humans.

To investigate whether the age-related elevation of plasma norepinephrine (NE) is due to impaired alpha-2 adrenergic inhibition of sympathetic nervous system (SNS) outflow, arterialized plasma NE kinetics were measured before and 120 to 140 min after 1.5 and 5.0 micrograms m/kg oral clonidine in 6 old (57 to 78 years) and 8 young (25 to 39 years) normotensive male volunteers. Baseline plasma NE levels were higher in old compared with young men (M +/- SEM, 355 +/- 58 vs. 197 +/- 22 pg/ml, p less than .02). Clonidine produced significant (p less than .05) dose-related reductions in plasma NE, NE appearance rate, NE clearance, and mean arterial blood pressure (MAP) in both groups. There was no difference between old and young men in response to low dose clonidine. Following the higher dose, both groups had similar suppression of plasma NE (-51 +/- 7% vs. -58 +/- 2%, p greater than .05) and NE appearance (-60 +/- 6% vs. -62 +/- 2%, p greater than .05), but older men had a greater fall in NE clearance (-20 +/- 2% vs. -10 +/- 1%, p less than .003) and MAP (-28 +/- 3% vs. -10 +/- 4%, p less than .006). These findings suggest that sensitivity to alpha-2 receptor-mediated suppression of plasma NE and NE appearance is not diminished in elderly men.