Norepinephrine Appearance Rate 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.

Neural and hypotensive effects of angiotensin II receptor blockade.

Angiotensin II participates in the neural regulation of the heart and circulation at both central and peripheral sites. To explore the role of endogenous angiotensin II in blood pressure regulation, we conducted a randomized double-blind crossover trial in nine young healthy men (aged 33+/-3 [mean+/-SE] years) studied in the absence of salt restriction, comparing the effect of 1 week treatment with the angiotensin II receptor antagonist losartan (100 mg daily) against placebo with respect to the following variables, recorded during supine rest: intra-arterial blood pressure (BP), heart rate (HR), forearm vascular resistance and norepinephrine appearance rate, total body norepinephrine spillover, variability of BP and HR (spectral analysis), and baroreflex sensitivity for HR (gain of the transfer function from systolic BP to HR). Blood pressure was 119+/-7/66+/-4 mm Hg (systolic BP/diastolic BP) after 1 week of placebo and 112+/-6/61+/-3 mm Hg after 1 week of losartan (P<.05). Forearm vascular resistance tended to fall, from 42.3+/-6.9 U on placebo to 32.8+/-5.0 U with losartan treatment (P=.07). Losartan had no effect on HR (60+/-3 on placebo versus 59+/-2 beats per minute with losartan), total body norepinephrine spillover (3.0+/-0.8 versus 3.3+/-1.2 nmol/min), forearm norepinephrine appearance rate (3.8+/-1.1 versus 5.3+/-1.1 pmol/100 mL forearm tissue per minute), power in the high- or low-frequency components of the HR variability and BP variability spectra or on baroreflex sensitivity for HR. Endogenous angiotensin II contributes to the maintenance of supine BP in normal subjects, studied in the absence of sodium restriction. The fall in BP caused by losartan is accompanied by a resetting of the baroreflex regulation of HR and sympathetic outflow, but baroreflex sensitivity for heart rate is not altered. Therefore, the reduction in BP observed after short-term angiotensin type 1 receptor antagonism may be achieved through a direct effect on vascular tone rather than through a primary reduction in sympathetic outflow.

Endurance training with constant energy intake in identical twins: Changes over time in energy expenditure and related hormones

The effects of exercise training and of its interaction with the genotype on components of energy expenditure and related hormones were examined in young male monozygotic twins. Energy intake was maintained at the pretraining level for a 93-day training period. The estimated net energy deficit induced by training was 244 MJ and was associated with a 5-kg body weight loss that was almost entirely explained by body fat loss. Resting metabolic rate (RMR) was significantly decreased by 8% after training despite the preservation of fat-free mass (FFM). Accordingly, plasma norepinephrine (NE) concentrations, NE appearance rate, and plasma levels of triiodothyronine (T 3), free T 3, and total thyroxine (T 4) were lower after training. The energy cost of standardized exercise was also reduced after the training program. A modest to significant within—twin-pair resemblance was observed for absolute changes in the RMR, thermic effect of food, energy cost of exercise, NE clearance, and plasma concentrations of thyroid hormones. These results suggest that when exercise training is associated with a substantial negative energy balance, energy expenditure and levels of related hormones are decreased, and this effect is partly accounted for by heredity.

Presynaptic inhibition of norepinephrine release from sympathetic nerve endings by endogenous adenosine.

ATP is coreleased with norepinephrine from sympathetic nerve endings and subsequently broken down to adenosine. In animal preparations, adenosine can inhibit norepinephrine release by stimulation of presynaptic receptors. We tested this feedback mechanism in humans by using a specific nucleoside transport inhibitor (draflazine) as a pharmacological tool to allow accumulation of endogenous adenosine in the synaptic cleft. In a dose-finding study on draflazine infusions into the brachial artery (n=10), we identified an optimal dose of 250 ng/min per deciliter of forearm tissue that induced considerable local nucleoside transport inhibition (approximately 40%) without systemic effects. In the main study, we investigated the effects of this draflazine dose on sympathetic-mediated norepinephrine spillover during lower body negative pressure (-25 mm Hg) by the use of the [3H]norepinephrine isotope dilution technique (n=25). Lower body negative pressure induced a significant increase in total body norepinephrine spillover, forearm norepinephrine appearance rate, forearm vascular resistance, and heart rate. During draflazine infusion into the brachial artery, the responses to lower body negative pressure were preserved for all parameters, with the exception of the median increase in forearm norepinephrine appearance rate, which was reduced from 54% to 2% (P <.05). We conclude that accumulation of endogenous adenosine in the synaptic cleft during sympathetic stimulation can inhibit norepinephrine release from sympathetic nerve endings.

Sympathetic nervous system activity, body fatness, and body fat distribution in younger and older males

It was hypothesized that an increase in total and central body fatness is related to higher sympathetic nervous system activity (SNSA) in older men. Resting SNSA was measured from norepinephrine (NE) kinetics in 69 younger (18-36 yr) and 69 healthy older men (55-80 yr). Body fat distribution was estimated from the waist circumference, body composition from underwater weighing, peak oxygen consumption from a treadmill test to exhaustion, and dietary intake from food diaries. Plasma NE concentrations were 41% higher (P < 0.001) in older men due to a 27% increase (P < 0.001) in NE appearance rate and a tendency for a lower NE clearance rate (P = 0.08). NE appearance rate was higher in individuals of both age groups who exhibited a greater waist circumference and body fatness (range of r values 0.49-0.69; P < 0.01). The waist circumference, and not age, was the strongest predictor of the increase in NE appearance rate in older men. Statistically controlling for the waist circumference or body fatness diminished age-related differences in NE concentrations and in NE appearance rate. These findings suggest that an accumulation of total and central body fat is associated with higher levels of SNSA in older males.

Effects of endurance training on total fat oxidation in elderly persons.

We examined the influence of 8 wk of endurance training on basal levels of fat oxidation and its association with changes in norepinephrine (NE) kinetics, resting metabolic rate (RMR), and body composition in 18 healthy elderly persons (66.1 +/- 1.4 yr; 10 men, 8 women). Fatty acid appearance rate and total body fat oxidation were determined from [14C]palmitate infusion and indirect calorimetry, NE kinetics were determined from infusions of [3H]NE, RMR was determined from the ventilated hood technique, and body composition was determined from underwater weighing. Endurance training increased peak oxygen consumption by 11% (1.9 +/- 0.1 to 2.1 +/- 0.1 l/min; P < 0.01) and increased RMR by 7% (1.20 +/- 0.02 to 1.28 +/- 0.02 kcal/min; P < 0.01). Endurance training increased NE appearance rate by 35% (0.51 +/- 0.04 to 0.69 +/- 0.04 micrograms/min; P < 0.01), whereas no change in NE clearance was noted. Endurance training increased fat oxidation by 22% (201.0 +/- 11.2 vs. 244.0 +/- 15.2 mumol/min; P < 0.01) but did not alter fatty acid appearance rate. Approximately two-thirds of the variation (r2 = 0.65) for the increase in fat oxidation was explained by increased NE appearance rate (r2 = 0.51; P < 0.01) and changes in fat-free weight (r2 = 0.14; P < 0.01). We conclude that 1) endurance training shifts in vivo basal substrate utilization toward greater fat oxidation in elderly individuals and 2) enhanced fat oxidation is associated with increased activity of the sympathetic nervous system and alterations in fat-free mass.

Sympathetic nervous system activity and resting metabolic rate in vegetarians

We examined the resting metabolic rate (RMR) and sympathetic nervous system activity of young male vegetarians (n = 17) and nonvegetarians (n = 40). Subjects were characterized for RMR by indirect calorimetry, norepinephrine kinetics from infusions of tritiated norepinephrine, energy and macronutrient intake from a 3-day food diary, and body composition by underwater weighing. Vegetarians reported a greater relative intake of carbohydrates (62% ± 5% v 51% ± 6%, P < .01) and a lower relative intake of fat (25% ± 5% v 33% ± 6%, P < .01) than nonvegetarians, whereas no differences were observed in daily energy intake, body composition, or maximal aerobic capacity (Vo 2max) between groups. Vegetarians exhibited an 11% higher absolute RMR (1.29 ± 0.15 v 1.16 ± 0.13 kcal/min, P < .01), a higher plasma concentration of norepinephrine (216 ± 33 v 165 ± 18 pg/mL, P < .01), and a greater norepinephrine appearance rate (0.50 ± 0.08 v 0.36 ± 0.09 μg/min, P < .01) than nonvegetarians. After statistically controlling for differences in relative amounts of carbohydrate and fat in the diet and for norepinephrine concentrations, no significant differences in adjusted RMR between vegetarians and nonvegetarians were noted. These results suggest that the higher RMR observed in young male vegetarians is partially mediated by differences in dietary macronutrient composition and increased sympathetic nervous system activity.

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.

Endurance training increases metabolic rate and norepinephrine appearance rate in older individuals

We examined the effects of an 8-wk endurance training program (cycling exercise) on resting metabolic rate (RMR) and norepinephrine (NE) kinetics in 19 older persons (64 +/- 1.6 yr). Before and after training, RMR, NE kinetics, maximal O2 consumption (VO2max), body composition, supine blood pressure, estimated energy intake, and fasting levels of glucose, insulin, and thyroid hormones were measured. RMR increased 10% after training. Resting concentrations of NE increased 24% after training due to a 21% increase in NE appearance rate and no change in NE clearance. Training increased VO2max (14%; P less than 0.01) and energy intake (12%; P less than 0.01), whereas no change was noted in body composition. Supine blood pressure and plasma glucose were lower after training, whereas no change was noted in fasting levels of plasma insulin. The increase in RMR was associated with a higher rate of NE appearance (r = 0.57; P = 0.05) and with increase in energy intake (r = 0.56; P = 0.05). Together these two factors accounted for 49% (r2) of the variation of the change in RMR. Changes in blood pressure were not associated with changes in NE kinetics. We conclude that endurance training increases total energy expenditure in older individuals by the direct energy cost of physical activity and by elevating RMR. This increase is partially mediated by an increased NE appearance rate and increased food intake in healthy older individuals.

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.

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.