Plasma Norepinephrine Kinetics Research Articles

Regional sympathetic nervous activity and oxygen consumption in obese normotensive human subjects.

Disturbed sympathetic nervous function may be of importance in obesity; sympathetic underactivity could contribute to deficient thermogenesis, positive energy balance, and weight gain, while in contrast, sympathetic nervous overactivity would predispose to the development of obesity-related hypertension. Global indices of sympathetic nervous system (SNS) function such as plasma or urinary norepinephrine (NE) have been unable to define SNS status in obesity. Since regional SNS activity can be altered in the absence of global changes, we investigated SNS activity in the heart, kidneys, and hepatomesenteric bed in healthy human subjects across a wide body mass index (BMI) range of between 19.6 and 35.5. Whole-body and regional plasma NE kinetics using [3H]-labeled NE were assessed. Regional oxygen consumption was measured by combining arteriovenous differences in oxygen content and regional blood flow. Arterial plasma NE and whole-body plasma NE spillover were unrelated to BMI. With a BMI cutoff of 27, mean cardiac NE spillover was 46% lower in the obese subjects when compared with the lean subjects (P=.017). Renal NE spillover was significantly correlated with BMI (r=.668, P=.001), the mean value in the obese subjects being more than twice that in the lean subjects. Hepatomesenteric NE spillover was comparable in lean and obese subjects. Renal and hepatomesenteric oxygen consumption were both significantly higher in the obese subjects compared with lean subjects. Regional SNS activity is heterogeneous in the obese state. Important regional alterations, which may be clinically relevant, occur in the absence of changes in global indices of sympathetic nervous function. The enhanced renal NE spillover in obesity may have implications for the development of hypertension in this group, whereas the low cardiac sympathetic tone would be expected to be cardioprotective. Enhanced visceral oxygen consumption evident in the kidneys and hepatomesenteric circulation in proportion to body mass contributes to the greater resting oxygen consumption in obesity.

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.

Subpressor angiotensin II infusions do not stimulate sympathetic activity in humans

Angiotensin II (ANG II) exerts significant direct and indirect pressor and chronotropic effects in experimental animals. The indirect effects have been shown to be due to interactions with the sympathetic nervous system at several levels. To test the hypothesis that ANG II in subpressor doses enhances the activity of the sympathetic nervous system in humans either at rest or in response to a stimulus from baroreceptor unloading, we measured mean arterial pressure (MAP), heart rate (HR), plasma norepinephrine (NE), and plasma NE kinetics during infusions of ANG II at 2 ng.kg-1. min-1 [or 5% dextrose in water (D5/W) control in six healthy volunteers in the supine position and during 60 degrees head-up tilt. No changes in any measured variable occurred during either infusion in the supine position. During upright tilt with D5/W, HR increased (58 +/- 8.4 to 68 +/- 7.7 beats/min, P less than 0.005), MAP rose slightly (90 +/- 3.9 to 94 +/- 4.0 mmHg, P less than 0.005), and plasma NE increased (213 +/- 3.8 to 366 +/- 83 pg/ml, P less than 0.005). The responses of the variables to tilt during ANG II were not different from those with D5/W.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma Norepinephrine Kinetics, Dopamine-β-Hydroxylase, and Chromogranin-A, in Hypothyroid Patients before and following Replacement Therapy*

Whether the increased plasma norepinephrine level reported in hypothyroidism is the result of impaired norepinephrine (NE) clearance or increased NE release by nerve terminals is unknown. We, therefore, measured plasma NE levels and clearance in 11 hypothyroid patients before [T4 index, 41.2 +/- 7.7 nmol/L (mean +/- SEM); TSH, 71.4 +/- 23.0 mU/L] and 4 +/- 0.5 months after thyroid replacement (T4 index, 136.4 +/- 24.4 nmol/L; TSH, 3.2 +/- 1.2 mU/L) and in 8 healthy volunteers. Plasma dopamine-beta-hydroxylase and chromogranin-A, which are coreleased with NE by sympathetic nerve endings, were also measured. Plasma NE was higher in the hypothyroid (2.37 +/- 0.24 nmol/L) than in the euthyroid state (1.86 +/- 0.24 nmol/L; P less than 0.02) or in the controls (1.87 +/- 0.27 nmol/L). Plasma clearance of NE, however, was not affected after thyroid replacement (hypothyroid, 2.08 +/- 0.31 L/min; euthyroid, 1.94 +/- 0.21 L/min; controls, 1.86 +/- 0.15 L/min). There was no significant change in plasma dopamine-beta-hydroxylase (hypothyroid, 720 +/- 139 nmol/mL.h; euthyroid, 553 +/- 97 nmol/mL.h) or plasma chromogranin-A (hypothyroid, 48.9 +/- 7.1 ng/mL; euthyroid, 42.9 +/- 5.3 ng/mL) after thyroid replacement. We conclude that the increased plasma NE in hypothyroid patients is not due to a change in plasma clearance, but is more likely secondary to increased NE release.

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.

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.

Effects of dietary potassium on the hemodynamics and plasma norepinephrine kinetics in patients with essential hypertension.

The effects of dietary potassium on the hemodynamics and plasma norepinephrine (NE) kinetics were studied in 10 patients with borderline hypertension. Potassium supplement (96 mEq daily for 5-7 days) induced a significant (p less than 0.05) fall in blood pressure and a slight decrease in cardiac output. Both urine volume and urinary sodium excretion increased significantly (p less than 0.05) for a first few days following the potassium supplement. The baseline values of the half-time of the rapid NE removal from plasma was significantly delayed in the hypertensive patients (1.05 +/- 0.06 min, p less than 0.05) when compared with those (0.88 +/- 0.04) in normal controls. Potassium supplement induced a significant rise in both plasma NE levels and NE outflow rate (p less than 0.01) in the hypertensive patients, while their half-times were significantly shortened (0.89 +/- 0.07 min, p less than 0.01). The pressor responsiveness to exogenously infused NE tended to diminish during the potassium supplement. These findings indicate that a high potassium intake might accelerate the slowed neuronal NE uptake in the hypertensive patients, while a potassium-induced fall in blood pressure might exert a baroreflex stimulation of NE release. As a net result, an increased NE outflow into the circulation has been confirmed. It is likely that a natriuresis-induced volume contraction might be a predominant factor responsible for the early reduction of blood pressure during the high potassium intake.

Effects of surgical stress and insulin on cardiovascular function and norepinephrine kinetics

In resting supine subjects the whole-body clearance of norepinephrine (NE) based on arterial and venous sampling averaged 1.4 and 2.5 liters/min, respectively (P less than 0.02). The difference in clearance values was due to a peripheral uptake of NE averaging 45%. The calculation of plasma NE clearance based on venous sampling results in values that are too high. The plasma appearance rate of NE increased considerably after surgery, whereas the arterial blood pressure remained unchanged. This suggests that the sensitivity to NE is reduced postsurgery. Insulin has certain acute effects on cardiovascular function and plasma NE kinetics that are unrelated to the counterregulatory response to decrements in plasma glucose concentration. Insulin may both induce antagonism to the action of NE and increase the release of NE from sympathetic nerves. Intravenous insulin decreases the plasma volume and increases the hematocrit by an adrenergic mechanism. Plasma NE increases in normal subjects after an oral glucose load. This response may be of importance because in sympathectomized patients both oral glucose and insulin administration decreases the arterial blood pressure. During an oral glucose load insulin-dependent diabetics show abnormalities in the regulation of cardiovascular function and sympathetic nervous activity that may be related to the lack of rise in endogenous insulin in these patients. These results suggest that insulin may be of importance for the normal function of the cardiovascular system.

The effect of sodium depletion on plasma norepinephrine kinetics in patients with essential hypertension.

The effects of sodium depletion on plasma norepinephrine (NE) kinetics were studied in 14 patients with essential hypertension using the steady state NE infusion technique on the theoretical basis of a two-compartmental open model. The calculated half time of rapid removal phase (t 1/2 alpha) of plasma NE was significantly delayed in the hypertensives (1.20 +/- 0.22 min, mean +/- SD) than in normal subjects (0.89 +/- 0.14) (p less than 0.01). The total clearance rates were comparable between the 2 groups (47 +/- 7 vs 48 +/- 11 ml/kg/min). The rates of the endogenous NE outflow into the circulation (RE-NE) were not significantly different between normal (5.29 +/- 1.68 ng/kg/min) and hypertensives (7.69 +/- 5.42), although 5 hypertensive patients (36%) showed an increased RE-NE above the normal range. The prolonged half time (t 1/2 alpha) in the hypertensives tended to be shortened after sodium depletion induced by either low sodium diet or diuretics (1.04 +/- 0.22, p less than 0.001). Both plasma NE and RE-NE were significantly increased after sodium depletion. A close correlation was observed between plasma NE and RE-NE (r = 0.907, p less than 0.001) in these subjects. These results suggest the slowed neuronal uptake of NE at the sympathetic nerve terminals in some patients with essential hypertension, occurring in part as a sodium-mediated consequence.