The thermic effect of feeding in older men: the importance of the sympathetic nervous system

We have previously published direct evidence that approximately one third of the thermic effect of feeding (TEF) in young healthy men can be accounted for by the meal-induced increment in sympathetic nervous system (SNS) activity. The elderly are known to have abnormal beta-adrenergic mechanisms and blunted responsiveness to sympathetic stimulation. Therefore, we postulated that the elderly might also have a blunted thermic response to a meal. In the present study, we evaluated the TEF in 25 young (age, 29.4 +/- 4.6 years) and 12 older (66.6 +/- 7.0 years), healthy weight-stable, untrained, nonsmoking men on no medications. Energy expenditure (ventilated hood system) and SNS activity (arterialized plasma catecholamine concentrations and norepinephrine [NE] kinetics) were measured before and following ingestion of an 800-kcal high-carbohydrate meal. At baseline, arterialized plasma NE concentration (P = .001) and appearance rate (P = .05) were 40% and 28% higher, respectively, in the elderly. Resting energy expenditure was related to fat-free mass (r = .54, P less than .01), and was 21% lower in the older men (P less than .01). Energy expenditure increased in both groups following the meal, but this TEF was 48% lower in the older men (P less than .001). This reduced TEF observed in the older subjects was associated with only a slight, nonsignificant, blunting of the SNS response to the meal. The TEF was related to the arterialized plasma NE appearance rate in the young, but not the older group. The TEF was unrelated to either glucose or insulin concentrations in either group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of diet on energy expenditure and plasma norepinephrine in lean and obese Pima Indians

To assess whether thermogenesis or sympathetic nervous system (SNS) function might differ between lean and obese human subjects, studies of thermic and sympathetic responses to standard stimuli were undertaken in Pima Indians, an ethnic group with a high prevalence of obesity. Plasma levels of norepinephrine (NE) and energy expenditure at rest and in response to feeding, exercise, and graded infusions of NE were compared in five lean and five obese Indians during a period of weight maintenance (WM), after 3 weeks of overfeeding (OF) and, in the obese, also after 6 weeks of underfeeding (UF). Basal energy expenditure, when adjusted for fat free mass, was equivalent during WM and increased 3% with OF (P less than 0.01) in both groups. Thermic responses to exercise or a test meal did not differ in lean and obese and did not change with OF, while thermic responses to NE infusion fell during OF to a greater degree in obese than lean (P less than 0.05). A similar pattern (decreased effect in obese with OF) was also noted in the glycemic response to infused NE (P less than 0.05). Although not quantitatively different in lean and obese, the plasma NE concentration appeared to vary more in response to feeding or dietary alteration in the obese than lean, a finding that may reflect lower plasma clearance of NE in the obese. These studies, therefore, raise the possibility that overfeeding in obese Pima Indians may limit the contribution of sympathetically mediated thermogenesis to energy expenditure, though the implications of this for body weight regulation are speculative.     

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.     

Postprandial lipemia after short-term variation in dietary fat and carbohydrate

Replacement of dietary fat with carbohydrate may not reduce the overall risk of coronary heart disease (CHD), because this elevates plasma triacylglycerol (TAG) concentrations. The lipoproteinemic effects of a high-carbohydrate diet are likely to be more marked shortly after the initiation of such a diet than after longer periods of intervention during which adaptive processes may counteract the initial effects. Therefore, we studied the postprandial responses to a standard meal after 3-day dietary intervention periods. An additional objective was to establish a model for future study of the mechanisms involved. Nine normolipidemic men consumed the meal (1.2 g fat, 1.1 g carbohydrate, and 0.2 g protein per 1 kg body mass) after 3 days on a high-carbohydrate diet (68% +/- 3% energy from carbohydrate, mean +/- SD) and also after 3 days on an isoenergetic high-fat diet (66% +/- 5% energy). Venous blood samples were obtained from fasted subjects and for 6 hours after the meal. In the fasted state, TAG was higher after the high-carbohydrate diet (1.18 +/- 0.18 v0.62 +/- 0.09 mmol/L, mean +/- SEM, P = .02) and high-density lipoprotein (HDL) cholesterol was lower (1.01 +/- 0.08 v 1.10 +/- 0.09 mmol/L, P = .002). The area under the plasma TAG concentration versus time curve was 42% +/- 7% higher after the high-carbohydrate diet (P = .003). After the high-carbohydrate diet, the postprandial insulin response did not differ between trials, but glucose and 3-hydroxybutyrate responses were lower (P = .009 and P = .02, respectively) and the lactate response was higher (P = .001). Plasma nonesterified fatty acids (NEFAs) were lower after the high-carbohydrate diet in the fasted state and for 4 hours postprandially, but were higher thereafter (interaction of time x trial, P = .001). These results indicate that compared with a high-fat diet, the plasma TAG response to a standard high-fat meal is markedly higher after a few days on a high-carbohydrate diet, with major differences in the associated metabolic milieu. The magnitude of these changes and the rapidity with which they developed suggest that this model may be attractive for future studies of the underlying mechanisms.     

Norepinephrine spillover from human adipose tissue before and after a 72-hour fast

Adipose tissue lipolysis is at least in part stimulated by the sympathetic nervous system (SNS). Although there is a generalized decrease in SNS activity with fasting, the rate of lipolysis during fasting increases. The aim of this study was to determine whether there is an association between activation of sympathetic nerves innervating adipose tissue and the increase in lipolysis seen during fasting in humans. We used the isotope dilution technique to measure regional norepinephrine spillover from abdominal sc adipose tissue from seven healthy subjects before and after a 72-h fast. Our results showed a significant increase in adipose tissue spillover of norepinephrine (mean +/- SEM, 0.40 +/- 0.09 vs. 1.08 +/- 0.18 pmol.100 g(-1).min(-1), P < 0.05) and arterial norepinephrine concentrations (0.92 +/- 0.10 vs. 1.23 +/- 0.08 nmol.liter(-1), P < 0.05) after the fast with no significant change in total body norepinephrine spillover, forearm norepinephrine spillover, epinephrine concentrations, or energy expenditure. We show for the first time, in humans, a selective regional increase in adipose tissue norepinephrine spillover in response to a 72-h fast and suggest that the SNS may play a greater role in the regulation of lipid metabolism during fasting than previously thought.     

Differential effects of high-fat and high-carbohydrate isoenergetic meals on cardiac autonomic nervous system activity in lean and obese women

Food ingestion can influence autonomic nervous system activity. This study compares the effects of 2 different isoenergetic meals on sympathetic nervous system (SNS) activity, assessed by heart rate variability (HRV) and plasma norepinephrine (NE) levels, in lean and obese women. Fifteen lean and 15 obese healthy women were examined on 2 occasions: after a carbohydrate (CHO)-rich and after a fat-rich test meal. Measurements of blood pressure, heart rate, resting energy expenditure, plasma glucose, lipids, insulin, leptin, and NE, as well as spectral analysis of the HRV, were performed at baseline and every 1 hour for 3 hours after meals. At baseline, obese women had higher SNS activity than lean controls (higher values of low-to-high frequency ratio [LF/HF], 1.52 +/- 0.31 v 0.78 +/- 0.13, P=.04; and plasma NE levels, 405.6 +/- 197.9 v 240.5 +/- 95.8 pg/mL, P<.0001). After the CHO-rich meal a greater increase in LF/HF and in plasma NE levels was observed in lean, compared to obese women (1.21 +/- 0.6 v 0.32 +/- 0.06, P=.04; and 102.9 +/- 35.4 v 38.7 +/- 12.3 pg/mL, P=.01, respectively), while no differences were observed after the fat-rich meal. Meal-induced thermogenesis was higher after the CHO-rich as compared to the fat-rich meal and was comparable between lean and obese women. Changes in HRV were not associated with the thermogenic response to the test meals. In conclusion, consumption of a CHO-rich meal causes greater cardiac SNS activation in lean than in obese women, while fat ingestion does not result in any appreciable change in either group. SNS activation does not appear to influence the thermic effect of the food in either lean or obese women.     

Effect of inhibition of prostaglandin synthesis on sympathetic nervous system function in man.

The effect of inhibition of prostaglandin synthesis by indomethacin on the function of the peripheral sympathetic nervous system was studied in eight normotensive subjects. Sympathetic nervous function was assessed by measurement of plasma norepinephrine, alpha-adrenergic receptor sites on platelet membranes, and urinary excretion of epinephrine and norepinephrine. Treatment with indomethacin for 7 days resulted in significant decreases in basal plasma norepinephrine from 134 +/- 7 to 99 +/- 6 (SEM) pg/ml (P less than 0.01), a 26% decrease. Posturally stimulated norepinephrine concentrations (337 +/- 14 pg/ml in control studies) were 255 +/- 18 pg/ml (P less than 0.02), 25% lower, with indomethacin. Plasma norepinephrine after 5-min compression of hand grip (468 +/- 47 pg/ml in control) was 331 +/- 30 pg/ml (P less than 0.005), 29% lower, with indomethacin. The number of platelet alpha-adrenergic receptor sites did not change with indomethacin, nor did prostaglandin E1-stimulated cAMP production by platelet membranes. In addition, indomethacin produced no change in urinary excretion of norepinephrine or epinephrine. It is suggested that inhibition of prostaglandin synthesis may lead, via baroreceptor feedback, to a decrease in plasma norepinephrine concentration.     

Elevated insulin, norepinephrine, and neuropeptide Y in hypertension

To investigate the relationship between insulin and sympathetic activity, plasma norepinephrine, neuropeptide Y, serum glucose and insulin concentrations were measured in ten age-, weight-, and sex-matched normotensive and untreated hypertensive subjects at fasting and 2 h following ingestion of a 75 g oral glucose dose. Hypertensives had higher fasting serum insulin (27 +/- 6 v 12 +/- 2 microU/mL; P = .02) and plasma norepinephrine (356 +/- 38 v 235 +/- 35 pg/mL; P = .03) concentrations than normotensives. Glucose load increased serum insulin (P less than .001) and plasma norepinephrine concentrations (P = .001) in both groups and hypertensives had still higher postglucose insulin (P = .003) and norepinephrine levels (P = .003) than normotensives. Fasting neuropeptide Y was higher in hypertensives than in normotensives (P = .03) and correlated with age in both groups (r = 0.7; r = 0.77). Postglucose serum insulin correlated positively with plasma norepinephrine (r = 0.75; P = .013) in normotensives, but these parameters correlated negatively in hypertensives (r = -0.7; P = .036). We hypothesize that elevated plasma norepinephrine and neuropeptide Y levels reflect an increased level of sympathetic nervous activity in hypertensives, which in turn may be responsible for the abnormal relationship between plasma NE and insulin levels.     

Participation of the sympathetic nervous system in hypertension in rats with subtotal renal ablation

To clarify the role of the sympathetic nervous system in the development of hypertension in chronic renal failure, plasma levels and urinary excretions of catecholamines were evaluated in male Sprague-Dawley rats. The renal mass of the rats was reduced by removing one kidney and two-thirds of the contralateral kidney (5/6 nephrectomy). Five-sixths nephrectomy was followed by significant increases in serum creatinine (to 0.55 +/- 0.03 mg/dl) and urea nitrogen (to 42.9 +/- 3.8 mg/dl). There was a concomitant increase in mean blood pressure, measured directly by an implanted aortic catheter, in comparison with control rats (155.3 +/- 8.3 versus 123.6 +/- 3.3 mmHg, P less than 0.01). Both plasma levels and urinary excretion of norepinephrine and epinephrine were elevated in the 5/6-nephrectomized rats compared with controls. Mean blood pressure correlated negatively with 24-h creatinine clearance (r = -0.66, P less than 0.05), and positively with plasma norepinephrine (r = 0.83, P less than 0.01) and urinary excretion of norepinephrine (r = 0.63, P less than 0.05). These results suggest that not only the decrease in renal function, but also hyperactivity of the sympathetic nervous system, may be involved in the pathogenesis of hypertension in rats with subtotal renal ablation.     

Elevated plasma levels of endothelin in patients with sepsis syndrome

The levels of the recently isolated endothelial-derived peptide, endothelin, which has potent vasoconstrictor properties, were analyzed by radioimmunoassay in plasma from six patients with sepsis syndrome. For comparison endothelin levels were also measured in plasma from ten healthy volunteers. In the septic group plasma endothelin-like immunoreactivity was five-fold higher (11.3 +/- 2.8 pmol/l) compared to the volunteers (2.4 +/- 0.07 pmol/l) (P less than 0.01). Three patients had anuria and were found to have the highest plasma endothelin levels, maximally 23.8 pmol/l. In the septic group plasma endogenous norepinephrine was increased to 8.3 +/- 2.2 nmol/l, as compared to 0.98 +/- 0.09 nmol/l in healthy volunteers (P less than 0.01). The results confirm that the sympathetic nervous system is activated in the septic patient. Plasma levels of endothelin, probably emanating from damaged endothelial cells by bacterial toxins, are also elevated indicating that this peptide may be involved in vasoconstrictor responses resulting in organ failure, which so often is encountered in septicemia.     

Liver hypermetabolism during alcohol withdrawal in humans. Role of sympathetic overactivity

Catecholamines, which are elevated during alcohol withdrawal, can alter hepatic blood flow and increase hepatic oxygen consumption. We hypothesized that, in the withdrawal state, hepatic oxygen consumption and delivery could be altered in relation to an increased sympathetic activity. Thirteen chronic alcoholics were studied 34-72 h after withdrawal and 10 days later (control period) using conventional hemodynamic methods. As compared with the control period, splanchnic oxygen uptake was elevated at withdrawal (74.5 +/- 27.1 vs. 59.2 +/- 16.8 ml/min, p less than 0.025) and its variation was correlated with that of plasma epinephrine (r = 0.70, p less than 0.01). The hepatic venous oxygen content was reduced at withdrawal (113 +/- 22 vs. 126 +/- 21 ml/L, p less than 0.025) and correlated inversely with plasma norepinephrine levels (r = 0.56, p less than 0.01). We conclude that, during alcohol withdrawal in humans, hepatic energy expenditure may be elevated in relation to epinephrine secretion and that sympathetic overactivity may hinder the adaptive response in hepatic blood flow. The wide range in sympathetic nervous response to alcohol withdrawal could explain some differences in individual susceptibility to liver damage caused by alcohol.     

The acute response of plasma norepinephrine, renin activity, and arginine vasopressin to short-term nitroprusside and nitroprusside withdrawal in patients with congestive heart failure

Activation of the sympathetic nervous system, manifested by an increase in heart rate and circulating plasma norepinephrine, can occur in normal subjects when they are given vasodilators. The extent to which this activation occurs in patients with congestive heart failure (CHF) and whether this activation could account for the hemodynamic rebound sometimes observed following abrupt withdrawal of nitroprusside in such patients are unclear. We prospectively and retrospectively studied the effects of nitroprusside on plasma norepinephrine in 38 patients with CHF to determine if acute vasodilator therapy activates this vasoconstrictor system during or following such treatment. Thirty-six of these patients also had plasma renin activity (PRA) measured and plasma arginine vasopressin was measured in 12 patients. Baseline supine plasma norepinephrine (714 +/- 72 pg/ml, +/- SEM), PRA (15 +/- 2 ng/ml/hr), and arginine vasopressin (10 +/- 1 pg/ml) were increased at least twofold in the CHF patients. Nitroprusside (96 +/- 11 micrograms/min) was infused for 63 +/- 5 minutes after achieving an optimal hemodynamic response: cardiac index increased (2.01 +/- 0.08 to 2.67 +/- 0.1 L/min/m2, p less than 0.001), pulmonary artery wedge pressure decreased (25 +/- 1 to 16 +/- 1 mm Hg, p less than 0.001), mean arterial pressure decreased (83 +/- 1 to 72 +/- 1 mm Hg, p less than 0.001), and heart rate was unchanged. Plasma norepinephrine (632 +/- 43 pg/ml), PRA (18 +/- 3 ng/ml/hr), and arginine vasopressin (11 +/- 1 pg/ml) did not change significantly for the group during peak effect of the vasodilator.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased sympathetic outflow in cirrhosis and ascites: direct evidence from intraneural recordings

OBJECTIVE: To determine if central sympathetic outflow is increased in patients with cirrhosis and ascites. PATIENTS: Eleven patients with cirrhosis and ascites, 8 patients with cirrhosis but without ascites, and 7 age-matched and 8 young healthy volunteers. METHODS: With subjects supine, direct microneurographic recordings of efferent post-ganglionic muscle sympathetic nerve activity were obtained from the peroneal nerve, and sympathetic burst frequency was compared with subjects' blood pressure, heart rate, sodium excretion, catecholamines, and plasma renin activity. All patients with cirrhosis were studied at least 5 days after withdrawal from all medications and after 7 days of a 20 mmol/d sodium, 1-L fluid-restricted diet. Age-matched volunteers were studied after 7 days of 20 mmol/d sodium intake and young healthy volunteers after 7 days of 150 mmol/d sodium intake. RESULTS: Sympathetic nerve activity in ascitic patients (65 +/- 15 bursts/min; mean +/- SD) was markedly increased, whether compared with patients with cirrhosis but without ascites (34 +/- 16 bursts/min; P less than 0.001), age-matched healthy volunteers on similar sodium intake (27 +/- 22 bursts/min; P less than 0.001), or young healthy subjects (21 +/- 10 bursts/min; P less than 0.001). The frequency of muscle sympathetic nerve discharge was directly related to plasma norepinephrine and epinephrine concentrations, plasma renin activity, and heart rate, all of which were increased in those patients with cirrhosis and ascites, and inversely related to 24-hour urinary sodium excretion, the fractional excretion of sodium, and subjects' pulse pressures. Sympathetic nerve activity fell from 78 to 6 bursts/min in one patient after liver transplantation. CONCLUSIONS: This study provides the first direct evidence that elevated plasma norepinephrine concentrations in patients with cirrhosis and ascites are due to increased central sympathetic outflow. Sympathetic nerve activity is not increased in patients with cirrhosis but without ascites. Because there were direct positive correlations of sympathetic nerve activity with plasma norepinephrine concentrations, plasma epinephrine concentrations, plasma renin activity, and heart rate, the increase in central sympathetic outflow in patients with cirrhosis and ascites appears generalized and not restricted to muscle nerves. The anti-natriuretic effects of parallel increases in renal and muscle sympathetic nerve activity could account for the inverse correlation between muscle sympathetic nerve activity and sodium excretion.     

The effect of selective beta adrenergic blockade on glucose-induced thermogenesis in man

We have previously shown that the increase in energy expenditure following glucose/insulin infusion is, in large part, mediated by the sympathetic nervous system and that this sympathetic component can be blocked by the nonselective beta-1, beta-2 antagonist propranolol. To examine which beta adrenergic receptor mediates this thermogenic response, we performed euglycemic insulin clamp studies in eight healthy control subjects with and without metoprolol at a dose known to block only the beta-1 adrenergic receptor. Basal glucose oxidation and energy expenditure were similar in the control and metoprolol groups. During the last hour of the insulin clamp study, glucose oxidation (3.06 +/- 0.25 v 2.92 +/- 0.21 mg/kg X min), total body glucose uptake (8.17 +/- 0.70 v 7.13 +/- 0.49 mg/kg X min), and nonoxidative glucose uptake (5.11 +/- 0.60 v 4.21 +/- 0.44 mg/kg X min) were not different in the control compared to the metoprolol group. However, the increment in energy expenditure was inhibited by 64% during metoprolol infusion (0.04 +/- 0.01 v 0.11 +/- 0.02 kcal/min, P less than 0.01). Glucose/insulin-induced thermogenesis was similarly reduced by metoprolol (2.56 +/- 0.81 v 5.04 +/- 0.74%, P less than 0.01). These results are quantitatively quite similar to those observed with propranolol. We conclude that the beta adrenergic nervous system and, specifically, the beta-1 receptor mediates the thermogenic response to glucose/insulin infusion.     

The effect of a high-carbohydrate meal on postprandial thermogenesis and sympathetic nervous system activity in boys with a recent onset of obesity

The purpose of the present study was to investigate the thermic effect of food (TEF) and sympathetic nervous system (SNS) activity in obese boys. Ten obese (9.2+/-0.4 years) and 13 lean boys (8.8+/-0.4 years) were examined for energy expenditure and fat oxidation measured via indirect calorimetry for 3 hours after a high-carbohydrate (HC; 70% carbohydrate, 20% fat, and 10% protein) or a high-fat (HF; 20% carbohydrate, 70% fat, and 10% protein) meal served on 2 different days at random. The activity of the SNS was assessed by means of a power spectral analysis of the heart rate variability. The TEF, expressed as a percentage of the consumed energy, was significantly lower in obese boys than in lean boys after the HC meal; however, such a difference was not observed after the HF meal. Multiple regression analysis revealed that obesity was a significant variable contributing to the variances in the TEF induced by the HC meal. Moreover, after the HC meal, the boys with a recent onset of obesity (duration, <3 years) manifested a lower TEF as well as a reduced very low frequency component of the heart rate variability, an index of thermoregulatory SNS functions, compared with the remaining obese and lean boys. In conclusion, obese boys possessed normal metabolic and sympathetic responses to the HF meal but showed a diminished thermogenic response to the HC meal, especially during the early phase of obesity.     

Effects of orthotopic heart transplantation on sympathetic control mechanisms in congestive heart failure

Abnormal sympathetic nervous system activity in severe congestive heart failure (CHF) was studied in 14 patients before and 3 to 6 months after orthotopic heart transplantation. Before transplantation plasma norepinephrine (NE) levels at rest were elevated (909 +/- 429 pg/ml, p less than 0.01 compared with normal, 185 +/- 60 pg/ml). No reflex activation of the sympathetic nervous system was seen with infusion of sodium nitroprusside despite a significant decrease in arterial pressure. The response to orthostatic tilt also was blunted in the patients before transplantation. Exercise capacity was reduced in these patients and plasma NE increased promptly at low exercise loads. After cardiac transplantation plasma NE levels returned to normal (319 +/- 188 pg/ml) and the sympathetic response to the stresses of orthostatic tilt (320 +/- 196 to 419 +/- 197, p less than 0.002) and nitroprusside infusion (255 +/- 94 to 555 +/- 130, p less than 0.001) normalized within 6 months after transplantation. Exercise capacity increased and the increase in plasma NE levels at various exercise loads was reduced for any given workload. Therefore, abnormal adrenergic activity in patients with severe CHF results mostly from the reduction in left ventricular pump function and is reversible if adequate pump function is restored.     

Plasma norepinephrine and dietary sodium intake in normal subjects and patients with essential hypertension

To evaluate the relationship between sodium intake and the activity of the sympathetic nervous system in patients with essential hypertension, plasma catecholamine levels were measured in 49 essential hypertensive patients and 38 age-matched normal subjects under regular-, high-, and low-sodium diets (mean 24-hour sodium excretions; 116 +/- 8, 267 +/- 29, 31 +/- 7 mEq/day, respectively). The levels of plasma norepinephrine were significantly (p less than 0.01) higher in hypertensive patients than in normal subjects. However, they were significantly reduced by high-sodium intake and increased by low-sodium intake in both patients and controls. The percent decrease and change in the absolute plasma norepinephrine levels from low- to high-sodium states were greater in normal subjects than in the hypertensive patients. The results are interpreted as indicating that an abnormal relationship exists between sodium intake and the activity of sympathetic nervous system in patients with essential hypertension.     

Hyponatremia in congestive heart failure: implications for neurohumoral activation and responses to orthostasis

To study the relationship between serum Na concentration and impairment of homeostatic mechanisms in advanced congestive heart failure (CHF), we evaluated the status of the sympathetic nervous system, renin-angiotensin system, and regional visceral blood flow in 26 patients with this syndrome. Compared with normal subjects, hyponatremic patients had marked stimulation of PRA (P = 0.012), norepinephrine (P less than 0.001), and epinephrine (P less than 0.001) with severe impairment of renal (P less than 0.001) and hepatic (P less than 0.003) plasma flows. In contrast, normonatremic patients, with an apparently similar degree of CHF, demonstrated less pronounced abnormalities in all of these parameters. Moreover, the responses of neurohormones and regional blood flow to orthostatic stress were greatly attenuated in the hyponatremic patients, whereas, the normonatremic subjects had more normal responses. We conclude that serum Na concentration serves as a useful index of activation of the sympathetic nervous system, renin-angiotensin system, and impairment of regional perfusion in patients with advanced CHF.     

Dissociation of sympathetic responses to baroreceptor loading and unloading in compensated congestive heart failure secondary to ischemic or nonischemic dilated cardiomyopathy.

This study tested the hypothesis that abnormalities of baroreceptor-mediated suppression of sympathetic activity may persist in chronic congestive heart failure (CHF) despite pharmacologic treatment and clinical stability. Plasma norepinephrine and norepinephrine kinetics (using 3HNE infusions) were measured during head-up and head-down tilt in 8 patients with chronic CHF and 6 normal control subjects. In response to upright tilt, normal subjects increased plasma norepinephrine (270 +/- 45 to 413 +/- 60 pg/ml, p less than 0.001) and norepinephrine spillover (540 +/- 103 to 781 +/- 124 ng/min, p less than 0.001). Patients also increased plasma norepinephrine (436 +/- 105 to 600 +/- 112 pg/ml, p less than 0.05) and norepinephrine spillover (802 +/- 180 to 1,037 +/- 370 ng/min). During head-down tilt, plasma norepinephrine decreased in normal subjects (from 413 +/- 60 to 256 +/- 26 pg/ml, p less than 0.001). The decrease was due entirely to a decrease in norepinephrine spillover (781 +/- 124 to 466 +/- 40 ng/min, p less than 0.001). In contrast, there was no significant change in norepinephrine spillover (1,037 +/- 370 to 949 +/- 338 ng/min) during head-down tilt in patients with CHF. These data suggest that suppression of sympathetic activity during baroreceptor loading may be defective in CHF despite relative preservation or correction of the response to baroreceptor unloading.     

Hamster adipocyte alpha 2-adrenoceptor changes during fat mass modifications are not directly dependent on adipose tissue norepinephrine content

It is questioned whether alterations of the sympathetic nervous system can explain the specific increment of the adipocyte alpha 2-adrenoceptor observed during white adipose tissue (WAT) enlargement and fat cell size increment. The impact of a 6-hydroxydopamine-induced sympathectomy, validated by determination of the WAT norepinephrine content, was tested on isolated white fat cell alpha 2-adrenoceptor function and binding [( 3H]RX 821002 and [3H]UK 14304 binding). Chemical sympathectomy of standard adult hamsters, neither alters the alpha 2-adrenergic-dependent antilipolysis nor the adipocyte alpha 2-adrenergic binding. A slight hypersensitivity of the beta 1-adrenergic lipolytic response was observed, without modification in beta-adrenergic binding [( 125I]cyanopindolol binding). Compared with controls, caloric restriction (10 days) of adult hamsters induced a large decrease in adipocyte alpha 2-adrenoceptor (P less than 0.001) with a parallel decrement in the mean fat cell size (P less than 0.001) and alpha 2-adrenergic responsiveness while there was no significant variation of the WAT norepinephrine content (on a per pad basis). 6-Hydroxydopamine treatment of the restricted animals (from day 6 to day 9) induced a higher preservation of adipocyte alpha 2-adrenoceptor density (P less than 0.001), no change in alpha 2-adrenergic responsiveness, and higher preservation of mean fat cell size (P less than 0.05) than in the restricted only animals. No significant modification in the beta-adrenergic binding was observed whatever the conditions. It was concluded that the specific increment in the adipocyte alpha 2-adrenoceptor during fat mass enlargement was not directly dependent on sympathetic nervous system alterations. Nevertheless, the sympathetic-dependent mobilization of the fat stores, after induction of caloric restriction, can indirectly modulate the alpha 2-adrenoceptor density in the adipocyte by promoting changes in white fat cell size.