Norepinephrine Spillover 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

Psychophysiological Mechanisms in Panic Disorder: A Correlative Analysis of Noradrenaline Spillover, Neuronal Noradrenaline Reuptake, Power Spectral Analysis of Heart Rate Variability, and Psychological Variables

The risk of adverse clinical cardiac events is increased in patients with panic disorder (PD). We evaluated possible mechanistic links between PD and heart disease. We estimated cardiac vagal activity from heart rate variability (HRV) measurements and quantified sympathetic nervous system (SNS) activity using plasma noradrenaline tracer kinetics methodology. Thirty-nine people with PD and 39 age- and gender-matched healthy volunteers were studied. In 19 participants with PD, both HRV and plasma noradrenaline kinetics were tested; in 20 with PD and 20 healthy volunteers, HRV measurements only were made, whereas in 19 healthy volunteers, noradrenaline kinetics only was tested. All panic disorder participants completed psychological measures of anxiety sensitivity and state and trait anxiety; healthy volunteers in whom HRV was measured also provided psychological measures. Sympathetic nervous tone in the heart, based on rates of cardiac noradrenaline spillover, was normal in PD. Noradrenaline and adrenaline plasma clearance and plasma tritiated noradrenaline and adrenaline extraction in transit through the heart, all dependent on the noradrenaline transporter (NET), were reduced in PD. Psychometric testing linked inhibition of anger to this deficit in NET functioning. Anxiety sensitivity was specifically associated with impaired cardiac NET. High- and low-frequency heart rate spectral power was unrelated to all plasma noradrenaline kinetics measurements. Defective neuronal reuptake of noradrenaline, by augmenting the sympathetic neural signal in the heart, might have a dual effect, sensitizing the heart such as to lead to symptom development (and thus perhaps causing panic disorder) and, second, potentially contributing to adverse cardiac events in established PD.

Effects of Dietary Weight Loss on Sympathetic Activity and Cardiac Risk Factors Associated with the Metabolic Syndrome

Weight reduction, the first line treatment for the metabolic syndrome, improves insulin sensitivity and associated metabolic and cardiovascular abnormalities, but there is a paucity of data regarding its effect on sympathetic nervous system (SNS) activity in this clinical setting. The objectives of this study were to test the hypothesis that dietary weight loss attenuates both insulin resistance and SNS activity and to examine the relationships between SNS activity and metabolic syndrome (MetS) components. This was a single-sample, repeated measures design study. This study was performed at a tertiary referral center. Twenty-three MetS subjects (age, 58 +/- 2 yr; body mass index, 33.3 +/- 0.8 kg/m2; mean +/- sem) were studied. A hypocaloric modified Dietary Approaches to Stop Hypertension diet (26% fat, 22% protein, and 51% carbohydrate; 100 mmol/d sodium) was consumed for 3 months. The main outcome measures were postganglionic muscle sympathetic nerve activity (microneurography at a peroneal nerve), whole-body plasma norepinephrine spillover rate, spontaneous cardiac baroreflex function, and insulin sensitivity. The hypocaloric diet significantly reduced body weight by 7% and improved all MetS components. Norepinephrine spillover decreased from 877 +/- 180 to 503 +/- 39 ng/min (P = 0.005), and muscle sympathetic nerve activity decreased from 40.6 +/- 2.1 to 34.6 +/- 2.4 bursts/min (P = 0.01), whereas cardiac baroreflex sensitivity increased by 23.0 +/- 8.0% (P = 0.02). The change in the norepinephrine spillover rate correlated positively and independently with the change in plasma leptin concentration (r = 0.49; P = 0.03). Weight loss by a hypocaloric diet with moderate sodium restriction diminishes SNS activity in MetS subjects. This may be due to the consequences of decreased leptin concentration, enhanced insulin sensitivity, or improvements in cardiac baroreflex function.

Sympathetic nerve function

Radioisotope dilution measurements of norepinephrine spillover (rate of entry of the transmitter into plasma) provide more accurate assessments of sympathoneural transmitter release than allowed by measurements of plasma catecholamine concentrations alone. Measurements of total body norepinephrine spillover, as an index of global sympathetic outflow, allow effects on plasma clearance to be distinguished from effects on release of catecholamines into plasma, while spillovers from specific tissues enable examination of regionalized sympathetic responses. However, spillovers of norepinephrine represent only a fraction of the transmitter that escapes neuronal and extraneuronal uptake after release by nerves. Numerous factors may influence this fraction and measures spillovers independently of transmitter release by nerves. Modified radioisotope dilution methods for assessment of rate processes operating within and between intracellular and extracellular compartments have further improved our understanding of the relationships of norepinephrine release, uptake, spillover, turnover, and metabolism. This article reviews the breadth of information about sympathetic nerve function attainable using catecholamine radioisotope dilution analyses against a backdrop of the relative advantages and methodological limitations associated with the methodology.

Pathogenesis and etiology of essential hypertension: role of dietary carbohydrate

The development of essential hypertension (EH) is proposed to be the result of a cascade of metabolic alterations, with high insulin levels/hyperinsulinemia and an abnormal reaction to the vasodilatory effect of insulin as the initiating factors. It is well established that insulin causes vasodilatation of peripheral resistance vessels. In normal subjects, this insulin-induced vasodilatation and decrease of the peripheral vascular resistance (PVR) is compensated by an SNS-mediated re-vasoconstriction in order to avoid hypotension, with the net effect of a slight decrease in blood pressure and no significant effect on peripheral vascular resistance. In contrast, in genetically predisposed subjects, prone to the development of essential hypertension, the insulin-induced vasodilatation is compensated by an increased heart rate and cardiac output (to avoid hypotension), mediated by an abnormal sympathetic overactivity, (characterised by high norepinephrine spillover rates and (frequently) a hyperdynamic circulation), while the PVR remains low during the early phase of developing EH. During the course of chronic hypertension, the SNS-overactivity leads to progressive trophic alterations of vessel walls, and structural and functional vascular remodeling, with narrowing of arterial resistance vessels and an increasing PVR. Vascular remodeling and lumen narrowing not only affect peripheral resistance vessels, but also kidney vessels. Narrowing and decreased distensibility of preglomerular kidney vessels lead to chronic activation of the Renin-Angiotensin-Aldosterone-System, with reinforcement and fixation of hypertension. High-glycemic index nutrition is suggested to play a key role in the etiology of hypertension: The chronic stimulus of pancreatic beta-cells due to high-glycemic index nutrition may cause cell hypertrophy and dysfunction, resulting in postprandial hyperinsulinemia, and -- in susceptible subjects -- the development of EH. Since significant evidence suggests that hyperinsulinemia also represents a key factor for the development of obesity, insulin resistance and the metabolic syndrome, the well-known common association of EH and these metabolic alterations becomes quite understandable.

Rate of fall of blood glucose and physiological responses of counterregulatory hormones, clinical symptoms and cognitive function to hypoglycaemia in Type I diabetes mellitus in the postprandial state.

The aim of this study was to establish the effect of a rate of decreasing plasma glucose concentrations on responses to hypoglycaemia, i.e. release of counterregulatory hormones, perception of symptoms, deterioration of cognitive function, and rates of forearm noradrenaline spillover, in the postprandial condition and in the sitting position. We studied 11 subjects with Type I (insulin-dependent) diabetes mellitus, twice during clamped insulin-induced hypoglycaemia (2.4 mmol/l) after eating in the sitting position. On one occasion, plasma glucose was decreased at the rate of 0.1+/-0.003 mmol x min(-1) x l(-1) (fast fall), on the other at the rate of 0.03+/-0.001 mmol x min(-1) x l(-1) (slow fall). Subjects underwent a control euglycaemic clamp study as well. In response to fast-fall as compared to slow-fall hypoglycaemia, which was about 30 min longer, cognitive tasks were performed as follows: Trail-Making B, PASAT 2 s, Digit Vigilance Test and Verbal Memory deteriorated more, adrenaline increased less (2.8+/-0.5 vs 3.5+/-0.7 nmol/l, p=0.03), forearm noradrenaline spillover was greater (6.5+/-1.0 vs 5.2+/-0.4 pmol x min(-1) x 100 ml(-1), p=0.04), and symptoms were no different. After recovery from hypoglycaemia, cognitive function was still deteriorated compared to the baseline with no difference between fast and slow-fall hypoglycaemia. The evident response of glucagon to postprandial hypoglycaemia contrasted with the blunted or absent response in the fasting state. In the postprandial condition and sitting position, fast-fall hypoglycaemia is more dangerous than slow-fall, because it deteriorates cognitive function more, and activates responses of counterregulatory hormones less than slow-fall hypoglycaemia.

Sympathetic nervous activation following subarachnoid hemorrhage: Influence of intravenous clonidine.

Subarachnoid hemorrhage is often accompanied by systemic complications and cerebral vasospasm. Elevated levels of circulating catecholamines may be involved in the pathophysiology behind these events. The alpha-2-agonist clonidine inhibits sympathetic outflow by a central mechanism. Unrestricted sympathoexcitation may be detrimental and administration of clonidine may be beneficial in these patients. Using isotope dilution methodology, norepinephrine kinetic determinations, comprising determination of arterial norepinephrine concentration and rates of norepinephrine spillover to and removal, or clearance, from plasma, were performed on three occasions during the first week after subarachnoid hemorrhage in 25 patients. Eleven of these patients received clonidine (continuous i.v. infusion 5.8 +/- 0.7 microg x kg(-1) x 24 h(-1)) and the remainder, standard therapy. Initial results were compared with 17 healthy age-matched subjects and eight patients suffering from severe traumatic brain injury without traumatic subarachnoid hemorrhage. Subarachnoid hemorrhage patients exhibited markedly elevated arterial plasma norepinephrine concentrations [3.74 +/- 0.48, P < 0.001 vs. healthy subjects (1.59 +/- 0.11 nmol/L) and P < 0.05 vs. head trauma patients (1.94 +/- 0.29 nmol/L)]. The rate of clearance of norepinephrine from plasma in the subarachnoid patients was also significantly greater than that observed in the healthy subjects (2.66 +/- 0.15 vs. 2.14 +/- 0.15 L/min, P < 0.05) and the head trauma patients (2.00 +/- 0.12 L/min, P < 0.05). Compared with both control groups, on admission the rate of spillover of norepinephrine to plasma following subarachnoid hemorrhage was markedly elevated (9.11 +/- 1.12, P < 0.001). Clonidine treatment (continuous i.v. infusion 5.8 +/- 0.7 microg x kg(-1) x 24 h(-1)) did not reduce the increased rate of spillover of norepinephrine to plasma following subarachnoid hemorrhage. Sympathetic nervous activity is markedly elevated following subarachnoid bleeding. Clonidine had no effect on the rate of norepinephrine spillover to, or clearance from, plasma in these patients. Clearly, further studies are required to elucidate the mechanisms responsible for generating sympathetic nervous activation following subarachnoid hemorrhage.

Adrenaline hypothesis: effect of formoterol on noradrenaline release.

1 Originally, the so-called 'adrenaline hypothesis' related the release of noradrenaline (NA) to stimulation of presynaptic beta2-receptors in nerve endings; now it confers a possible role to adrenaline taken up then released by nerves endings. It represents a potentially useful therapeutic pathway. The present study aims to investigate the effects of formoterol, a highly selective beta2-adrenoceptor agonist. 2 It was carried out in freely moving rats, the isotope dilution technique being used to measure the NA spill over rate (NA-SOR) and metabolic clearance rate (MCR). 3 A series of three results are reported. (a) When compared with adrenaline on equimolar basis, formoterol (2.3 micro kg-1 min-1) increased NA-SOR while mean arterial blood pressure was decreased and heart rate increased. Thus, it was difficult to separate a direct presynaptic effect from indirect baroreflex-dependent activation of the sympathetic system. (b) When formoterol was infused at 1 ng kg-1 min-1, a dose empirically defined to induce no haemodynamic effect, NA-SOR was significantly increased, while NA-MCR remained unchanged. (c) The NA-SOR response to formoterol was not amplified by the presynaptic alpha2-adrenoceptor blocker, yohimbine, in contrast to the NA-SOR response to adrenaline. 4 In conclusion, formoterol, a beta2-adrenoceptor agonist, is shown to increase the release and plasma concentration of NA while its clearance was not changed.

Norepinephrine kinetics in freely moving rats.

Norepinephrine (NE) kinetics were investigated in freely moving (FM) and minimally stressed (MS) rats with the isotope dilution technique. 1) The mean NE spillover rate (NE-SOR) was 79 +/- 6 ng. kg(-1). min(-1), and the mean NE metabolic clearance rate (NE-MCR) 179 +/- 9 ml. kg(-1). min(-1) (n = 31). Thus the NE kinetics in FM and MS rats are much faster than in human beings, probably related to a higher sympathetic drive. 2) Whether the magnitude of NE-MCR is related to the level of plasma NE concentration was investigated. No significant correlation was calculated between plasma NE concentration and NE-MCR in 31 control rats. When plasma NE concentration was varied during either acute or chronic infusion of exogenous NE, NE-MCR remained unchanged as long as animal hemodynamics were not altered. When plasma NE concentration was high enough to increase mean arterial pressure (MAP), NE-MCR was decreased. However, when MAP was increased within comparable magnitude, NE-MCR was decreased during NE and increased during epinephrine (Epi) infusion. Thus the existence of an alpha-/beta-adrenergic mechanism involved in the regulation of NE-MCR independent of known hemodynamic mechanisms is suggested. 3) The "epinephrine hypothesis" was revisited in FM and MS rats. At variance with humans, very high plasma Epi concentrations have to be induced to increase NE-SOR in resting rats. Furthermore, NE-MCR was also increased, accounting for the nonsignificant increase of plasma NE concentration. Within the range of Epi concentrations with no effect on NE-SOR, an increase of NE release was revealed when the presynaptic alpha(2)-adrenoreceptors were partially inhibited by yohimbine. This suggests the existence of a second epinephrine hypothesis.

Norepinephrine kinetics in dogs with experimentally induced renal vascular hypertension.

To determine norepinephrine (NE) kinetics in dogs with experimentally induced renal vascular hypertension. 4 mixed-breed dogs. The study comprised a control and hypertensive period. The hypertensive period followed induction of renal vascular hypertension achieved by surgical placement of clips on both renal arteries to reduce diameter by approximately 80%. Arterial blood pressure, renal clearance, and NE kinetics were measured during each period while dogs were receiving a low-sodium diet. Measurements of NE kinetics and renal clearance during the hypertensive period were made 5 days after induction of hypertension. Five days after induction of hypertension, arterial blood pressure increased by 15 to 20 mm Hg. Mean (+/- SEM) plasma NE concentration and NE spillover rate increased significantly from 151.5+/-14.1 pg/ml and 8.03+/-0.62 ng/kg/min, respectively, during the control period to 631.4+/-30.5 pg/ml and 54.0+/-5.2 ng/kg/min, respectively, during the hypertensive period. Norepinephrine clearance rate also increased (54.0+/-2.4 vs. 86.0+/-9.3 ml/kg/min). Positive associations between mean arterial pressure (MAP) and NE concentration and spillover rate were detected. However, MAP and NE clearance rate were not associated. Increased blood pressure during the hypertensive period was likely attributable to increased NE spillover rate, which resulted in a significant increase in plasma NE concentration. Analysis of these results suggests that central sympathetic outflow was increased and may be responsible for the pathogenesis of high blood pressure during the acute phase of renal vascular hypertension in dogs.

Comparison of two indices for forearm noradrenaline release in humans

Although there is as yet no method which measures directly the neuronal release of noradrenaline in humans in vivo, the isotope dilution technique with [(3)H]noradrenaline has been applied to estimate forearm neuronal noradrenaline release into plasma. Two different equations have been developed for this purpose: one to estimate the spillover of noradrenaline into the venous effluent, and a modified formula (often referred to as the appearance rate) which may reflect more closely changes in the neuronal release of noradrenaline into the synaptic cleft, particularly during interventions that alter forearm blood flow. The present study was performed to compare the effects of two interventions known to exert contrasting actions on neuronal forearm noradrenaline release and forearm blood flow. Intra-arterial infusion of sodium nitroprusside at doses without systemic effect increases forearm blood flow, but not neuronal noradrenaline release. In contrast, lower-body negative pressure at -25 mm Hg causes forearm vasoconstriction by stimulating neuronal noradrenaline release. During sodium nitroprusside infusion, forearm noradrenaline spillover increased from 1.1+/-0.3 to 2.2+/-1.0 pmol x min(-1) x 100 ml(-1) (P<0.05), whereas the forearm noradrenaline appearance rate was unchanged. Lower-body negative pressure did not affect the forearm noradrenaline spillover rate, but increased the forearm noradrenaline appearance rate from 3.4+/-0.4 pmol x min(-1) x 100 ml(-1) at baseline to 5.0+/-0.9 pmol x min(-1) x 100 ml(-1) (P<0.05). These results indicate that the noradrenaline appearance rate provides the better approximation of changes in forearm neuronal noradrenaline release in response to stimuli which alter local blood flow.

The 'adrenaline hypothesis' of hypertension revisited: evidence for adrenaline release from the heart of patients with essential hypertension.

Whether adrenaline acts as a sympathetic nervous cotransmitter in humans and stimulates beta2-adrenoceptors to augment neuronal noradrenaline release remains a subject of considerable dispute. The aim of this study was to test if adrenaline is released from regional sympathetic nerves (in the heart) in patients with essential hypertension, and to investigate whether locally released adrenaline might enhance cardiac noradrenaline release. Using dual isotope dilution methodology, adrenaline and noradrenaline plasma kinetics was measured for the whole body and in the heart in 13 untreated patients with essential hypertension and 27 healthy volunteers. All research participants underwent cardiac catheterization under resting conditions. At rest, there was negligible adrenaline release from the sympathetic nerves of the heart in healthy subjects, 0.27 +/- 1.62 ng/min. In contrast, in patients with essential hypertension, adrenaline was released from the heart at a rate of 1.46 +/- 1.73 ng/min, equivalent on a molar basis to approximately 5% of the associated cardiac noradrenaline spillover value. Cardiac noradrenaline spillover was higher in hypertensive patients, 24.9 +/- 17.0 ng/min compared to 15.4 +/- 11.7 ng/min in healthy volunteers (P< 0.05). Among patients, rates of cardiac adrenaline and noradrenaline spillover correlated directly (r= 0.59, P< 0.05). This study, in demonstrating release of adrenaline from the heart in patients with essential hypertension, and in disclosing a proportionality between rates of cardiac adrenaline and noradrenaline release, provides perhaps the most direct evidence to date in support of the 'adrenaline hypothesis' of essential hypertension.

Neural mechanisms in human obesity-related hypertension.

Two hypotheses concerning mechanisms of weight gain and of blood pressure elevation in obesity were tested. The first hypothesis is that in human obesity sympathetic nervous system underactivity is present, as a metabolic basis for the obesity. The second hypothesis, attributable to Landsberg, is that sympathetic nervous activation occurs with chronic overeating, elevating blood pressure. These are not mutually exclusive hypotheses, since obesity is a heterogeneous disorder. Whole body and regional sympathetic nervous system activity, in the kidneys and heart, was measured at rest using noradrenaline isotope dilution methodology in a total of 86 research voluteers in four different subject groups, in lean and in obese people who either did, or did not, have high blood pressure. In the lean hypertensive patients, noradrenaline spillover for the whole body, and from the heart and kidneys was substantially higher than in the healthy lean volunteers. In normotensive obesity, the whole body noradrenaline spillover rate was normal, mean renal noradrenaline spillover was elevated (twice normal), and cardiac noradrenaline spillover reduced by approximately 50%. In obesity-related hypertension, there was elevation of renal noradrenaline spillover, comparable to that present in normotensive obese individuals but not accompanied by suppression of cardiac noradrenaline spillover, which was more than double that of normotensive obese individuals (P<0.05), and 25% higher than in healthy volunteers. There was a parallel elevation of heart rate in hypertensive obese individuals. The sympathetic underactivity hypothesis of obesity causation now looks untenable, as based on measures of noradrenaline spillover, sympathetic nervous system activity was normal for the whole body and increased for the kidneys; the low sympathetic activity in the heart would have only a trifling impact on total energy balance. The increase in renal sympathetic activity in obesity may possibly be a necessary cause for the development of hypertension in obese individuals, although clearly not a sufficient cause, being present in both normotensive and hypertensive obese individuals. The discriminating feature of obesity-related hypertension was an absence of the suppression of the cardiac sympathetic outflow seen in normotensive obese individuals. Sympathetic nervous changes in obesity-related hypertension conformed rather closely to those expected from the Landsberg hypothesis.

Hypoglycemia per se stimulates sympathetic neural as well as adrenomedullary activity, but, unlike the adrenomedullary response, the forearm sympathetic neural response is not reduced after recent hypoglycemia.

We tested the hypotheses that 1) hypoglycemia per se stimulates the sympathetic neural as well as the adrenomedullary component of the sympathochromaffin system, and 2) sympathetic neural responses to hypoglycemia, like adrenomedullary responses, are reduced after recent hypoglycemia. To this end, we studied 10 healthy young adults on 2 consecutive days on two separate occasions, on one occasion with euglycemia (5.0 mmol/l) and on the other occasion with hypoglycemia (2.8 mmol/l) from 1000 to 1200 and 1400 to 1600 on day 1 of each occasion. On day 2 of each occasion, plasma epinephrine and norepinephrine (NE) concentrations and rates of systemic NE spillover (SNESO) and forearm NE spillover (FNESO) were measured during hyperinsulinemic (12.0 pmol x kg(-1) x min(-1)) euglycemia (5.0 mmol/l) and hypoglycemia (2.8 mmol/l). Compared with values during euglycemia, plasma epinephrine and NE and rates of SNESO and FNESO all increased during hypoglycemia (P < 0.01). After day 1 hypoglycemia, there were reductions during hypoglycemia on day 2 in plasma epinephrine (2,050 +/- 500 vs. 2,960 +/- 400 pmol/l; P < 0.02), plasma NE (1.35 +/- 0.16 vs. 1.92 +/- 0.20 nmol/l; P < 0.01), and SNESO rates (5.13 +/- 0.84 vs. 6.87 +/- 0.81 nmol/min; P < 0.02). However, FNESO rates were unaltered (1.16 +/- 0.25 vs. 1.27 +/- 0.17 pmol x min(-1) x 100 ml tissue(-1). Thus we conclude that 1) hypoglycemia per se stimulates both the sympathetic neural and adrenomedullary components of the sympathochromaffin system and 2) adrenomedullary, but not forearm sympathetic neural, responses to hypoglycemia are reduced after recent hypoglycemia. The extent to which the lower plasma NE levels and reduced SNESO responses to hypoglycemia after day 1 hypoglycemia reflect reduced NE release from the adrenal medullae, sympathetic nerves other than those in the forearm, or both cannot be determined from these data.

Antiadrenergic effect of chronic amiodarone therapy in human heart failure

OBJECTIVESThe aim of the present study was to evaluate the influence of amiodarone on neurochemical parameters of sympathetic nervous activity in patients with congestive heart failure.BACKGROUNDUnlike most antiarrhythmic agents, amiodarone has been shown to exert a beneficial effect on survival in some studies of patients with congestive heart failure. The pharmacology of this agent is complex, and as such, the mode of its action is unclear in humans. Some experimental studies suggest that amiodarone exerts a sympatholytic effect.METHODSTo evaluate the effect of amiodarone on sympathetic nervous activity, we measured the total systemic and cardiac norepinephrine (NE) spillover rate by isotope dilution in 58 patients with severe heart failure (left ventricular ejection fraction 20 ± 1%), 22 of whom were receiving chronic amiodarone treatment. Release rates for dihydroxyphenylalanine (DOPA, a precursor of NE), and endogenous and radiolabeled dihydroxyphenylglycol (DHPG and 3H-DHPG, intraneuronal metabolites of NE and 3H-NE, respectively) were also determined to assess sympathetic neuronal integrity.RESULTSAmiodarone-treated patients had significantly lower cardiac spillover rates for NE (42%, p = 0.001), DOPA (74%, p < 0.001), DHPG (44%, p < 0.01) and 3H-DHPG (51%, p < 0.01) than those patients not treated with amiodarone. Hemodynamic assessment of amiodarone-treated patients revealed higher cardiac output (4.4 ± 0.2 vs. 3.7 ± 0.2 liters/min, p < 0.01), and slightly lower pulmonary capillary wedge pressure (18 ± 2 vs. 22 ± 1, p = NS) than in untreated patients. After correction for the potential confounding effect of hemodynamic differences, amiodarone-treated patients continued to demonstrate significantly lower spillover rates of NE, DOPA and DHPG from the heart.CONCLUSIONSThese data indicate that amiodarone may exert beneficial effects on the failing human heart through a sympatholytic process, and this action appears to be relatively cardioselective.

Forearm norepinephrine spillover during standing, hyperinsulinemia, and hypoglycemia.

Plasma norepinephrine (NE) concentrations are a fallible index of sympathetic neural activity because circulating NE can be derived from sympathetic nerves, the adrenal medullas, or both and because of regional differences in sympathetic neural activity. We used isotope dilution measurements of systemic and forearm NE spillover rates (SNESO and FNESO, respectively) to study the sympathochromaffin system during prolonged standing, hyperinsulinemic euglycemia, and hyperinsulinemic hypoglycemia in healthy humans. Prolonged standing led to decrements in blood pressure without increments in heart rate, the pattern of incipient vasodepressor syncope. FNESO was not increased (0.58 +/- 0.20 to 0. 50 +/- 0.21 pmol. min-1. 100 ml tissue-1), suggesting that the approximately twofold increments in plasma NE and SNESO were derived from sympathetic nerves other than those in the forearm (with a possible contribution from the adrenal medullas). Hyperinsulinemia per se (euglycemia maintained) stimulated sympathetic neural activity, as evidenced by increments in FNESO (0.57 +/- 0.11 to 1.25 +/- 0.25 pmol. min-1. 100 ml tissue-1, P < 0.05), but not adrenomedullary activity. Hypoglycemia per se stimulated adrenomedullary activity (plasma epinephrine from 190 +/- 70 to 1720 +/- 320, pmol/l, P < 0.01). Although SNESO (P < 0.05) and perhaps plasma NE (P < 0.06) were raised to a greater extent during hyperinsulinemic hypoglycemia than during hyperinsulinemic euglycemia, FNESO was not. Thus these data do not provide direct support for the concept that hypoglycemia per se also stimulates sympathetic neural activity.

Whole body, adipose tissue, and forearm norepinephrine kinetics in lean and obese women

We evaluated whole body and regional (subcutaneous abdominal adipose tissue and forearm) norepinephrine (NE) kinetics in seven lean (body mass index 21.3 +/- 0.5 kg/m2) and six upper body obese (body mass index 36.4 +/- 0.4 kg/m2) women who were matched on fat-free mass. NE kinetics were determined by infusing [3H]NE and obtaining blood samples from a radial artery, a deep forearm vein draining mostly skeletal muscle, and an abdominal vein draining subcutaneous abdominal fat. Mean systemic NE spillover tended to be higher in obese (2.82 +/- 0.49 nmol/min) than in lean (2.53 +/- 0.40 nmol/min) subjects, but the differences were not statistically significant. Adipose tissue and forearm NE spillover rates into plasma were greater in lean (0.91 +/- 0.08 pmol. 100 g tissue-1. min-1 and 1.01 +/- 0.09 pmol. 100 ml tissue-1. min-1, respectively) than in obese (0.26 +/- 0.05 pmol. 100 g tissue-1. min-1 and 0.58 +/- 0.11 pmol. 100 ml tissue-1. min-1, respectively) subjects (P < 0.01). These results demonstrate that adipose tissue is an active site for NE metabolism in humans. Adipose tissue NE spillover is considerably lower in obese than in lean women, which may contribute to the lower rate of lipolysis per kilogram of fat mass observed in obesity.

Sympathetic Activity in Patients With Panic Disorder at Rest, Under Laboratory Mental Stress, and During Panic Attacks

The sympathetic nervous system has long been believed to be involved in the pathogenesis of panic disorder, but studies to date, most using peripheral venous catecholamine measurements, have yielded conflicting and equivocal results. We tested sympathetic nervous function in patients with panic disorder by using more sensitive methods. Sympathetic nervous and adrenal medullary function was measured by using direct nerve recording (clinical microneurography) and whole-body and cardiac catecholamine kinetics in 13 patients with panic disorder as defined by the DSM-IV, and 14 healthy control subjects. Measurements were made at rest, during laboratory stress (forced mental arithmetic), and, for 4 patients, during panic attacks occurring spontaneously in the laboratory setting. Muscle sympathetic activity, arterial plasma concentration of norepinephrine, and the total and cardiac norepinephrine spillover rates to plasma were similar in patients and control subjects at rest, as was whole-body epinephrine secretion. Epinephrine spillover from the heart was elevated in patients with panic disorder (P=.01). Responses to laboratory mental stress were almost identical in patient and control groups. During panic attacks, there were marked increases in epinephrine secretion and large increases in the sympathetic activity in muscle in 2 patients but smaller changes in the total norepinephrine spillover to plasma. Whole-body and regional sympathetic nervous activity are not elevated at rest in patients with panic disorder. Epinephrine is released from the heart at rest in patients with panic disorder, possibly due to loading of cardiac neuronal stores by uptake from plasma during surges of epinephrine secretion in panic attacks. Contrary to popular belief, the sympathetic nervous system is not globally activated during panic attacks.

Angiotensin converting enzyme inhibition improves baroreflex-induced noradrenaline spillover responses in rabbits with heart failure

Impaired baroreflex function is a characteristic feature of congestive heart failure (CHF), although the mechanism is obscure. This study examined the hypothesis that activation of the renin–angiotensin system contributes to baroreflex dysfunction in CHF. The acute effects of an angiotensin converting enzyme inhibitor, enalaprilat, on baroreflex-mediated changes in heart rate (HR), total and renal noradrenaline (NA) spillover rates were examined in conscious rabbits with doxorubicin-induced cardiomyopathic CHF. Studies were performed under resting conditions and in response to changes in mean arterial pressure (MAP) induced by sodium nitroprusside and phenylephrine infusions. Seven saline-treated (normal group) and 11 doxorubicin-treated rabbits (1 mg/kg administered intravenously twice weekly) were studied after 4 and 6 weeks' treatment. Five CHF rabbits received saline (C group) and 6 enalaprilat infusion (ACEI group) during each study period. After 4 weeks of doxorubicin, baroreflex-HR responses were normal, whereas baroreflex-NA spillover responses were enhanced. Enalaprilat infusion shifted the HR–MAP curve downwards to the left but had no effect on the NA spillover–MAP curves. After 6 weeks of doxorubicin, when CHF was established, baroreflex-HR and NA spillover curves were depressed. At this stage, enalaprilat had little effect on the HR–MAP curve but restored towards normal the NA spillover–MAP curves. The results suggest that the endogenous renin–angiotensin system contributes to attenuated baroreflex responses when CHF is established.

Long-term beta 1-adrenergic blockade restores adrenomedullary activity in primary hypertension.

In this study we examined the effects of long-term treatment of 19 patients with primary hypertension with the beta 1-adrenoceptor antagonist atenolol on norepinephrine and epinephrine kinetics, at rest and during sympathoadrenal stimulation by lower body negative pressure. Norepinephrine and epinephrine kinetics were measured by using the radioisotope-dilution technique by steady-state infusion of tritiated norepinephrine and epinephrine. The patients were studied before and at the end of 3 months of treatment with atenolol (50 or 100 mg daily). A control group of four normotensive subjects was studied before and after 3 months without any drug treatment. In this group, only arterial blood samples were collected without infusion of the tritiated catecholamines. Atenolol decreased blood pressure and heart rate, but forearm vascular resistance was not affected by atenolol. During atenolol, baseline arterial plasma epinephrine decreased from 0.23 +/- 0.02 to 0.17 +/- 0.01 nM (p < 0.05), and this was accompanied by a decrease in total body epinephrine spillover from 0.50 +/- 0.05 to 0.35 +/- 0.04 nmol/min (p < 0.05). In the control group, arterial plasma epinephrine had not decreased after 3 months. In addition, the increment of arterial plasma epinephrine during lower body negative pressure at -40 mm Hg was attenuated during atenolol. Atenolol had no effect on total body and forearm norepinephrine spillover rates, either at rest or during lower body negative pressure. Clearance rates of epinephrine and norepinephrine were not significantly affected by atenolol. These results suggest that treatment of patients with primary hypertension with the beta 1-adrenoceptor blocker atenolol inhibits the adrenomedullary secretion of epinephrine, but it does not affect the biochemical indices of sympathoneural activity. It remains speculative whether this selective effect of atenolol on epinephrine secretion contributes to its hypotensive action and to its cardioprotective effects in the long term.