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Biomedical subjects

M D Esler

Publications and source records attributed to M D Esler.

At least 73 records · Page 4Linked to original sources
PubMed1995

Fallibility of plasma noradrenaline measurements in studying postprandial sympathetic nervous responses.

The use of the plasma noradrenaline (NA) concentration as an index of sympathetic nervous system (SNS) activity in the postprandial state is associated with several problems: (i) It does not take into account the contribution of alterations in clearance to the plasma NA level, (ii) when antecubital venous blood is sampled, it reflects regional forearm rather than whole body SNS activity and (iii) no insight is gained into the regional pattern of SNS activation. These potential confounders were addressed in this study performed in 17 healthy young men. The validity of plasma NA measurements in assessing postprandial changes in sympathetic nervous activation was evaluated in relation to that of whole body and regional plasma NA spillover, derived using isotope dilution methodology. Plasma clearance of NA is significantly altered following a meal, with a transient elevation in the early postprandial phase which may lead to an underestimation of SNS activation when assessed from arterial plasma NA levels. Forearm plasma NA spillover increases postprandially, such that despite significant postprandial elevations in arterial plasma NA, the plasma arterial contribution to antecubital venous plasma NA levels is maintained at less than 40%, the rest being derived locally from the forearm. This makes venous plasma samples unsuitable for the assessment of SNS activation in organs and vascular sites distant from the sampling site. The kidneys and skeletal muscle are the major regional sites of postprandial sympathetic nervous activation, while cardiac plasma NE spillover is unaltered postprandially. This regional pattern of SNS activation postprandially must be taken into account when relating increments in plasma NA levels to specific physiological events.

Adolescent↗
PubMed1995

Regional origins of 3-methoxy-4-hydroxyphenylglycol in plasma: effects of chronic sympathetic nervous activation and denervation, and acute reflex sympathetic stimulation.

The plasma level and urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), the principal metabolite of noradrenaline in the brain, are often used as indicators of central nervous system noradrenergic activity. Using percutaneously placed catheters, we studied the regional inputs into the plasma MHPG pool in 62 healthy volunteers. Veno-arterial plasma concentration differences and regional organ blood flows were used to quantify the relative amounts of MHPG contributed by various sites into plasma. Positive veno-arterial concentration gradients were found across the forearm, cardiac and jugular vessels in the healthy subjects. By far the majority of MHPG in plasma was derived from skeletal muscle, 5.3 +/- 1.8 nmol/min, with only minimal contribution (0.9 +/- 0.2 nmol/min) from the brain. Thus, to obtain an accurate indication of central nervous system noradrenergic activity the confounding influences of regional MHPG production must be excluded. 34 patients with chronic congestive heart failure, 6 patients with pure autonomic failure and 9 recent heart transplant recipients were used to investigate the possible effects of chronic sympathetic nervous system overactivity and sympathetic underactivity and denervation on peripheral MHPG production and plasma MHPG concentration. To examine the utility of plasma MHPG determinations as an indicator of acute alterations in sympathetic nervous activity we examined the influence of a variety of laboratory stressors on the arterial level and cardiac production of MHPG. The resting arterial plasma MHPG concentration mirrored sympathetic function in the patients with cardiac failure (sympathetic activation) and pure autonomic failure (sympathetic denervation), with mean MHPG plasma concentrations being 180 and 40% of those in healthy subjects. Cardiac MHPG production was increased in heart failure patients, and near zero with the cardiac sympathetic denervation accompanying transplantation and pure autonomic failure. In contrast, acute reflex stimulation of sympathetic nervous activity was not associated with parallel changes in the arterial level or cardiac production of MHPG. Measurements of peripheral plasma MHPG levels provide an index of prevailing sympathetic nervous function in clinical models of sympathetic overactivity and denervation, but are insensitive to acute sympathetic nervous system responses.

Adrenergic Uptake Inhibitors↗
PubMed1995

Total norepinephrine spillover, muscle sympathetic nerve activity and heart-rate spectral analysis in a patient with dopamine beta-hydroxylase deficiency.

Dopamine-beta-hydroxylase (D beta H) is the enzyme responsible for intraneural conversion of dopamine to norepinephrine. Its deficiency results in failure of norepinephrine synthesis, excessive dopamine release and orthostatic hypotension. We studied a young patient with this deficiency using the currently available methods to assess sympathetic function namely measurement of norepinephrine kinetics, microneurography to assess muscle sympathetic nerve activity (MSNA), and heart-rate spectral analysis. We compared these findings with those in 24 young healthy controls, and 4 patients with peripheral autonomic failure (PAF). Recordings were made in our subject before and after 5 months of treatment with L-threo-3,4-dihydroxyphenylserine (DOPS) (which is converted directly into L-norepinephrine bypassing the D beta H enzymatic step); measurements were made at rest in the supine position and after 15 min of 30 degrees head-up tilt. Our subject with D beta H deficiency had a high resting nerve firing rate (40.3 bursts/min) compared with the mean value in normal controls (19.3 bursts/min), and an appropriate increase in nerve firing rate during tilt. Total body norepinephrine spillover at rest was very low, 38 ng/min, compared with age-matched normals (519 +/- 43.3 ng/min, mean +/- SEM), and epinephrine secretion was undetectable. Conversely, the plasma concentrations of dopamine, DOPAC, HVA and DOPA were raised. At rest, low-frequency heart-rate variability (0.1 Hz) was absent with preservation of the respiratory-related high-frequency peak. In contrast, the PAF subjects had no detectable muscle sympathetic nerve activity, very low levels of norepinephrine spillover and epinephrine secretion and a reduction in heart rate variability at all frequencies. After 5 months treatment with L-threo-3,4-dihydroxyphenylserine (DOPS) in the D beta H deficiency patient there was a dramatic clinical improvement with resolution of the orthostatic symptoms, dramatic reduction in MSNA activity at rest, and return of plasma norepinephrine, norepinephrine spillover, DHPG and MHPG to within the normal range, indicating intraneuronal production of norepinephrine.

Adolescent↗
PubMed1995

Adverse consequences of high sympathetic nervous activity in the failing human heart.

OBJECTIVES: In view of previous experimental evidence relating sympathetic nervous overactivity in the heart to myocardial necrosis and ventricular arrhythmias, we prospectively examined the hypothesis that heightened cardiac sympathetic nervous activity is associated with an adverse outcome in patients with moderate to severe heart failure. BACKGROUND: Despite recent therapeutic advances, patients with heart failure continue to have high mortality from progressive hemodynamic decompensation and lethal ventricular arrhythmias. It is believed that initially compensatory increases in sympathetic nervous system activity may ultimately be maladaptive, potentially contributing to subsequent adverse events. METHODS: Sixty patients with moderate to severe heart failure (left ventricular ejection fraction 18.9 +/- 0.9% [mean +/- SE]) were studied prospectively. In addition to the compilation of a hemodynamic, biochemical and electrocardiographic profile for each patient, whole-body and cardiac sympathetic activity were determined by isotope dilution. The relation of these variables to outcome was determined by Cox proportional hazards analysis. RESULTS: The mean follow-up period of the study group was 7 +/- 1 months (range 1 to 24) with a 12-month actuarial survival of 75%. Deaths (14 in all) were accounted for either by sudden death or progressive heart failure in equal numbers. The rate of release of norepinephrine from the heart was significantly higher in patients with heart failure than in healthy subjects (402 +/- 37 vs. 105 +/- 19 pmol/min, p < 0.01), although the values for heart failure ranged widely from normal to 10 times normal. By univariate Cox proportional hazards analysis, pulmonary capillary wedge pressure (p < 0.01), mean pulmonary artery pressure (p < 0.001), serum sodium levels (p < 0.01) and cardiac norepinephrine spill-over rate (p < 0.001) were identified as significant prognostic markers. In a multivariate analysis, cardiac norepinephrine spillover rate was identified as the most powerful prognostic marker (p = 0.0006) of those evaluated in this study. CONCLUSIONS: These results suggest that activation of the sympathetic nervous system in patients with heart failure, specifically the cardiac sympathetic nerves, may contribute to the poor prognosis associated with severe heart failure. The data therefore provide a rationale for the use of drugs such as beta-adrenergic blocking agents in the management of patients with heart failure.

Adult↗
PubMed1995

Increased central nervous system monoamine neurotransmitter turnover and its association with sympathetic nervous activity in treated heart failure patients.

BACKGROUND: Congestive heart failure is a debilitating disease characterized by impaired cardiac function with accompanying activation of a variety of neural and hormonal counter-regulatory systems. Abnormal activity of the sympathetic nervous system and renin-angiotensin-aldosterone axis and a predisposition to the generation of fatal ventricular arrhythmias are often associated with the development of the disease. Although the underlying cause of sudden death in these patients remains to be unequivocally elucidated, abnormally increased cardiac sympathetic nervous activity may be involved. METHODS AND RESULTS: Twenty-two patients with severe congestive heart failure (New York Heart Association functional class III or IV with left ventricular ejection fraction of 18 +/- 1%) and 29 healthy male volunteers participated in this study. By combining direct sampling of internal jugular venous blood via a percutaneously placed catheter with a norepinephrine and epinephrine isotope dilution method for examining neuronal transmitter release, we were able to quantify the release of central nervous system monoamine and indoleamine neurotransmitters and investigate their association with the increased efferent sympathetic outflow that is variably present in treated patients with this condition. Mean cardiac norepinephrine spillover was 145% higher in treated heart failure patients than in healthy subjects (P < .05), with norepinephrine release from the heart in 6 of 22 patients being more than the highest control value. Raised internal jugular venous spillover of epinephrine (26 +/- 12 versus 2 +/- 4 pmol/min, P < .05) and of norepinephrine and its metabolites (2740 +/- 480 versus 875 +/- 338 pmol/min, P < .05), indicative of increased central nervous system turnover of both catecholamines, occurred in cardiac failure and was quantitatively linked to the degree of activation of the cardiac sympathetic nervous outflow, as was the jugular overflow of the principal serotonin metabolite, 5-hydroxyindoleacetic acid. CONCLUSIONS: An association between the degree of activation of central monoaminergic neurons and the level of sympathetic nervous tone in the heart was identified in treated patients with heart failure. Epinephrine neurons in the brain may contribute to the sympathoexcitation that is seen in this condition, with the activation of sympathoexcitatory noradrenergic neurons, most likely those of the forebrain, playing an accessory role.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Effects of aging on the responsiveness of the human cardiac sympathetic nerves to stressors.

BACKGROUND: Aging increases human sympathetic nervous activity at rest. Beause of the probable importance of neural stress responses in the heart as triggers for clinical end points of coronary artery disease, it is pertinent to investigate whether sympathetic nervous responses to stresses are increased by aging. METHODS AND RESULTS: We applied kinetic methods for measuring the fluxes to plasma of neurochemicals relevant to sympathetic neurotransmission in younger (aged 20 to 30 years) and older (aged 60 to 75 years) healthy men during mental stress (difficult mental arithmetic), isometric exercise (sustained handgrip), and dynamic exercise (supine cycling). The increase in total norepinephrine spillover to plasma with mental stress was unaffected by age. In contrast, the increase in cardiac norepinephrine spillover was two to three times higher in the older subjects (P < .05). The probable mechanism of this higher cardiac norepinephrine spillover was reduced neuronal reuptake of the transmitter, because age had no influence on the overflow of the norepinephrine precursor, dihydroxyphenylalanine, or intraneuronal metabolite, dihydroxyphenylglycol (levels of these two substances reflect rates of cardiac norepinephrine synthesis and intraneuronal metabolism), and the transcardiac extraction of plasma radiolabeled norepinephrine was lower in the older subjects (P < .05). An almost identical pattern of neurochemical response was seen with isometric exercise. During cycling, total norepinephrine spillover was 16% lower in the older men, but cardiac norepinephrine spillover was 53% higher. CONCLUSIONS: Reduced norepinephrine reuptake increases the overflow of the neurotransmitter to plasma from the aging heart during stimulation of the cardiac sympathetic outflow. Failure of transmitter inactivation at postjunctional receptors with aging would amplify the neural signal, and in the presence of myocardial disease could trigger adverse stress-induced cardiovascular events, particularly when accompanied by an age-dependent reduction in vagal tone. Reduction of postsynaptic adrenergic responsiveness with aging, however, might protect against this, as indicated by our finding that in no case was the heart rate increase during stress greater in older men, despite their having larger increases in cardiac norepinephrine spillover.

Adult↗
PubMed1995

Sympatholytic action of intravenous amiodarone in the rat heart.

BACKGROUND: Amiodarone is a commonly used antiarrhythmic agent with complex pharmacological effects. Although ventricular arrhythmias can be suppressed soon after intravenous amiodarone, the mechanisms responsible for this action are unclear. We studied the effects of acute treatment with amiodarone on the metabolism and release of norepinephrine (NE) in intact rats and in perfused rat hearts. METHODS AND RESULTS: Experiments were performed in anesthetized rats and in perfused, innervated hearts with amiodarone administered intravascularly. NE release was induced by electrical stimulation of the sympathetic ganglion. Concentrations of NE and its intraneuronal metabolite dihydroxyphenylglycol (DHPG) in hearts, plasma, and coronary venous effluent were measured by high-performance liquid chromatography. Acute administration of amiodarone induced dose-dependent increases in DHPG concentrations in plasma (5 mg/kg, +48%; 15 mg/kg, +84%; and 50 mg/kg, +467%) and in coronary venous effluent (1 mumol/L, +37%; 3 mumol/L, +510%; and 10 mumol/L, +1100%) together with an unchanged basal overflow of NE. In perfused hearts, NE release evoked by nerve stimulation was inhibited by infusion of amiodarone (1 mumol/L, -16%; 3 mumol/L, -24%; and 10 mumol/L, -64%) or by intravenous amiodarone (50 mg/kg) given 1 hour before heart perfusion (-70%), and the extent of this suppression correlated well with levels of DHPG overflow present immediately before nerve stimulation. When given in vitro and in vivo, amiodarone also significantly reduced NE and increased DHPG content in the heart, leading to a raised DHPG/NE ratio. All these effects of amiodarone were similar to those found with reserpine but less potent. In contrast, oral amiodarone produced none of these effects. CONCLUSIONS: Acute administration of amiodarone in perfused hearts or intact rats induces partial NE depletion in the heart by interfering with vesicular NE storage and enhancing intraneuronal NE metabolism, effects associated with an impaired NE release during sympathetic activation. Oral dosing with amiodarone has no such effect. Further study is required to test whether this novel sympatholytic effect of amiodarone contributes to its antiarrhythmic action after intravenous administration.

Administration, Oral↗
PubMed1995

Central nervous system noradrenergic and dopaminergic turnover in response to acute neuroleptic challenge.

The objective of this study was to obtain direct neurochemical measures of the central nervous system's response to a typical neuroleptic, haloperidol, in human subjects. Nine healthy volunteers participated in this study. Central nervous system neuronal activity was assessed by measuring the plasma concentration and overflow from the brain of dopamine, norepinephrine, and their lipophilic and acidic metabolites after acute intravenous administration of haloperidol. By combining bilateral internal jugular vein blood sampling with cerebral blood flow scans we were able to differentiate between cortical and subcortical responses to haloperidol. The central nervous system response to haloperidol administration displayed a degree of regional specificity. Dopamine release, estimated from the overflow of homovanillic and dihydroxyphenylacetic acids, was reduced in cortical but not subcortical brain regions. Norepinephrine turnover was increased in cortical and subcortical brain regions. The overflow of homovanillic acid from the brain into the internal jugular veins was not related quantitatively to the arterial plasma concentrations of the catecholamines examined, homovanillic and dihydroxyphenylacetic acids or prolactin. Measurements of catecholamines and their metabolites in arterial plasma gave little indication as to monoaminergic neuronal activity in the brain.

Adolescent↗
PubMed1995

Regional 5-hydroxyindoleacetic acid production in humans.

Veno-arterial plasma concentration differences and regional organ plasma flows were used to quantify the relative amounts of 5-hydroxyindoleacetic acid (5-HIAA) contributed by various sites into the peripheral circulation. Positive venoarterial concentration gradients were found in the hepatosplanchnic, forearm, cardiac and jugular vessels in the healthy subjects. The renal circulation was determined to be the principal site of 5-HIAA clearance, extracting 18 +/- 2 nmol/min. The gut was the greatest contributor to the total 5-HIAA plasma pool with the relative contributions of the various organs being as follows: hepatosplanchnic organs 58%, skeletal muscle 26%, brain 6% and the heart 3%. The source of 5-HIAA stemming from these regional beds remains unknown, it may derive from serotonin taken up by and deaminated in ubiquitous endothelial cells, enterochromaffin cells of the gut, peripheral serotonergic nerves, serotonin turnover in platelets or perhaps the metabolism of serotonin taken up by sympathetic nerves. To test the latter hypothesis we examined 23 patients with chronic congestive heart failure and 9 patients with pure autonomic failure to investigate the possible effects of sympathetic nervous system overactivity and underactivity on peripheral 5-HIAA production and plasma 5-HIAA concentration. The resting arterial plasma 5-HIAA concentration in the heart failure patients was increased three-fold. This elevated plasma 5-HIAA concentration was attributable to an increased rate of whole body 5-HIAA production. The arterial 5-HIAA plasma concentration in the autonomic failure patients was paradoxically elevated, being 70% greater than that of the healthy subjects. The increased 5-HIAA plasma concentration in these patients was accounted for by a reduction in 5-HIAA plasma clearance. In all subjects studied there was a weak relationship only between total body norepinephrine spillover to plasma and the arterial 5-HIAA plasma concentration. We found that in healthy subjects the overflow of 5-HIAA into the hepatic vein was significantly related to the underlying degree of sympathetic activity. It can be concluded that 5-HIAA is produced at a number of sites throughout the body with the arterial plasma concentration being dependent on both the level of production and plasma clearance. By far the majority of 5-HIAA in plasma is derived from the gut with only minimal contribution from the brain.

Adolescent↗
PubMed1995

Regional sympathetic nervous activation after a large meal in humans.

1. To investigate the link between post-prandial thermogenesis and sympathetic nervous activation we have studied the effects of a single large meal on regional sympathetic nervous activity in healthy, lean subjects. 2. In nine male subjects, noradrenaline spillover was measured from the heart, kidney and liver using isotope dilution, both while fasting and after consumption of a high-energy liquid meal of composition 53% carbohydrate, 32% fat and 15% protein (energy value 2.64-3.51 MJ). Regional oxygen consumption, whole-body oxygen consumption and, in a subset of subjects, muscle sympathetic nerve firing (microneurography) were also measured. 3. Both whole-body oxygen consumption (P < 0.03) and total body spillover of noradrenaline (P < 0.01) rose after the meal, with peak increases of 24% and 56% respectively. Spillover of noradrenaline from the heart was unchanged, that from the hepatosplanchnic circulation increased marginally (0.377 nmol/min to 0.480 nmol/min, P = 0.09), while renal noradrenaline spillover more than doubled (0.440 nmol/min to 0.937 nmol/min, P < 0.05). Skeletal muscle sympathetic nerve activity (peroneal nerve) increased from 7.7 bursts/min at rest to peak at 17.9 bursts/min 60 min after the meal in the three subjects in whom stable recordings were obtained. 4. The meal increased oxygen consumption in the kidneys and liver significantly, from 11.5 +/- 1.6 ml/min to 14.5 +/- 1.1 ml/min and from 46 +/- 7 ml/min to 57 +/- 6 ml/min respectively (P < 0.05), but not in the heart. 5. Consumption of a large meal produces a substantial and relatively selective increase in sympathetic outflow to the kidneys and skeletal muscle. While resting regional oxygen consumptions and noradrenaline spillovers were related, the changes that occurred in each were unrelated, so that no direct relationship could be demonstrated between postprandial thermogenesis and sympathetic activity.

Adolescent↗
PubMed1995

Regional epinephrine kinetics in human heart failure: evidence for extra-adrenal, nonneural release.

A number of neurohumoral processes are activated in heart failure, including an increase in the plasma concentration of epinephrine. Radiotracer methods were applied in 42 patients with severe heart failure and 31 healthy volunteers to ascertain the rate at which epinephrine is released to plasma and to evaluate the contribution of extra-adrenal sources. The increase in arterial plasma epinephrine observed in the heart failure patients was explained principally by a 34% (P < 0.001) reduction in the whole body clearance rate of epinephrine from plasma. Regional venous sampling from the heart, lungs, and hepatomesenteric beds was performed in a subgroup of the study population, revealing a significant increase in the release rate of epinephrine to plasma from these organs in heart failure which accounted for 26% of the whole body plasma epinephrine appearance rate. To establish whether the cardiac epinephrine release was of neuronal origin, a physical (cycling) or mental (difficult mental arithmetic) stressor was applied as a sympathoexcitatory stimulus, given that a proportional release of norepinephrine and epinephrine could be expected if sympathetic nerves were the source. These interventions caused significant increases in the regional spillover of norepinephrine to plasma but not that of epinephrine. These findings suggest that nonadrenal tissues contribute significantly to the whole body epinephrine release rate in heart failure and that this may arise from a site other than sympathetic neurons.

Adrenal Glands↗
PubMed1995

Aging effects on human sympathetic neuronal function.

To study the effect of aging on human sympathetic nervous function, we applied kinetic methods for measuring the fluxes to plasma of neurochemicals relevant to sympathetic neurotransmission in younger (aged 20-30 yr) and older (aged 60-75 yr) healthy men. Mean plasma norepinephrine concentration was 66% higher in older men, attributable to 22% lower norepinephrine plasma clearance (P < 0.05) and 29% higher norepinephrine spillover to plasma (difference not statistically significant). Regional venous sampling disclosed that sympathetic outflow to all organs was not activated by aging. Renal norepinephrine spillover was normal in older men. Although spillover of norepinephrine from the heart was increased in older men, 21.1 +/- 11.4 ng/min compared with 11.4 +/- 8.6 ng/min (P < 0.05), diminished norepinephrine reuptake rather than increased cardiac sympathetic nerve firing was the most likely cause, although somewhat reduced intracardiac methylation of norepinephrine with aging also possibly contributed. The extraction of tritiated norepinephrine from plasma during transit through the heart was reduced, suggesting neuronal norepinephrine reuptake was lowered and overflow of the norepinephrine precursor dihydroxyphenylalanine and metabolites dihydroxyphenylglycol and 3-methoxy-4-hydroxy phenylglycol was normal, indicating that norepinephrine synthesis and release were not increased.

Adult↗
PubMed1994

Neurochemical evidence of cardiac sympathetic activation and increased central nervous system norepinephrine turnover in severe congestive heart failure.

OBJECTIVES: The aim of this study was to characterize cardiac sympathetic nervous function in patients with severe heart failure and to investigate the influence of the cause of heart failure, hemodynamic variables and central nervous system catecholamine release on cardiac sympathetic tone. BACKGROUND: Although heart failure is generally accompanied by sympathoexcitation, the integrity of cardiac sympathetic nerve function in heart failure remains controversial, particularly in relation to nerve firing activity and to the capacity of sympathetic nerves to recapture norepinephrine. Additionally, the location of the afferent and central neural pathways implicated in heart failure-induced sympathoexcitation remains unclear. METHODS: Radiotracer techniques were applied in 41 patients with severe heart failure and 15 healthy control subjects to study the biochemical aspects of whole body and cardiac sympathetic activity. Hemodynamic indexes of cardiac performance were measured in the heart failure group, and their association with sympathetic activity was studied. Jugular venous catechol spillover was measured to study the central noradrenergic control of sympathetic outflow. RESULTS: Sympathoexcitation was evident in the heart failure group, reflected by a 62% increase (p < 0.001) in total body and a 277% increase (p < 0.001) in cardiac norepinephrine spillover rates. These changes were accompanied by significant increases in the cardiac spillover of the norepinephrine precursor dihydroxyphenylalanine, the sympathetic cotransmitter neuropeptide Y and the extraneuronal metabolite 3-methoxy-4-hydroxyphenylglycol. The level of cardiac sympathetic activity was significantly correlated (r = 0.59, p < 0.001) with the mean pulmonary artery pressure. An increase in the spillover of dihydroxyphenylalanine and 3-methoxy-4-hydroxyphenylglycol from the brain was present, suggesting activation of central noradrenergic neurons. CONCLUSIONS: Cardiac sympathetic activation is present in severe heart failure, bearing a close relation with pulmonary artery pressures, independent of heart failure etiology. Activation of noradrenergic neurons in the brain is also present and may be the underlying central nervous mechanism of the sympathoexcitation observed in heart failure.

Brain↗
PubMed1994

Measurement of human sympathetic nervous responses to stressors by microneurography.

Human sympathetic nervous responses have been extensively studied using various stressors; however, there have been few comparisons of the patterns of sympathetic nervous activation which may be produced by different stressors. The purpose of this study was to explore whether different stressors produce differing degrees of sympathetic activation in muscle vasoconstrictor nerve fibres.

Adult↗
PubMed1994

The influence of aging on the plasma concentration and renal clearance of homovanillic acid.

Using percutaneously placed arterial and venous catheters, we examined the influence of aging on the plasma concentration, whole body production rate, and renal clearance of homovanillic acid (HVA) in 60 healthy adult volunteers. The arterio-renal fractional extraction of HVA combined with the renal plasma flow (Fick Principle) were used to estimate the whole body HVA production rate and the renal plasma HVA clearance. The arterial HVA plasma concentration, whole body rate of HVA production, and HVA plasma clearance were determined to be 54 +/- 3 nmol/l, 27 +/- 2 nmol/min and 502 +/- 32 ml/min, respectively. The resting arterial HVA plasma concentration was positively correlated with aging, with the increased HVA concentrations in the older subjects being due to a diminished renal HVA plasma clearance. The diminished clearance of HVA occurred in response to a decreased renal plasma flow; the fractional extraction of HVA across the kidney remained unchanged with aging. This study emphasises the need for using age-matched control groups in neurochemical and neuropsychiatric studies, and demonstrates that increases in the arterial level of HVA do not necessarily reflect an increased rate of HVA production but may arise due to a diminished excretion rate of HVA from the body.

Adolescent↗
PubMed1994

Heart rate spectral analysis, cardiac norepinephrine spillover, and muscle sympathetic nerve activity during human sympathetic nervous activation and failure.

BACKGROUND: Although heart rate variability (HRV) at 0.1 Hz has been proposed as a noninvasive clinical measure of cardiac sympathetic nerve firing, this premise has not been sufficiently validated by comparison with techniques such as microneurography and the measurement of norepinephrine spillover from the heart that more directly reflect presynaptic sympathetic activity. METHODS AND RESULTS: We compared the three techniques under conditions of effective cardiac sympathetic denervation, pure autonomic failure (n = 4), dopamine beta-hydroxylase deficiency (n = 1), and after cardiac transplantation (n = 9) as well as in the context of sympathetic nervous activation in cardiac failure (n = 15) and with aging (n = 10). Age-matched comparisons were made in each case with healthy individuals drawn from a pool of 52 volunteers. In pure autonomic failure and early after transplantation, cardiac norepinephrine spillover was negligible, and HRV was low. Late after transplantation, however, cardiac norepinephrine spillover returned to normal levels, and HRV remained low. In comparison to younger subjects (18 to 35 years old), older individuals (60 to 75 years old) had higher muscle sympathetic nerve activity (young, 22.9 +/- 1.9; old, 31.3 +/- 5.8 bursts per minute; P < .05) and cardiac norepinephrine spillover (young, 14.3 +/- 2.5; old, 20.1 +/- 3.0 ng/min; P < .05). In contrast, total HRV was reduced by 89%, and at 0.1 Hz it was reduced by 93% (P < .05). Cardiac failure was also characterized by elevated cardiac norepinephrine spillover (cardiac failure patients, 59 +/- 4; healthy volunteers, 18 +/- 3 ng/min; P < .01) but reduced 0.1 Hz HRV (cardiac failure patients, 49 +/- 17; healthy volunteers, 243 +/- 4 ms2; P < .05). CONCLUSIONS: HRV at 0.1 Hz depends on factors in addition to cardiac sympathetic nerve firing rates, including multiple neural reflexes, cardiac adrenergic receptor sensitivity, postsynaptic signal transduction, and electrochemical coupling, and is not directly related to cardiac norepinephrine spillover, which is a more direct measure of the sympathetic nerve firing rate.

Adolescent↗
PubMed1994

Monoaminergic neuronal activity in subcortical brain regions in essential hypertension.

In this study we aimed to elucidate the role of central noradrenergic, dopaminergic, adrenergic and serotonergic neuronal systems in the development of essential hypertension. Fifteen untreated essential hypertensive subjects (aged 44 +/- 3 years) and 32 healthy volunteers (aged 38 +/- 3 years) participated in this study. By combining direct blood sampling techniques with cerebral blood flow scans we were able to differentiate between cortical and subcortical venous drainage of the brain. Veno-arterial MHPG, HVA and 5-HIAA plasma concentration gradients combined with internal jugular vein plasma flows were used, according to the Fick Principle, to derive metabolite spillovers which in turn were used as indicators of central noradrenergic, dopaminergic and serotonergic neuronal activity, respectively. These amine systems, in both the brainstem and forebrain, have been implicated in the regulation of sympathetic outflow and blood pressure. Total body noradrenaline spillover to plasma was concurrently measured to assess the relationship between central monoamine turnover and sympathetic activity. Compared to their healthy counterparts the hypertensive subjects had an elevated release of MHPG from subcortical brain regions (1.4 +/- 0.3 v 0.5 +/- 0.2 nmol/min, p < 0.05). An inverse relationship between blood pressure and subcortical HVA overflow existed, with the HVA overflow being significantly lower in the hypertensives (0.5 +/- 0.2 v 2.1 +/- 0.5 nmol/min, p < 0.05). Subcortical 5-HUAA overflow did not differ between the two groups, and adrenaline spillover from the brain was not detected in either group. Subcortical MHPG overflow was significantly correlated with total body NA spillover to plasma (p < 0.05). These results indicate that reciprocal aberrations in subcortical noradrenaline and dopamine turnover exist in essential hypertension. Although the physiological significance of this remains to be unequivocally elucidated we postulate that elevated subcortical noradrenergic activity, presumably in the forebrain where noradrenergic neurons are pressor, may cause sympathoexcitation and play a role in the development of essential hypertension.

3,4-Dihydroxyphenylacetic Acid↗