PubMed Health⌕ Search

Biomedical subjects

H S Cox

Publications and source records attributed to H S Cox.

At least 19 recordsLinked to original sources
PubMed1999

Human obesity is associated with a chronic elevation in brain 5-hydroxytryptamine turnover.

The afferent signals that evoke changes in energy intake with regard to body weight regulation are presumed to arise partly from body stores, with the most likely candidate being adipose tissue depots. However, clinical investigation of the neuronal circuitry involved in the central nervous system's processing of such satiety signals remains largely unexplored. Using percutaneously placed catheters in either the right or left internal jugular veins, we were able to quantify the release of central nervous system monoamine and indoleamine neurotransmitters in 64 weight-stable male subjects with varying degrees of adiposity. Veno-arterial plasma concentration differences and internal jugular blood or plasma flow were used, according to the Fick Principle, to quantify the amount of neurotransmitter stemming from the brain. By combining this technique with a noradrenaline and adrenaline isotope dilution method for examining neuronal transmitter release, we were able to examine the association between central nervous system neurotransmitters and efferent sympathetic nervous outflow and adrenomedullary function in human obesity. We found that brain 5-hydroxytryptamine (serotonin) turnover is chronically elevated in proportion to adiposity and is increased postprandially to a similar degree in lean and obese individuals. There was no difference in the degree of sympathetic nervous activity or rate of adrenaline secretion in the subjects examined. It therefore seems that in human obesity, in the face of a chronic elevation in peripheral satiety signals, brain serotonergic processes are switched on accordingly, but the subsequent physiological response involving a reduction in food intake, increased thermogenesis and sympathetic activity is in some way impeded.

Adult↗
PubMed1999

Contribution of lungs to desipramine-induced changes in whole body catecholamine kinetics in newborn lambs.

To characterize pulmonary and total body norepinephrine and epinephrine kinetics in the immediate newborn period, the effects of desipramine were studied in six fetal lambs chronically instrumented at 133-134 days gestation (term 147 days) and delivered 1 wk later by cesarean section under spinal anesthesia. Norepinephrine and epinephrine kinetics were determined with isotope dilution methodology 4 h after birth and repeated 30 min after desipramine (2 mg/kg iv). At baseline, the lungs accounted for 35 +/- 10 and 47 +/- 13% of whole body norepinephrine clearance (93 +/- 8 ml. min-1. kg-1) and spillover (188 +/- 29 ng. min-1. kg-1) and 15 +/- 2 and 19 +/- 7% of whole body epinephrine clearance (82 +/- 4 ml. min -1. kg -1) and release (22.7 +/- 2.7 ng. min-1. kg-1), respectively. Desipramine decreased pulmonary norepinephrine and epinephrine clearance and spillover to near-zero levels, whereas whole body norepinephrine clearance fell by 51 +/- 3% (P < 0.001), norepinephrine spillover by 54 +/- 6% (P < 0.005), epinephrine clearance by 30 +/- 6% (P < 0.01), and epinephrine spillover by 34 +/- 11% (P < 0.05). These results indicate that, in the immediate newborn period, pulmonary removal and release of norepinephrine and epinephrine is mediated by a desipramine-sensitive process that accounts for a major portion of associated reductions in whole body norepinephrine and epinephrine clearance and release.

Animals↗
PubMed1998

Internal jugular venous spillover of noradrenaline and metabolites and their association with sympathetic nervous activity.

It is recognized that the brain plays a pivotal role in the maintenance of blood pressure and the control of myocardial function. By combining direct sampling of internal jugular venous blood with a noradrenaline isotope dilution method, for examining neuronal transmitter release, and microneurographic nerve recording, we were able to quantify the release of central nervous system noradrenaline and its metabolites and investigate their association with efferent sympathetic nervous outflow in healthy subjects and patients with pure autonomic failure. To further investigate the relationship between brain noradrenaline, sympathetic nervous activity and blood pressure regulation we examined brain catecholamine turnover, based on the internal jugular venous overflow of noradrenaline and its principal central nervous system metabolites, in response to a variety of pharmacological challenges. A substantial increase was seen in brain noradrenaline turnover following trimethaphan, presumably resulting from a compensatory response in sympathoexcitatory forebrain noradrenergic neurones in the face of interruption of sympathetic neural traffic and reduction in arterial blood pressure. In contrast, reduction in central nervous system noradrenaline turnover accompanied the blood pressure fall produced by intravenous clonidine administration, thus representing the blood pressure lowering action of the drug. Following vasodilatation elicited by intravenous adrenaline infusion, brain noradrenaline turnover increased in parallel with elevation in muscle sympathetic nervous activity. While it is difficult to assess the source of the noradrenaline and metabolites determined in our studies, available evidence implicates noradrenergic cell groups of the posterolateral hypothalamus, amygdala, the A5 region and the locus coeruleus as being involved in the regulation of sympathetic outflow and autonomic cardiovascular control.

Adolescent↗
PubMed1998

Depression of efferent parasympathetic control of heart rate in rats with myocardial infarction: effect of losartan.

Heart failure is associated with attenuation of parasympathetic nervous function and enhanced renin-angiotensin activity. We tested whether there was a dysfunction in the efferent cholinergic neurotransmission in the heart of rats with chronic myocardial infarction (MI) and the potential role of angiotensin II (Ang II) receptors in such changes. Rats with MI and sham-operation were anesthetized, and heart rate (HR) reduction in response to vagal nerve stimulation was measured before and after losartan administration (10 mg/kg, i.v.) in the presence or absence of physostigmine to inhibit acetylcholinesterase. Infarcted rats had an average infarct size (IS) of 38% of the left ventricle (LV), depressed LV dP/dtmax, elevated LVEDP, and cardiac hypertrophy. Nerve stimulation (1-16 Hz) reduced HR in a frequency-dependent manner. The bradycardiac responses were significantly attenuated in infarcted versus control rats (p < 0.01), indicating an impaired efferent vagal tone. In contrast, the bradycardic response to exogenous acetylcholine was similar in both groups, implying an unchanged muscarinic receptor responsiveness in hearts with MI. HR response to nerve stimulation was potentiated by losartan in infarcted rats by 21 +/- 4 versus 4 +/- 2 beats/min (p < 0.01) but was unaffected in control rats. This effect of losartan was inversely related to the extent of attenuation of vagally mediated HR reduction. IS was correlated with both the extent of attenuation in vagally mediated bradycardia and the effect of losartan. In conclusion, the efferent vagal control of HR is attenuated in rats with MI and heart failure. This attenuation may be partly due to a presynaptic inhibition of acetylcholine release through the tonic activation, by Ang II, of neuronal AT1 receptors.

Acetylcholine↗
PubMed1997

Cerebral noradrenaline spillover and its relation to muscle sympathetic nervous activity in healthy human subjects.

Studies using internal jugular vein blood sampling in human subjects have demonstrated the release of noradrenaline from the brain and have provided a link between central nervous system noradrenergic neuronal activity and renal, cardiac and total body sympathetic activity. The aim of this study was to further categorise the dependence of regional sympathetic nervous function on central nervous system noradrenergic neuronal processes by combining measures of internal jugular venous noradrenaline spillover, as an indicator of brain noradrenaline release, and cerebral blood flow scans with measures of the overall integrated neuronal firing rate for the body as a whole, the spillover of noradrenaline into the coronary sinus and with measurements of resting muscle sympathetic nerve activity. Positive veno-arterial plasma noradrenaline gradients were found across the brain, with the plasma concentration being 17 +/- 3% (p < 0.01) greater in the internal jugular vein. Linear regression analysis revealed a significant relationship between the degree of muscle sympathetic nerve activity and the spillover of noradrenaline from subcortical brain regions (y = 0.1 x + 16.0; r = 0.81, p < 0.02). The rate of spillover of noradrenaline for the body as a whole also bore a significant association with the rate of subcortical noradrenaline spillover (y = 0.01x + 2.33; r = 0.71, p < 0.05). Cortical noradrenaline spillover was not related to any of the sympathetic nervous system parameters measured in this study. The demonstration of a direct relationship between the rate of peroneal nerve firing and the spillover of noradrenaline from subcortical brain regions provides further support for the concept of central nervous system noradrenergic cell groups behaving in a sympathoexcitatory role.

Adult↗
PubMed1997

Pulmonary clearance and release of norepinephrine and epinephrine in newborn lambs.

To examine the pulmonary kinetics of the catecholamines norepinephrine and epinephrine immediately after birth, eight fetal lambs were instrumented with vascular catheters under general anesthesia at 133-134 days gestation (term = 147 days) and were delivered by cesarean section 1 wk later. Pulmonary norepinephrine and epinephrine kinetics were then studied 1 and 4 h after birth using radiotracer dilution methodology. The pulmonary fractional extraction of norepinephrine was similar in 1-h (0.111 +/- 0.021) and 4-h (0.117 +/- 0.023) lambs and constituted 24 +/- 5 and 32 +/- 9% of total body norepinephrine clearance, respectively. Pulmonary removal of epinephrine was less pronounced with a fractional extraction of 0.035 +/- 0.017 in 1-h and 0.036 +/- 0.013 in 4-h lambs, which corresponded to 8 +/- 4 and 9 +/- 3% of total body epinephrine clearance, respectively. Pulmonary spillover of norepinephrine into the circulation was similar in 1-h (79 +/- 26 ng.min-1.kg-1) and 4-h (82 +/- 18 ng.min-1.kg-1) lambs, and this comprised 27 +/- 8 and 42 +/- 8% of total body norepinephrine spillover, respectively. Pulmonary epinephrine spillover was not detectable at 1 h, but it occurred in all 4-h lambs, averaging 4.7 +/- 0.8 ng.min-1.kg-1 or 20 +/- 6% of epinephrine total body spillover. These findings indicate that the lungs of newborn lambs 1) are a major site for removal of norepinephrine and epinephrine from the circulation; 2) release a substantial quantity of norepinephrine into the circulation, consistent with the presence of tonic pulmonary sympathetic nerve activity; and 3) constitute a significant extra-adrenal source of plasma epinephrine.

Animals↗
PubMed1997

Region-specific neuropeptide Y overflows at rest and during sympathetic activation in humans.

Neuropeptide Y coexists with norepinephrine in sympathetic nerves and is coreleased into the circulation on sympathetic activation. Little is known about the regional release of neuropeptide Y in humans under normal conditions or in pathophysiological situations of sympathetic activation or denervation. We measured plasma neuropeptide Y-like immunoreactivity and norepinephrine concentrations in samples taken from the brachial artery; coronary sinus; and internal jugular, antecubital, or hepatic veins in volunteers aged 20 to 64 years. Regional neuropeptide Y overflow at rest was calculated from venoarterial plasma concentration differences and plasma flow, and norepinephrine spillover was determined by [3H]norepinephrine infusion techniques. Cardiac release of neuropeptide Y and norepinephrine was examined in response to various stressors as well as in clinical models of sympathetic activation, cardiac failure, and denervation after cardiac transplantation. In healthy volunteers, cardiac, forearm, and jugular venous sample neuropeptide Y concentrations were similar to arterial levels. Hepatic vein plasma neuropeptide Y was greater than arterial both at rest (119 +/- 5% of arterial, n = 7) and after a meal (132 +/- 12%, n = 7), with neuropeptide Y overflows of 6 +/- 2 and 11 +/- 2 pmol/min, respectively. In contrast, hepatomesenteric norepinephrine spillover was not significantly increased by feeding. Although coronary sinus plasma norepinephrine concentrations increased significantly with the cardiac sympathetic activation accompanying mental arithmetic, coffee drinking, isotonic exercise, and bicycle exercise, only the latter powerful sympathetic stimulus increased neuropeptide Y overflow. Cardiac failure was associated with increased resting release of both norepinephrine and neuropeptide Y from the heart, whereas postcardiac transplant norepinephrine spillover from the heart was reduced. The net overflow of neuropeptide Y to plasma observed at rest across the hepatic circulation, but not the cardiac, forearm, or cerebral circulations, indicates that the gut, the liver, or both make a major contribution to systemic plasma neuropeptide Y levels in humans. Sympathetic activation by exercise produced a modest increase in cardiac neuropeptide Y overflow but to only approximately 25% of the resting input from the gut and without a change in arterial neuropeptide Y concentration. Plasma neuropeptide Y measurements are less sensitive than those of plasma norepinephrine concentrations as an index for quantifying sympathetic neural responses regulating the systemic circulation.

Adult↗
PubMed1997

Left ventricular norepinephrine and epinephrine kinetics at birth in lambs.

Little is known about the changes in the left ventricular (LV) kinetics of the catecholamines norepinephrine and epinephrine occurring at birth and their relationship to perinatal alterations in LV function and whole-body catecholamine kinetics. To address this issue, whole-body and LV catecholamine kinetics (radiotracer dilution methodology) and fetal LV output and myocardial blood flow (radioactive microspheres) were measured in chronically instrumented near-term fetuses and in the same animals 1 and 4 hours after birth. Between fetal and 1-hour lambs, LV external work increased 115% (P<.005); carotid arterial plasma norepinephrine concentration, 148% (P<.01); carotid arterial plasma epinephrine concentration, 546% (P<.005); LV norepinephrine spillover, a measure of LV sympathetic activity, 4.1-fold (P<.005); LV epinephrine spillover, 3-fold (P<.05); total-body spillover of norepinephrine, 52% (P<.025); and total-body spillover of epinephrine, 460% (P<.005). Arterial catecholamine concentrations and total-body catecholamine spillovers were unchanged between 1- and 4-hour lambs, but LV external work fell (P<.05) to a level still 77% greater than in fetal lambs (P<.005); LV norepinephrine spillover returned to near-fetal levels, and LV epinephrine spillover became undetectable. These results suggest that (1) a transient increase in LV sympathetic activity occurs at birth and may contribute to the immediate postnatal augmentation of LV performance, (2) organ differences in the pattern of sympathetic activation occur at birth, and (3) birth-related increases in LV sympathetic activity are accompanied by release of epinephrine from the heart.

Animals↗
PubMed1996

Oxygen consumption in the heart, hepatomesenteric bed, and brain in young and elderly human subjects, and accompanying sympathetic nervous activity.

Although the reduction in whole-body energy expenditure with aging has been well documented, there is little information about the changes that individual organs undergo. We therefore measured oxygen consumption in the heart, hepatomesenteric bed, and brain in elderly subjects and young controls, using central venous catheter techniques and the application of Fick's principle. We also measured whole-body, cardiac, and hepatomesenteric sympathetic nervous activity using isotope dilution methodology. Cardiac, hepatomesenteric, and cerebral oxygen consumption was similar in both groups. Whole-body and hepatomesenteric sympathetic nervous activity was also similar in the study groups, whereas cardiac norepinephrine (NE) spillover was significantly higher in the elderly. In contrast to the young, cardiac sympathetic nervous activity as assessed from NE spillover was not related to either cardiac oxygen consumption or cardiac work in the elderly. The data suggest that although oxygen consumption in the heart, hepatomesenteric bed, and brain are not different between young and elderly individuals, the relationship between sympathetic nervous activity and oxygen consumption in individual organs may alter with aging.

Adult↗
PubMed1996

Increased spillover and reduced clearance both contribute to rise in plasma catecholamines after birth in lambs.

We studied the relationship between changes in norepinephrine (NE) and epinephrine (Epi) levels, total body spillover, and total body clearance at birth. Near-term fetal lambs were chronically instrumented under general anesthesia with arterial, venous, and left atrial catheters. One week later, NE and Epi kinetics (isotope dilution methodology) and systemic blood flows (radioactive microspheres) were measured in fetuses and then in the same animals 1 and 4 h after cesarean section delivery. Comparing fetal and 1-h lambs 1) systemic output fell by 33% (P < 0.005); 2) systemic plasma NE increased by 144% (P < 0.005), and plasma Epi increased sevenfold (P < 0.005); 3) total body NE spillover rose by 63% (P < 0.01) and Epi spillover by fivefold (P < 0.005); and 4) total body NE clearance decreased by 34% (P < 0.005) and Epi clearance by 37% (P < 0.005). Systemic blood flow and kinetic data were similar in 1- and 4-h lambs and were therefore pooled to define the interrelationship among perinatal changes in NE and Epi plasma levels, spillover, and clearance. Between fetal and newborn lambs, plasma NE rose by 1,375 +/- 207 pg/ml, of which 604 +/- 119 pg/ml (approximately 44%) resulted from increased NE total body spillover and 771 +/- 160 pg/ml from reduced NE total body clearance. In the same interval, plasma Epi rose by 292 +/- 30 pg/ml, of which 123 +/- 18 pg/ml (approximately 42%) was due to Epi total body spillover and 169 +/- 19 pg/ml to reduced Epi total body clearance. These findings indicate that 1) sympathoadrenal activity increases with birth, and 2) increased total body spillover and reduced total body clearance contribute a similar portion of the plasma NE and Epi surge at birth.

Animals↗
PubMed1996

Cerebral metabolism and its relationship with sympathetic nervous activity in essential hypertension: evaluation of the Dickinson hypothesis.

OBJECTIVE: To examine Dickinson's hypothesis in mild essential hypertension, in which neurogenic mechanisms are believed to be particularly relevant, by combining measures of cerebral oxygen consumption with the concurrent assessment of sympathetic nervous activity. DESIGN AND METHODS: Twenty-five untreated essential hypertensive subjects and 28 healthy age-matched volunteers underwent direct blood sampling using percutaneously inserted catheters advanced into the internal jugular vein, with cerebral blood flow scans to differentiate between cortical and subcortical venous drainage of the brain. Venoarterial blood gas measurements and internal jugular vein blood flows were used to calculate cerebral respiratory quotients and cerebral oxygen utilization. The total body rate of noradrenaline spillover into plasma was measured to assess relationships between cerebral oxidative metabolism and sympathetic nervous activity. RESULTS: Compared with controls, the hypertensive subjects exhibited reductions in internal jugular vein blood flow (482 +/- 29 versus 410 +/- 15 ml/min), cerebral oxygen consumption (27 +/- 2 versus 23 +/- 1 ml/min) and cerebral oxygen supply (93 +/- 6 versus 78 +/- 3 ml/min). The cerebral respiratory quotients were identical (1.00 +/- 0.04 in normotensives and 0.98 +/- 0.03 in hypertensives). Technetium blood flow scans revealed that the reductions in internal jugular blood flow and cerebral oxygen consumption in the hypertensive patients were confined to cortical brain regions. Cortical blood flow was quantitatively linked to the matching respiratory quotient and oxygen consumption, neither of which bore any relation to the level of sympathetic nervous activity. The spillover of noradrenaline into the plasma for the body as a whole did not differ between the two groups. CONCLUSIONS: In accord with Dickinson's hypothesis, we have established a reduction in internal jugular vein blood flow and cerebral oxygen utilization in hypertension. These reductions were confined to cortical brain regions. However, cerebral respiratory quotients in our hypertensive study group were no different from those in our controls, suggesting that glucose remained as the major cerebral metabolic substrate in hypertension. We were not able to establish a link between cerebral metabolism and blood pressure or sympathetic nervous activity in mildly hypertensive patients.

Adult↗
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

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↗