(Circulation. 1995;92:1813-1818.)
© 1995 American Heart Association, Inc.
Articles |
Increased Central Nervous System Monoamine Neurotransmitter Turnover and Its Association With Sympathetic Nervous Activity in Treated Heart Failure Patients
From the Human Autonomic Function Laboratory and Alfred Baker Medical Unit, Baker Medical Research Institute, Commercial Road, Prahran, Vic, Australia.
Correspondence to Dr Gavin W. Lambert, Human Autonomic Function Laboratory, Baker Medical Research Institute, Commercial Road, Prahran Vic 3181, Australia.
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Abstract |
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Background Congestive heart failure is a debilitating disease characterized by impaired cardiac function with accompanying activation of a variety of neural and hormonal counterregulatory 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 ouflow 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.
Key Words: nervous system • sympathetic • heart failure • arrhythmia
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Introduction |
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Congestive heart failure is characterized by diminished pumping performance of the heart, by complex neural pathophysiology, and by substantial morbidity and mortality.1 2 3 4 It is generally acknowledged that sympathetic nervous system stimulation is commonly present in patients with heart failure1 2 5 to the possible detriment of the failing myocardium,6 predisposing even in mild failure to lethal ventricular arrhythmias.7 The level of sympathetic nervous stimulation appears to be substantially greater in untreated or minimally treated heart failure patients2 7 than in optimally treated patients.4 The afferent circulatory stimulus responsible for the sympathoexcitation associated with cardiac failure and the central nervous system neuronal circuitry involved remains to be elucidated.
In the present study, our aim was to investigate the relation between central nervous system monoamine neuronal systems and the genesis of the sympathetic nervous stimulation accompanying severe congestive heart failure. Norepinephrine-, epinephrine-, and serotonin-releasing neurons in the brainstem and forebrain have an important regulatory influence over sympathetic nervous outflows to the cardiovascular system.8 9 10 11 To investigate central nervous system monoamine release, we measured the internal jugular venous overflow in heart failure patients and healthy volunteers of epinephrine, norepinephrine, its precursor dihydroxyphenylalanine (DOPA) and major lipophilic metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylglycol (DHPG), and 5-hydroxyindoleacetic acid (5-HIAA), the major acidic central nervous system metabolite of serotonin. We measured concurrently the rate of total body and cardiac norepinephrine spillover to plasma to investigate possible relations between cerebral neuronal systems and sympathetic outflow.
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Methods |
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Results for twenty-two congestive heart failure patients (age, 51±2 years) and 29 healthy volunteers (age, 48±3 years) form the basis for this report. The heart failure group were all moderately to severely symptomatic (New York Heart Association functional class III or IV) with profoundly impaired left ventricular function (left ventricular ejection fraction as assessed by radionuclide ventriculography, 18±1%) and were undergoing assessment for suitability as candidates for cardiac transplantation. Ten of the patients had angiographically demonstrated ischemic cardiomyopathy, whereas the remaining patients' failure was due to nonischemic etiologies (9 patients with idiopathic dilated cardiomyopathy, 2 patients with valvular heart disease, and 1 patient whose cardiac failure was attributable to hypertension). All patients were treated with conventional antifailure drugs that typically included a diuretic (in 95% of patients), an angiotensin-converting enzyme inhibitor (in all patients), warfarin (in 86% of patients), and digoxin (in 86% of patients). In view of the severity of heart failure, medication was continued throughout the research testing. All subjects gave written informed consent for their participation in the study, which was approved by the Alfred Hospital Ethics Review Committee.
Blood samples were obtained through central venous and arterial catheters percutaneously inserted under strict aseptic conditions in the cardiac catheterization laboratory of the Alfred Baker Medical Unit according to our established protocols.4 12 Subjects were studied in the supine position on a maneuverable laboratory table (model 1212, NVC Australia Pty Ltd) equipped with fixed anteroposterior fluoroscopic screening facilities (model DC 12MB-1, Toshiba Industries).
After skin preparation and adequate local anesthesia (1 to 2 mL of 2% lignocaine, Delta West Pty Ltd) a model C-PMS-301-RA 3F, 5-cm arterial catheter (Cook Australia) was inserted percutaneously into a brachial artery. The arterial catheter was used for a continuous infusion of 5% dextrose containing 4 U/mL heparin (David Bell Laboratories) via an intraflow adaptor and pressure bag, which ensured delivery of 3 mL/h at a bag pressure of 300 mm Hg, if the system was not flushed manually. Intra-arterial pressure was recorded continuously via a Spacelabs Inc model 90603 two-channel pressure monitor.
In the cardiac failure patients, a pulmonary arterial thermodilution catheter, percutaneously placed in an antecubital vein, was advanced under fluoroscopic control to the pulmonary circulation for diagnostic measurement of right-side heart pressure, pulmonary capillary wedge pressure, and cardiac output. This catheter was replaced by a 7F CCS-7U coronary sinus thermodilution catheter (Webster Laboratories), which, in 18 patients, was positioned in the coronary sinus for blood sampling and for the determination of coronary sinus blood flow. The catheter was subsequently repositioned into the right internal jugular vein beyond the mandibular angle upstream to points of entry of veins draining the face and neck to minimize any contamination of the cerebral venous effluent. The catheter was used for sampling internal jugular venous blood and for the determination of jugular blood flow. All healthy subjects underwent right internal jugular vein catheterization and, in 14 of them, the catheter was also positioned in the coronary sinus as previously described. Blood and plasma flows were interconverted using the subjects' hematocrit.
The overall, cardiac, and central nervous system release rates to plasma of endogenous norepinephrine were determined by the principle of isotope dilution during an infusion of tritiated norepinephrine as previously described.13 14 The epinephrine spillover from the brain was estimated with an analagous method using a simultaneous infusion of tritiated epinephrine.15 The central nervous system norepinephrine turnover was estimated by summing the internal jugular vein overflows of norepinephrine, DHPG, and MHPG. The internal jugular venous overflow of 5-HIAA was used as an indicator of serotonin turnover. Venoarterial plasma concentration differences combined with an appropriate internal jugular vein flow measurement were used, according to the Fick principle, to determine metabolite overflows from the brain as previously described.16 Plasma neurochemical concentrations were determined by high-performance liquid chromatography coupled with electrochemical detection according to established techniques.16 17 18 The interassay coefficients of variation, determined from approximately 80 consecutive assay runs, were ±11% for norepinephrine, ±8% for DHPG, ±4% for MHPG, ±3% for epinephrine, and ±5% for 5-HIAA. The intra-assay coefficients of variation, determined from five to eight repeated measurements of pooled venous plasma, were ±3% for norepinephrine, ±2% for DHPG, ±5% for MHPG, ±6% for epinephrine, and ±2% for 5-HIAA. All assays were linear within the physiological range with a sensitivity (signal-to-noise ratio of 3) of 0.1 pmol for the catechols, 1.0 pmol for MHPG, and 0.5 pmol for 5-HIAA.
All results, unless specified otherwise, are expressed as mean±SEM. Between-group comparisons were made with one-way ANOVA. Relations between continuous variables were examined by the least-squares method of linear regression. Variables that were significantly related to the rate of cardiac norepinephrine spillover to plasma in a univariate analysis were entered into a stepwise multivariate analysis. ANCOVA was used to compare the slopes and intercepts of the relation for two continuous variables between groups. The null hypothesis was rejected at P<.05.
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Results |
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Rates of total body norepinephrine spillover to plasma, an index of integrated neuronal firing, and cardiac norepinephrine spillover to plasma, indicative of cardiac sympathetic neuronal activity,14 were significantly elevated overall in the heart failure patients. Total body norepinephrine spillover was increased by approximately 40% in the heart failure patients (5.25±0.55 versus 3.73±0.28 nmol/min; P<.05; normal range, 1.44 to 7.62 nmol/min; Fig 1
). This elevated spillover of
norepinephrine for the body as a whole was accompanied by a
145% increase in the rate of spillover of
norepinephrine into the coronary sinus (383±76
versus 156±23 pmol/min; P<.05; normal range, 30 to 343
pmol/min; Fig 1). It was evident, however, that sympathetic activation
was not present in all patients. Norepinephrine
release from the heart in 6 of 22 heart failure patients was greater
than the highest value in the healthy subjects (Fig 1).
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In the heart failure patients, the pattern of release of
norepinephrine, its precursor DOPA, and lipophilic
metabolites from the brain into the internal jugular vein were
indicative of an approximately threefold increase in mean central
nervous system norepinephrine turnover (P<.01;
Fig 2). The mean internal jugular venous spillover
of epinephrine was increased by more than 10-fold in the heart
failure group of patients (P<.05), but central nervous
system epinephrine spillover values were widely dispersed,
undetectable in some patients, and as high as 50 to 100 pmol/min in
others. The overflow from the brain of the principal
serotonin metabolite 5-HIAA also displayed a high degree of
biological variability. Although the reasons for the scatter of this
data remain obscure, it cannot be attributable to lack of
analytical precision or reproducibility, given the small coefficients
of variation for the assay. Patients with heart failure had an
approximately threefold increase in the overflow from the brain of
5-HIAA (Fig 2). Although this elevated internal jugular venous 5-HIAA
overflow failed to attain statistical significance, subjects with the
highest cerebrovascular 5-HIAA tended to have elevated cardiac
sympathetic nervous activity, as indicated by the significant relation
between internal jugular venous 5-HIAA overflow and the cardiac
norepinephrine spillover (Fig 3). These
increases in internal jugular venous overflow in the heart failure
patients were not accounted for by differences in internal jugular vein
blood flow, which, if anything, tended to be reduced in the cardiac
failure group (512±32 versus 449±27 mL/min).
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The level of sympathetic activity for the body as a whole was significantly related to the internal jugular venous overflow of epinephrine (y=0.05x+3.84, r=.61, P<.01), norepinephrine, and its metabolites (y=x+3.39, r=.48, P<.01) and 5-HIAA (y=x+4.13, r=.40, P<.05). Multivariate analysis of these three variables revealed the central nervous system overflow of epinephrine to be that most strongly related to whole body norepinephrine spillover to plasma.
Least-squares linear regression demonstrated the degree of
activation of the cardiac sympathetic nervous outflow, gauged from the
cardiac norepinephrine spillover, to be significantly
related to indicators of central nervous system
noradrenergic (P<.01), adrenergic
(P<.01), and serotonergic neuronal activity
(P<.01, Fig 3
). Multivariate
analysis of internal jugular venous overflow of
epinephrine, norepinephrine, and 5-HIAA identified
central adrenergic activity as being most strongly related to cardiac
norepinephrine spillover (P<.01).
The hemodynamic profile of the congestive heart failure patients was consistent with the severity of their cardiac failure. Pulmonary capillary wedge and mean pulmonary artery pressures were 20±2 and 26±2 mm Hg, respectively. Mean arterial blood pressure was 78±2 mm Hg, and the cardiac output was 3.88±0.24 L/min. There was a nonsignificant trend for mean pulmonary artery pressure in heart failure patients to be related to cerebral turnover of epinephrine (P=.07), serotonin (P=.08), and norepinephrine (P=.09).
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Discussion |
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In the present study, we examined the cardiac and whole body sympathetic nervous system activity in patients with severe congestive heart failure and were able to demonstrate an association between the increased release of central nervous system monoamine neurotransmitters and the sympathoexcitation that is variably present in treated heart failure patients. Norepinephrine release from the heart in 6 of 22 patients was greater than the highest value in healthy subjects. Although changes in the rate of spillover of norepinephrine to plasma could derive from enhanced neuronal firing or diminished neuronal reuptake, previous experiments suggest that any impairment of uptake1 is minimal in patients with congestive heart failure.2 4 19 Supportive of increased nerve firing rates in the sympathetic nerves of the heart is the observation that cardiac release of neuropeptide Y, which coexists with norepinephrine in the terminals of noradrenergic nerves and is not subject to neuronal reuptake,20 21 is enhanced in patients with congestive heart failure.4
Although a diffusional barrier limits the passage of catecholamines from the circulation to the brain, movement in the reverse direction, from the brain to plasma, is less restricted.14 22 23 In the heart failure patients, the pattern of release of norepinephrine and its lipophilic metabolites, DHPG and MHPG, from the brain into the internal jugular vein indicated the presence of increased central nervous system norepinephrine turnover. Given the evidence that pharmacological blockade of norepinephrine reuptake results in decreased central nervous system norepinephrine turnover24 and reduced neuronal firing of the locus ceruleus,25 26 with subsequent diminution of sympathetic nervous outflow,27 it would appear that in heart failure patients increased neuronal firing rather than diminished neuronal reuptake is most likely responsible for the observed elevation in central nervous system norepinephrine turnover. Furthermore, unlike in healthy subjects in whom epinephrine spillover from the brain was minimal, brain epinephrine spillover was as high as 50 to 100 pmol/min in some heart failure patients, although it was negligible in others. The degree of activation of the cardiac sympathetic nervous outflow, as indicated by the cardiac norepinephrine spillover, was significantly related to indicators of central nervous system noradrenergic, adrenergic, and serotonergic neuronal activity, with the relation of central adrenergic activity to cardiac norepinephrine spillover being strongest.
Following von Euler's28 characterization of norepinephrine as the sympathetic neurotransmitter and the subsequent demonstration of a direct relation between rates of sympathetic nerve firing and neurotransmitter release,29 30 31 32 33 the potential to use norepinephrine washout, or spillover to plasma, as an index of sympathetic nervous function was clear. Maas and colleagues34 extended this reasoning to central nervous system neurons and demonstrated the usefulness of direct internal jugular vein blood sampling techniques in the assessment of central nervous system neuronal activity by demonstrating a reduction in MHPG jugular overflow from the brain of stump-tailed monkeys (Macaca arctoides) after clonidine administration.34 Clonidine is a centrally acting suppressant of sympathetic nervous system activity known to inhibit the firing rate of locus ceruleus neurons35 36 and decrease the concentration of MHPG in the brain.37 The observations by Maas and colleagues34 on jugular venous MHPG overflow after clonidine have subsequently been reproduced in healthy human subjects.38
The clinical application of such methodology is a relatively recent development. With radioenzymatic and high-performance liquid chromatography methodologies, we studied the release of norepinephrine and its metabolites into the cerebrovascular circulation in 22 patients with congestive heart failure, 35 hypertensive subjects, more than 60 healthy volunteers, and 5 patients with idiopathic peripheral autonomic insufficiency.16 24 39 40 41 42 The demonstration of similar cerebral norepinephrine overflows in healthy subjects and in patients with autonomic failure, in whom there was biochemical evidence of almost complete postganglionic sympathetic denervation,7 suggested that the norepinephrine emanated from central noradrenergic neurons and not from cerebrovascular sympathetic nerves. Supporting this view is the observation that ganglion blockade with trimethaphan does not diminish norepinephrine overflow41 and causes a compensatory increase in central nervous system norepinephrine turnover and increased overflow of lipophilic metabolites of norepinephrine.38 In congestive heart failure, however, where peripheral sympathetic neuronal activation may be extreme in some patients, we cannot categorically discount regional sources as a possible minor contributor to our cerebral overflow determinations.
Central monoaminergic systems are recognized as being important in the regulation of cardiovascular reflexes.43 Transneuronal labeling techniques with the retrograde transport of pseudo–rabies virus have identified the rostral ventrolateral and ventromedial medulla, serotonin-containing cells in the caudal raphe nuclei, the A5 noradrenergic group, and the hypothalamus as brain regions innervating sympathetic outflow at all thoracolumbar levels44 45 ; furthermore, an increased serotonergic activity has been demonstrated in brainstem and forebrain regions in the cardiomyopathic Syrian hamster, an experimental paradigm of heart failure.46 One finding from the present study—that in some patients with heart failure (ie, the four with the highest level of cardiac sympathetic nervous activity) there was substantial spillover of epinephrine from the brain—may be in accordance with previous observations indicating that a major source of projections determining the tonic discharge of sympathetic outflow is the C1 group of epinephrine-containing neurons located in the rostral portion of the ventrolateral medulla.47 48 Along with the A5 group, several other central nervous system noradrenergic nuclei, including those of the locus ceruleus, lateral and paraventricular nuclei of the hypothalamus, and the amygdala are unequivocally sympathoexcitatory.8 10 11
The basis of the differing degree of sympathetic nervous activation found among heart failure patients is not clear. It appears not to be due to the etiology of the heart failure as cardiac norepinephrine spillover is identical in patients with idiopathic congestive cardiomyopathy and those whose failure is attributable to ischemia and myocardial infarction4 or to its therapy. Although the level of sympathetic nervous stimulation appears to be substantially greater in untreated or minimally treated heart failure patients2 7 than in optimally treated patients,4 Kaye and colleagues4 demonstrated that individual antifailure drugs do not differentially influence the cardiac and total body kinetics of norepinephrine. Among patients with heart failure encompassing a broad spectrum from mild to very severe, the extent of sympathetic stimulation is related to heart failure severity,7 but in the present study all patients had profoundly impaired left ventricular function and were undergoing assessment for suitability as candidates for cardiac transplantation. In the recent report by Kaye and colleagues,4 a strong relation between biochemical measures of cardiac sympathetic activity and pulmonary artery pressures was demonstrated in patients with severe heart failure, raising the possibility of reflex linkage of cardiopulmonary baroreceptors, and pressures in the right side of the heart, with efferent cardiac sympathetic activity.4 In the present study, there was a trend for mean pulmonary artery pressure to be related to cerebral monoamine turnovers and for peripheral sympathetic activity to be increased most in those patients with highest intracardiac pressures.
This finding of intracardiac pressures being a determinant of the degree of sympathetic activation in patients with cardiac failure is contrary to an alternative explanation of the sympathetic nervous stimulation present, which emphasizes a desensitization of low-pressure baroreflexes as a basis for withdrawal of tonic inhibition of peripheral sympathetic activity.3 Whether elevated pulmonary pressures provide the hemodynamic signal for increased sympathetic outflow to the myocardium remains to be established. Cardiopulmonary volume receptor afferents do project to the noradrenergic nuclei of the locus ceruleus, and the firing rate of locus ceruleus neurons is changed by alterations in cardiopulmonary pressures.49 50 Functionally, the locus ceruleus and its hypothalamic and amygdala projections are also closely linked with behavioral responses involving autonomic activation.36 This convergence of inputs to the locus ceruleus may be pertinent in the context of reports indicating that experimental hypothalamic stimulation can induce cardiac arrhythmias51 52 and that psychological stress is a common antecedent of potentially fatal ventricular fibrillation in those with underlying heart disease.53 54
Although sympathetic nervous system activation in heart failure may have adverse consequences,6 55 56 the reflex mechanisms of sympathetic nervous stimulation in heart failure and its central nervous system integration remain uncertain. We provide evidence here that release of central nervous system monoaminergic neuronal transmitters is increased in human heart failure and that the apparent degree of activation of aminergic brain neurons is linked to the magnitude of peripheral sympathetic nervous stimulation present in treated heart failure patients. Although these findings are not immediately clinically applicable, they do suggest that forms of sympathetic suppressant therapy in heart failure in addition to peripheral blockade of ß-adrenoceptors, specifically the use of centrally acting inhibitors of sympathetic nervous outflow, such as clonidine, might be beneficial. Clonidine inhibits noradrenergic neurons of the forebrain,57 where released norepinephrine stimulates sympathetic outflow8 10 11 and lowers sympathetic nervous tone in the periphery.
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Acknowledgments |
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This work was supported by a National Health and Medical Research Council Grant to the Baker Medical Research Institute. Dr Gavin Lambert is supported by a Dora Lush National Health and Medical Research Postgraduate Scholarship. The authors wish to thank Elizabeth Dewar, Sister Leonie Johnston, and Kaye Varcoe for their expert assistance in the research catheter laboratory. The photographic expertise of Neil Potter is gratefully acknowledged.
Received January 23, 1995; revision received March 29, 1995; accepted April 16, 1995.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Cohn J, Levine T, Olivari M, Garberg V, Tura D, Francis G, Simon A, Rector T. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984;311:819-823. [Abstract]
2.
Hasking GJ, Esler MD, Jennings GL, Burton D, Korner
PI. Norepinephrine spillover to plasma in
patients with congestive heart failure: evidence of increased overall
and cardiorenal sympathetic nervous activity.
Circulation. 1986;73:615-621.
3. Thames MD, Kinugawa T, Smith ML, Dibner-Dunlap ME. Abnormalities of baroreflex control in heart failure. J Am Coll Cardiol. 1993;22(suppl A):56A-60A.
4. Kaye DM, Lambert GW, Lefkovits J, Morris M, Jennings G, Esler MD. Neurochemical evidence of cardiac sympathetic activation and increased central nervous system norepinephrine turnover in congestive heart failure. J Am Coll Cardiol. 1994;23:570-578. [Abstract]
5.
Leimbach WN, Wallin GB, Victor RG, Aylward PE.
Direct evidence from intraneural recordings for
increased central sympathetic outflow in patients with heart
failure. Circulation. 1986;73:913-919.
6.
Mann DL, Kent RL, Parsons B, Cooper G.
Adrenergic effects on the biology of the adult mammalian
cardiocyte. Circulation. 1992;85:790-804.
7.
Meredith IT, Eisenhofer G, Lambert GW, Dewar EM,
Jennings GL, Esler MD. Cardiac sympathetic nervous activity in
congestive heart failure: evidence for increased neuronal
norepinephrine release and preserved neuronal
uptake. Circulation. 1993;88:136-145.
8.
Huangfu D, Koshiya N, Guyenet P. A5
noradrenergic unit activity and sympathetic nerve
discharge in rats. Am J Physiol. 1991;261:R393-R402.
9. Chalmers J, Pilowsky P. Brainstem and bulbospinal neurotransmitter systems in the control of blood pressure. J Hypertens. 1991;9:675-694. [Medline] [Order article via Infotrieve]
10.
Qualy JM, Westfall TC. Age-dependent
overflow of endogenous norepinephrine from
paraventricular hypothalamic nucleus of hypertensive
rats. Am J Physiol. 1993;265:H39-H46.
11. Singewald S, Philippu A. Catecholamine release in the locus coeruleus is modified by experimentally induced changes in haemodynamics. Naunyn Schmiedebergs Arch Pharmacol. 1993;347:21-27. [Medline] [Order article via Infotrieve]
12. Lambert GW, Eisenhofer G, Jennings GL, Esler MD. Regional homovanillic acid production in humans. Life Sci. 1993;53:63-75. [Medline] [Order article via Infotrieve]
13. Esler M, Jackman G, Bobik A, Kelleher D, Jennings G, Leonard P, Skews H, Korner P. Determination of norepinephrine apparent release rate and clearance in humans. Life Sci. 1979;25:1461-1470. [Medline] [Order article via Infotrieve]
14.
Esler M, Jennings G, Lambert G, Meredith I, Horne M,
Eisenhofer G. Overflow of catecholamine
neurotransmitters to the circulation: source, fate, and
functions. Physiol Rev. 1990;70:963-985.
15. Esler M, Eisenhofer G, Dart A, Chin J, Cox H, Lambert G, Jennings G. Adrenaline release by the human heart. Clin Exp Pharmacol Physiol. 1991;18:67-70. [Medline] [Order article via Infotrieve]
16. Lambert GW, Ferrier C, Kaye DM, Kalff V, Kelly MJ, Cox HS, Turner AG, Jennings GL, Esler MD. Monoaminergic neuronal activity in subcortical brain regions in essential hypertension. Blood Pressure. 1994;3:55-66. [Medline] [Order article via Infotrieve]
17. Eisenhofer G, Goldstein DS, Stull R, Keiser T, Sunderland T, Murphy DL, Kopin I. Simultaneous liquid chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines, and 3,4-dihydroxyphenylalanine in plasma and their responses to inhibition of monoamine oxidase. Clin Chem. 1986;31:2030-2033. [Abstract]
18. Medvedev OS, Esler MD, Angus JA, Cox HS, Eisenhofer G. Simultaneous determination of plasma noradrenaline and adrenaline kinetics, responses to nitroprusside-induced hypotension and 2-deoxyglucose-induced glucopenia in the rabbit. Naunyn Schmiedebergs Arch Pharmacol. 1990;341:192-199. [Medline] [Order article via Infotrieve]
19.
Clemson B, Baily RG, Davis D, Zelis R. Effects
of desipramine on norepinephrine and isoproterenol
clearance in congestive heart failure. Am J Physiol. 1990;259:E261-E265.
20. Pernow J, Lundberg JM, Kaijser L. Plasma neuropeptide Y-like immunoreactivity and catecholamines during various degrees of sympathetic activation in man. Clin Physiol. 1986;6:561-578. [Medline] [Order article via Infotrieve]
21. Lundberg JM, Fried G, Purnow J, Theodorsson-Norheim E. Co-release of neuropeptide and catecholamines upon adrenal activation in the cat. Acta Physiol Scand. 1986;126:231-238. [Medline] [Order article via Infotrieve]
22. Glowinski J, Baldessarini RJ. Metabolism of norepinephrine in the central nervous system. Pharmacol Rev. 1966;13:1201-1238.
23. Hardebo JE, Owman CH. Barrier mechanisms for neurotransmitter monoamines and their precursors at the blood-brain interface. Ann Neurol. 1980;8:1-11. [Medline] [Order article via Infotrieve]
24.
Ferrier C, Esler MD, Eisenhofer G, Wallin BG, Horne M,
Cox HS, Lambert G, Jennings G. Increased
norepinephrine spillover into the jugular veins in
essential hypertension. Hypertension. 1992;19:62-69.
25. Nyback HV, Walters JR, Aghaganian GK, Roth RH. Tricyclic antidepressants: effects on the firing rate of brain noradrenergic neurons. Eur J Pharmacol. 1975;32:302-312. [Medline] [Order article via Infotrieve]
26.
Svensson TH, Thoren T. Feedback inhibition of
brain noradrenaline neurons by tricyclic antidepressants:
-receptor mediation. Science (Washington D
C). 1978;202:1089-1091.
27.
Esler MD, Wallin BG, Dorward PK, Eisenhofer G,
Westerman R, Meredith I, Lambert G, Cox HS, Jennings G. Effects
of desipramine on sympathetic nerve firing and
norepinephrine spillover to plasma in humans.
Am J Physiol. 1991;260:R817-R823.
28. von Euler US. A specific sympathetic ergone in adrenergic nerve fibres (sympathin) and its relation to adrenaline and noradrenaline. Acta Physiol Scand. 1946;12:73-97.
29. Peart WS. The nature of splenic sympathin. J Physiol. 1949;108:491-501.
30.
Yamaguchi NJ, De Champlain J, Nadeau R.
Correlation between the response of the heart to sympathetic
stimulation and the release of endogenous
catecholamines into the coronary sinus of the
dog. Circ Res. 1975;36:662-668.
31.
Blombery PA, Heinzow BGJ. Cardiac and
pulmonary norepinephrine release and removal in the
dog. Circ Res. 1983;53:688-694.
32. Bradley T, Hjemdahl P. Further studies on renal nerve stimulation induced release of noradrenaline and dopamine from the canine kidney in situ. Acta Physiol Scand. 1984;122:369-379. [Medline] [Order article via Infotrieve]
33. Kahan T, Hjemdahl P, Dahlof C. Relationship between the overflow of endogenous and radiolabelled noradrenaline from canine blood perfused gracilis muscle. Acta Physiol Scand. 1984;122:571-582. [Medline] [Order article via Infotrieve]
34. Maas JW, Hattox SE, Landis DH, Roth RH. A direct method for studying 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) production by brain in awake animals. Eur J Pharmacol. 1977;46:221-228. [Medline] [Order article via Infotrieve]
35.
Svensson TH, Bunney BS, Aghajanian GK.
Inhibition of both noradrenergic and
serotonergic neurons in brain by the -adrenergic agonist
clonidine. Brain Res. 1975;92:291-306. [Medline]
[Order article via Infotrieve]
36.
Foote SL, Bloom FE, Aston-Jones G. Nucleus locus
coeruleus: new evidence of anatomical and
physiological specificity. Physiol
Rev. 1983;63:844-914.
37. Braestrup C. Effects of phenoxybenzamine, aceperone and clonidine on the level of 3-methoxy-4-hydroxyphenylglycol (MOPEG) in rat brain. J Pharm Pharmacol. 1974;26:139-141. [Medline] [Order article via Infotrieve]
38. Esler MD, Lambert GW, Ferrier C, Kaye DM, Wallin BG, Kalff V, Kelly MJ, Jennings GL. Central nervous system noradrenergic control of sympathetic outflow in normotensive and hypertensive humans. Clin Exp Hypertens. 1995;17:409-423.
39. Esler MD, Jennings GL, Lambert GW. Release of noradrenaline into the cerebrovascular circulation in patients with primary hypertension. J Hypertens. 1988;6(suppl 4):493-496.
40. Esler M, Ferrier C, Lambert G, Eisenhofer G, Cox H, Jennings G. Biochemical evidence of sympathetic hyperactivity in human hypertension. Hypertension. 1991;17(suppl III):III-29-III-35.
41. Ferrier C, Jennings GL, Eisenhofer G, Lambert G, Cox H, Kalff V, Kelly M, Esler MD. Evidence for increased noradrenaline release from subcortical brain regions in essential hypertension. J Hypertens. 1993;11:1217-1227. [Medline] [Order article via Infotrieve]
42. Lambert GW, Ferrier C, Jennings GL, Kalff V, Kelly MJ, Cox HS, Turner AG, Esler MD. Central nervous system norepinephrine turnover in essential hypertension. Ann N Y Acad Sci. In press.
43. Palkovits M. Neuropeptides and biogenic amines in central cardiovascular control mechanisms. In: Buckley JP, Ferrario CM, eds. Central Nervous System Mechanisms in Hypertension. New York, NY: Raven; 1981:F3-F8.
44. Strack AM, Sawyer WB, Hughes JH, Platt KB, Loewy AD. A general pattern of CNS innervation of the sympathetic outflow demonstrated by transneuronal pseudorabies viral infections. Brain Res. 1989;491:156-162. [Medline] [Order article via Infotrieve]
45. Strack AM, Sawyer WB, Platt KB, Loewy AD. CNS cell groups regulating the sympathetic outflow to adrenal gland as revealed by transneuronal cell body labelling with pseudorabies virus. Brain Res. 1989;491:274-296. [Medline] [Order article via Infotrieve]
46. Sole MJ, Benedict CR, Versteeg DHG, DeKloet ER. Digoxin therapy partially restores cardiac catecholamine and brain serotonin metabolism in congestive heart failure. J Mol Cell Cardiol. 1985;17:1055-1063.[Medline] [Order article via Infotrieve]
47. Ross CA, Ruggiero DA, Joh TH, Park DH, Reis DJ. Rostralventrolateral medulla: selective projections to the thoracic autonomic cell column from the region containing C1 adrenaline neurons. J Comp Neurol. 1984;228:168-185. [Medline] [Order article via Infotrieve]
48. Reis DJ, Ruggiero DA, Morrison SF. The C1 area of the rostral ventrolateral medulla oblongata: a critical brainstem region for control of resting and reflex integration of arterial pressure. Am J Hypertens. 1989;2:363S-374S. [Medline] [Order article via Infotrieve]
49. Elam M, Yao T, Svensson H, Thoren P. Regulation of locus coeruleus neurons and splanchnic, sympathetic nerves by cardiovascular afferents. Brain Res. 1984;290:281-287. [Medline] [Order article via Infotrieve]
50. Elam M, Svensson TH, Thoren P. Differentiated cardiovascular afferent regulation of locus coeruleus and sympathetic nerves. Brain Res. 1985;358:77-84. [Medline] [Order article via Infotrieve]
51. Hockman LH, Mauck HP, Hoff EC. Changes resulting from cerebral stimulation: a spectrum of ventricular arrhythmia of sympathetic origin. Am Heart J. 1966;71:695-700. [Medline] [Order article via Infotrieve]
52. Verrier RL, Calvert A, Lown B. Effect of posterior hypothalamic stimulation on the ventricular fibrillation threshold. Am J Physiol. 1975;225:923-927.
53. Engel GL. Sudden and rapid death during psychological stress: folk lore or folk wisdom? Ann Intern Med. 1971;74:771-782.
54. Trichopoulos D, Katsouyanni K, Zavitsanos X, Tzonou A, Dalla-Vorgia P. Psychological stress and fatal heart attack: the Athens (1981) earthquake natural experiment. Lancet. 1983;1:441-444. [Medline] [Order article via Infotrieve]
55. Meredith IT, Broughton A, Jennings GL, Esler MD. Evidence for a selective increase in resting cardiac sympathetic activity in some patients suffering sustained out of hospital ventricular arrhythmias. N Engl J Med. 1991;325:618-624. [Abstract]
56.
Bristow MR, Anderson FL, Port DJ, Skerl L, Hershberger
RE, Larrabee P, O'Connell JB, Renlund DG, Volkman K, Murray J, Feldman
AM. Differences in ß-adrenergic neuroeffector mechanisms
in ischemic versus idiopathic dilated
cardiomyopathy.
Circulation. 1991;84:1024-1039.
57. Isaac L. Clonidine in the central nervous system: site of mechanism of hypotensive action. J Cardiovasc Pharmacol. 1980;2(suppl 1):S5-S19.
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