(Circulation. 1996;93:1667-1676.)
© 1996 American Heart Association, Inc.
Articles |
Cardiac Sympathetic Nerve Function in Congestive Heart Failure
From the Clinical Neuroscience Branch, National Institute of Neurological Disorders and Stroke (G.E., I.J.K., D.S.G.), Bethesda, Md; the Cardiology Branch, National Heart, Lung, and Blood Institute (A.A.Q.), National Institutes of Health, Bethesda, Md; the Departments of Cardiology and Clinical Physiology, University of Göteborg, Göteborg, Sweden (P.F., B.R.); and the Baker Medical Research Institute, Prahran, Victoria, Australia (G.L., D.M.K., M.D.E.).
Correspondence to Graeme Eisenhofer, Bldg 10, Room 5N-214, 10 Center Dr MSC 1424, National Institutes of Health, Bethesda, MD 20892-1424. E-mail ge@box-g.nih.gov.
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background Increased availability of norepinephrine (NE) for activation of cardiac adrenoceptors (increased cardiac adrenergic drive) and depletion of myocardial NE stores may contribute to the pathophysiology and progression of congestive heart failure. This study used a comprehensive neurochemical approach to examine the mechanisms responsible for these abnormalities.
Methods and Results Subjects with and without congestive heart failure received intravenous infusions of [3H]NE. Cardiac spillover, reuptake, vesicular-axoplasmic exchange, and tissue stores of NE were assessed from arterial and coronary venous plasma concentrations of endogenous and [3H]-labeled NE and dihydroxyphenylglycol. Tyrosine hydroxylase activity was assessed from plasma dopa, and NE turnover was assessed from measurements of NE metabolites. NE release and reuptake were both increased in the failing heart; however, the efficiency of NE reuptake was reduced such that cardiac spillover of NE was increased disproportionately more than neuronal release of NE. Cardiac NE stores were 47% lower and the rate of vesicular leakage of NE was 42% lower in the failing than in the normal heart. Cardiac spillover of dopa and NE turnover were increased similarly in congestive heart failure.
Conclusions Increased neuronal release of NE and decreased efficiency of NE reuptake both contribute to increased cardiac adrenergic drive in congestive heart failure. Decreased vesicular leakage of NE, secondary to decreased myocardial stores of NE, limits the increase in cardiac NE turnover in CHF. Decreased NE store size in the failing heart appears to result not from insufficient tyrosine hydroxylation but from chronically increased NE turnover and reduced efficiency of NE reuptake and storage.
Key Words: norepinephrine • heart failure • nervous system, autonomic • radioisotopes
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Introduction |
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Elevated plasma NE,1 increased spillover of NE into plasma,2 3 and increased directly recorded muscle sympathetic nerve firing4 all demonstrate sympathetic activation in CHF. Increased cardiac NE spillover5 6 7 and desensitization of cardiac ß-adrenoceptors8 9 are also consistent with increased availability of NE for activation of cardiac adrenoceptors (increased cardiac adrenergic drive). Another repeatedly confirmed observation in CHF is that cardiac stores of NE are depleted.10 11 12 13 14 15
Although it is indisputable that adrenergic drive to the failing heart is increased and cardiac NE stores are depleted, the underlying mechanisms of these changes are unclear. Given the sympathetic activation that accompanies CHF, it has been assumed that increased adrenergic drive in the failing heart reflects increased neuronal release of NE. However, the amount of NE available after release also depends importantly on subsequent inactivation by neuronal uptake. Thus, Rose et al16 reported that neuronal release of NE in the failing heart is actually decreased and that this is obscured by a concomitant decrease in NE reuptake. Although this conclusion is disputed,6 reduced efficiency of cardiac NE uptake in CHF is now supported by numerous other studies17 18 19 20 and could explain many of the abnormalities of the failing heart, including increased adrenergic drive, desensitization of ß-adrenoceptors, and depletion of NE stores. In turn, depletion of NE stores has been proposed to contribute to decreased cardiac neuronal release of NE21 and insufficient inotropic support of the failing myocardium.22
The present study applied a previously documented method23 24 to assess cardiac NE reuptake and release in CHF. The method relies on measurements of [3H]-labeled and endogenous DHPG, the intraneuronal NE metabolite, in arterial and coronary venous plasma during intravenous infusion of [3H]NE. This also enables examination of the exchange of NE between the storage vesicles and axoplasm. As the main determinant of NE turnover,24 this exchange could play a crucial role in the depletion of cardiac NE stores in CHF. Measurements of plasma dopa, an index of tyrosine hydroxylase activity,25 were compared with estimates of NE turnover derived from measurements of NE and its metabolites. Finally, measurements of time-dependent changes in the specific activity of [3H]DHPG were used to estimate the size of cardiac NE stores. The current study provides a comprehensive assessment of cardiac sympathetic nerve function to elucidate the mechanisms of cardiac adrenergic activation and depletion of myocardial NE stores in CHF.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Study Population
Subjects included 54 patients with CHF (42 men, 12 women) aged 29 to 75 years (mean age, 52 years) and 57 control subjects (53 men, 4 women) aged 18 to 74 years (mean age, 50 years). All patients with CHF had left ventricular ejection fractions <35% (mean±SD, 22±7%). Most CHF patients (n=45) were in New York Heart Association functional class III, 6 were in class II, and 3 in class IV. Ischemic cardiomyopathy was demonstrated in 25 patients by angiography, 1 patient had CHF secondary to valvular heart disease, and the rest had idiopathic dilated cardiomyopathy. At the time studied, most patients were receiving two or more of the following agents: diuretics, angiotensin-converting enzyme inhibitors, anticoagulants, ß-blockers, or digoxin. Control subjects included 32 normal volunteers and 25 patients with angina pectoris (15 patients with chest pain and coronary artery disease with >50% narrowing of the lumen of any major coronary artery, and 10 patients with chest pain but without coronary artery disease). Subjects were studied as part of ongoing protocols at three different institutions: the National Institutes of Health (Bethesda, Md); Sahlgrenska University Hospital (Göteborg, Sweden); and the Baker Medical Research Institute (Prahran, Victoria, Australia). All procedures were approved by the appropriate review committees, and subjects provided informed consent to participate in studies.
Catheterization
Subjects were studied in the morning in a cardiac
catheterization laboratory after refraining from
smoking and consumption of caffeinated beverages overnight. Medications
were withheld for 12 hours before studies. A cannula inserted under
local anesthesia in a radial, brachial, or femoral artery
was used to monitor arterial pressure and obtain
arterial blood samples. A thermodilution catheter advanced
under fluoroscopic guidance into the coronary sinus was used to
sample coronary venous blood and measure coronary sinus
blood flow. A forearm venous cannula was used for infusion of
[3H]NE and desipramine.
Radiotracer Infusion
All subjects received an intravenous infusion of
[3H]NE (levo-[2,5,6-3H]NE or
levo-[7-3H]NE; New England Nuclear) delivered at a rate
of 0.5 to 1.5 µCi/min. In most studies, the [3H]NE was
infused simultaneously with [3H]-labeled
epinephrine
(levo-N-methyl-[3H]epinephrine, also from New
England Nuclear). Since deamination of
[3H]epinephrine results in loss of3H,
production of [3H]DHPG from [3H]NE
is not obscured by simultaneous administration of
[3H]epinephrine.
Blood Samples and Coronary Blood Flow
Arterial and coronary venous blood
samples (10 to 20 mL) were drawn simultaneously starting 15
minutes after radiotracer infusions were begun. Samples were collected
into ice-chilled tubes containing heparin or EDTA. Plasma was
separated by centrifugation and stored at
-80°C. Coronary sinus blood flow was measured by
thermodilution before each blood collection.
Desipramine Administration
Desipramine hydrochloride (Ciba-Geigy) was administered by
intravenous infusion to 16 CHF patients and 19 normal
volunteers to inhibit neuronal uptake of NE. Infusions began
immediately after withdrawal of baseline arterial and
coronary sinus blood samples and lasted 15 to 30 minutes
(cumulative dose of 0.25 to 0.5 mg/kg). Arterial and
coronary venous blood samples were drawn within 30 minutes
after the infusion.
Cycling Exercise
Twenty-four CHF patients and 31 normal control subjects
performed supine cycling exercise during radiotracer infusions. Cycling
was performed for 10 to 20 minutes at 50% of each subject's maximum
work capacity. Arterial and coronary venous blood
samples were drawn before exercise and during the last minute of
exercise. Increases in cardiac spillovers of DHPG relative to those
of NE provided indexes of NE reuptake.24 Increases in
cardiac dopa spillover in relation to increases in NE turnover
served as indexes of NE biosynthesis.25
Assays
Catechols in plasma (1 mL) and samples of the infusion
preparation (10 µL) were adsorbed onto alumina and quantified by
LCED.26 Timed collections of the eluant as it left the
electrochemical cell enabled separation of [3H]-labeled
DHPG, NE, and epinephrine for assay by liquid scintillation
spectrometry. Interassay CVs were 8.4% for DHPG, 6.5% for NE, 5.9%
for dopa, 11.6% for DA, and 11.6% for DOPAC. Intra-assay CVs were
4.8% for DHPG, 1.9% for NE, 3.8% for dopa, 8.1% for DA, and 3.9%
for DOPAC.
Plasma concentrations of NMN and MN were determined by LCED after extraction by cation-exchange chromatography.27 Concentrations of [3H]-labeled NMN and MN were measured as described above. Interassay CVs were 12.2% for NMN and 11.2% for MN. Intra-assay CVs were 4.2% for NMN and 3.3% for MN.
LCED was also used to measure plasma MHPG after its extraction into ethyl acetate.24 The interassay CV was 7.0% and the intra-assay CV was 4.8%.
Plasma concentrations of HVA and VMA were determined by gas chromatography/mass spectrometry after ethyl acetate extraction and derivatization with pentafluoropropionic anhydride.28 Interassay CVs were 6.8% for HVA and 3.9% for VMA. Intra-assay CVs were 3.8% for HVA and 2.9% for VMA.
Concentrations of sulfate-conjugated catecholamines and metabolites were determined by each of the above procedures after enzymatic hydrolysis of the conjugates by incubation of plasma samples with saturating quantities of sulfatase (Sigma Chemical Co).
Cardiac Spillover of NE
Cardiac spillover of NE into plasma (SPNE)—the
rate of entry into the coronary venous drainage of the NE
released by cardiac tissues (pmol/min)—was estimated by a
rearrangement of the equation described by Esler et
al.29
 | (1) |
The numerator—the rate of entry of [3H]NE into the venous drainage (dpm/min)—was estimated from the product of the coronary venous plasma concentration of [3H]NE ([3H]NEV, dpm/mL) and the coronary sinus plasma flow (Qp, mL/min). The denominator—the specific activity of [3H]NE (dpm/pmol) that resulted from dilution of the [3H]NE entering the venous drainage by the endogenous NE released by cardiac tissues—was estimated from the specific activities (dpm/pmol) of [3H]NE in arterial (SAA) and coronary venous plasma (SAV). These specific activities were calculated from the respective arterial or venous plasma concentrations of [3H]NE (dpm/mL) and endogenous NE (pmol/mL).
Cardiac Spillovers of NMN, DHPG, MHPG, Dopa, and
DOPAC
Cardiac spillover of NMN was estimated after correction for
the amount removed by use of the extraction of MN.30 The
NMN formed in the heart is derived mainly from metabolism
of locally released NE. The small portion of NMN spillover derived
from circulating NE was estimated as described
elsewhere.30 Cardiac spillovers of DHPG, MHPG, dopa,
and DOPAC—none of which are extracted appreciably by the
heart—were estimated from the product of the
arterial-venous difference in plasma concentrations and
coronary plasma or blood flow as
appropriate.24 25
Cardiac NE Turnover
Cardiac NE turnover was estimated from the sum of differences in
rates at which NE and its metabolites entered and left the
coronary circulation. This represents the rate of net
loss of NE (pmol/min) by metabolism and loss into plasma,
which at steady state is matched by an equal rate of NE synthesis.
Cardiac [3H]NE Extraction
The fractional cardiac extraction of [3H]NE
(F)—the proportion of [3H]NE removed from plasma during
passage through the coronary circulation—was calculated
from
 | (2) |
where [3H]NEA and [3H]NEV are the plasma concentrations of [3H]NE (dpm/mL) in arterial and coronary venous plasma, respectively.
Specific Activity of [3H]DHPG Produced in the
Heart
The specific activity of [3H]DHPG produced in the
heart (SADHPG)—which represents the specific
activity of the [3H]NE precursor in the cardiac
sympathetic axoplasm (dpm/pmol)—was estimated according to the
equation
 | (3) |
where [3H]DHPGAV and DHPGAV are the respective arterial-coronary venous increments in plasma concentrations of [3H]-labeled DHPG (dpm/mL) and endogenous DHPG (pmol/mL).
Cardiac Neuronal Removal of [3H]NE and Spillover
of [3H]DHPG
The desipramine-sensitive removal of [3H]NE
([3H]NEU)—the rate of entry of
[3H]NE into cardiac sympathetic neurons (dpm/min)—was
estimated by
 | (4) |
where F and Fdmi are the fractional extractions of
[3H]NE before and after desipramine, respectively
(estimated by use of Equation 2
), Qp is the plasma flow
(mL/min), and [3H]NEA is the
arterial plasma concentration of [3H]NE
(dpm/mL).
The cardiac spillover of [3H]DHPG derived from [3H]NE removed by cardiac sympathetic neurons and metabolized before storage ([3H]DHPGS), ie, not that derived from [3H]NE leaking from storage vesicles (dpm/min), was estimated from differences in cardiac spillovers of [3H]DHPG immediately before and after desipramine using the equation
 | (5) |
where Q and Qdmi are coronary blood flows (mL/min) before and after desipramine, respectively, and [3H]DHPGAV and [3H]DHPGAVdmi represent the arterial-coronary venous increases in plasma concentrations (dpm/mL) of [3H]DHPG immediately before and after desipramine, respectively.
Statistical Methods
Results are expressed as mean±SEM. Differences were assessed by
ANOVA or by paired or unpaired Student's t test as
appropriate. Linear regression analysis was by least squares.
Statistical significance was defined as a value of
P<.05.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Baseline Plasma Catechols and Metabolites
Patients with CHF had elevated (P<.005) arterial plasma concentrations of NE and most of its metabolites, including DHPG, NMN, MHPG, VMA, and the sulfate conjugates of NE, NMN, and MHPG (Table 1
). Arterial
plasma concentrations of dopa, HVA, and DA sulfate were also higher
(P<.02) in CHF patients than in control subjects. There
were significant (P<.02)
arterial-coronary venous increments in plasma
concentrations of DHPG, NMN, MHPG, dopa, and DOPAC in both subject
groups; however, only CHF patients had arterial-venous
increments (P<.0001) in plasma NE, and only control
subjects had increments (P<.0001) in DHPG sulfate. There
were no arterial-coronary venous increments in
plasma VMA, HVA, or the sulfate conjugates of NE, NMN, or DA in either
group. Arterial-coronary venous increments in
plasma NE and MHPG were larger (P<.005) in CHF patients
than in control subjects, whereas control subjects had larger
(P<.01) arterial-coronary venous
increments in plasma DHPG, DHPG sulfate, and DOPAC.
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Baseline Cardiac Spillovers of NE, Metabolites, and
Dopa
Cardiac NE spillover was fourfold higher (P<.0001)
in CHF patients than in control subjects, whereas spillovers of
other compounds showed variable differences between the two groups
(Table 2). Cardiac spillover of NMN was 60% higher
(P<.03) and MHPG 91% higher (P<.0001) in CHF
patients. Cardiac spillovers of unconjugated DHPG did not differ,
whereas those of DHPG sulfate were higher (P<.03) in
control subjects. There was a nonsignificant trend (P=.13)
for the cardiac spillover of DOPAC to be higher in control
subjects. Cardiac spillover of dopa was 32% higher
(P<.05) in CHF patients than in control subjects, a
difference matched closely by the 31% higher (P<.006) rate
of cardiac NE turnover. There were no significant differences in
cardiac spillovers of NE or its metabolites or of dopa and DOPAC
between CHF patients with ischemic
cardiomyopathy and those with idiopathic dilated
cardiomyopathy (data not shown).
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Cardiac Removal of NE and Production of NMN
The cardiac removal of endogenous NE from the
circulation was much larger (P<.0001) in CHF patients than
in control subjects (Table 3), reflecting the higher
rate of delivery (flowxconcentration) of NE to the coronary
bed. The cardiac spillover of NMN that was derived from extracted
NE was also considerably larger (P<.0001) in CHF patients
than in control subjects.
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Cardiac Extraction of [3H]NE and Production
of [3H]DHPG
In control subjects, 79.3±1.3% of the [3H]NE
entering the coronary circulation was extracted by the heart.
In patients with CHF, the fractional cardiac extraction, at
60.2±2.0%, was 24% lower (P<.0001) than in control
subjects.
Arterial-coronary venous increments in plasma
concentrations of [3H]DHPG increased with time of the
[3H]NE infusion; this resulted in time-dependent
increases in the specific activity of [3H]DHPG produced
in the hearts of both control subjects and CHF patients (Fig 1). In CHF patients, the rate of increase in the
specific activity of [3H]DHPG produced by the heart was
twice that in control subjects (0.128 versus 0.066
dpm·pmol-1·min-1).
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) and patients with
cardiac failure (
) as a function of time after the start of
infusion of [3H]-labeled NE. Data were derived from
simultaneously obtained samples of arterial and
coronary venous plasma (186 paired samples from CHF patients
and 426 paired samples from control subjects) drawn at different times
after the start of [3H]NE infusions and partitioned into
20-minute periods. Concentrations of [3H]DHPG were
normalized to arterial plasma concentrations of
[3H]NE of 1000 dpm/mL. The
arterial-coronary venous increment in
normalized plasma [3H]DHPG concentrations was divided by
the arterial-coronary venous increment in
plasma DHPG concentrations to estimate the specific activity of
[3H]DHPG according to Equation 3
Cardiac Neuronal Removal of NE and Production of
DHPG
Cardiac extractions of [3H]NE were lower in CHF
patients before (P<.0001) and after (P<.03)
administration of desipramine (Fig 2A). The cardiac
extraction of [3H]NE was decreased (P<.0001)
considerably by desipramine in both groups of subjects. The
desipramine-induced decrease in cardiac extraction of
[3H]NE was 22% smaller (P<.0001) in CHF
patients than in control subjects (ratio of 0.457 versus 0.589).
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P<.01 vs
baseline.
Desipramine reduced (P<.01) the
arterial-coronary venous increments in plasma
concentrations of [3H]DHPG by 46% in control subjects
and by 39% in CHF patients (Fig 2B).
Arterial-coronary venous increments in plasma
[3H]DHPG did not differ between control subjects and CHF
patients, before or after desipramine.
Desipramine reduced (P<.0002) the
arterial-coronary venous increments in plasma
concentrations of endogenous DHPG by 20% in control
subjects and by 31% in CHF patients (Fig 2C).
Arterial-coronary venous increments in plasma
DHPG were smaller (P<.001) in CHF patients, both before and
after desipramine.
Comparison of the rates of removal of [3H]NE by cardiac
sympathetic neurons with the much smaller cardiac spillovers of
[3H]DHPG (Table 4) indicated that only a
small portion of the [3H]NE removed by cardiac
sympathetic nerves was deaminated immediately after uptake and appeared
in coronary venous plasma as [3H]DHPG. In control
subjects, 5.5±1.3% (2845 of 51 538 dpm/min) of the
[3H]NE removed by cardiac sympathetic neurons appeared in
coronary venous plasma as [3H]DHPG. In CHF
patients, this value was 7.1±1.6% (3475 of 48 768 dpm/min).
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Cardiac Production of DHPG From Recaptured NE During
Exercise
Cycling exercise caused large increases (P<.0001) in
cardiac spillovers of NE in both groups (Fig 3A).
Spillovers of NE were higher (P<.0001) at baseline in
CHF patients than in control subjects but did not differ during
exercise. The absolute increments in cardiac spillovers of NE
during exercise were similar in both groups (1330±276 versus 1363±151
pmol/min).
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Exercise also increased (P<.005) cardiac spillovers of
DHPG in both groups (Fig 3B). Spillovers of DHPG were similar at
baseline but were lower (P<.006) during cycling exercise in
CHF patients. The absolute increment in cardiac spillover of DHPG
during exercise was also smaller (P<.002) in CHF patients
than in control subjects (571±174 versus 930±98 pmol/min).
The ratio of the exercise-induced increase in cardiac
spillover of DHPG to that of NE (an index of NE reuptake
efficiency) was 44% lower (P<.001) in CHF patients than in
control subjects (0.413±0.057 versus 0.735±0.060) (Fig 3C).
NE Turnover and Tyrosine Hydroxylase Activity During
Exercise
In contrast to the manyfold increases in cardiac spillover of
NE during exercise (Fig 3A), cardiac turnover of NE increased
(P<.0001) consistently but by only 2-fold in CHF
patients and 2.8-fold in control subjects (Fig 4A).
Cardiac spillover of dopa also increased (P<.003)
during exercise in both groups (Fig 4B). The magnitude of increases in
dopa spillover was similar to that in cardiac NE turnover; in
control subjects, cardiac dopa spillover increased by 2.4-fold and
in CHF patients by 2-fold. The ratio of the exercise-induced
increase in cardiac spillover of dopa to the increase in NE
turnover did not differ among the two groups.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The differences in disposition and metabolism of NE in control subjects and CHF patients indicate that sympathetic nerves of the failing myocardium release more NE and remove it less efficiently by reuptake. Cardiac NE stores are depleted, and there is a corresponding decrease in leakage of NE from vesicular stores but an adequate capacity for tyrosine hydroxylation.
Neuronal Reuptake of NE
Use of radiotracer-dilution analysis to estimate the
rate of entry of NE into a compartment depends on a general
formula31 consisting of a numerator (the rate of entry of
[3H]NE into the compartment) and a denominator (the
specific activity of [3H]NE resulting from dilution of
the [3H]-labeled NE with the endogenous NE
entering the compartment) (eg, see Equation 1 in "Methods"). As
described elsewhere,23 24 the specific activity of
[3H]NE that enters cardiac sympathetic nerves by neuronal
uptake equals that of the [3H]DHPG produced from the same
source. DHPG, however, has two intraneuronal sources: NE recaptured
after release and NE that is leaked from storage
vesicles.24 Blockade of neuronal uptake with desipramine
enables separate estimation of these two components.
The ratios of desipramine-induced decrements in
arterial-coronary venous gradients of plasma
[3H]-labeled DHPG to endogenous DHPG (Fig 2)
provide estimates of the specific activity of [3H]NE
removed by neuronal uptake in control subjects (21.2 dpm/pmol) and CHF
patients (14.65 dpm/pmol). Division of these specific activities into
the rates of cardiac neuronal removal of [3H]NE (Table 4)
yields rates of NE reuptake. Estimated NE reuptake was higher in CHF
patients than in control subjects (3329 versus 2431 pmol/min) and, in
both groups, manyfold higher than the corresponding rate of NE
spillover (Fig 5).
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Extraneuronal Uptake of NE
NMN is produced in extraneuronal tissues from both circulating and
locally released NE.30 The data in Table 3 indicate that
in control subjects, 0.29% (0.29 of 99 pmol/min) of the NE removed by
the heart is O methylated and appears in outflowing
coronary venous plasma as NMN. This compares with 0.67% (1.47
of 221 pmol/min) in CHF patients. These low conversion rates reflect
the greater importance of neuronal than extraneuronal removal
mechanisms in the heart.32 From these conversion rates,
together with the total cardiac spillovers of NMN (Table 2), it can
be estimated30 that the rate of extraneuronal uptake of NE
is 96 pmol/min in control subjects and 169 pmol/min in CHF patients. In
keeping with other findings,31 these rates are much lower
than rates of NE reuptake but similar to those of NE spillover (Fig 5). Thus, differences in extraneuronal uptake are too small to explain
overall group differences in the disposition of NE.
NE Release and Efficiency of NE Reuptake
The higher rates of neuronal reuptake, extraneuronal uptake, and
spillover of NE indicate increased cardiac neuronal release of NE
in CHF (Fig 5). However, larger proportional increases in cardiac
spillover than in reuptake of NE (270% versus 37% increase)
indicate decreased efficiency of NE reuptake in CHF. Decreased cardiac
extractions of [3H]NE in CHF are also consistent
with decreased efficiency of cardiac NE reuptake. Thus, increased
adrenergic drive in the failing heart results from both increased
neuronal release of NE and decreased efficiency of NE reuptake.
Twofold larger exercise-induced increases in cardiac DHPG relative
to NE spillover in control subjects than in CHF patients (Fig 3)
provide further evidence for decreased efficiency of NE reuptake in the
failing heart. At rest, most DHPG is derived from NE that is leaked
from vesicles, whereas during sympathetic activation, increases in DHPG
production depend entirely on NE reuptake.23 24
Ratios of increases in cardiac DHPG to NE spillover (Fig 3) and of
cardiac [3H]DHPG spillover to [3H]NE
removal (Table 4) indicate24 that during exercise, rates
of cardiac NE reuptake were 13.4-fold (0.735 divided by 0.055) higher
than NE spillover rates in control subjects and 5.8-fold (0.413
divided by 0.071) higher in CHF patients. Thus, NE reuptake is less
efficient in the failing than in the normal heart, both at rest and
during sympathetic activation.
Decreased efficiency of NE reuptake during exercise, as reflected by decreased ratios of reuptake to spillover, could reflect a washout effect, in which increased blood flow increases the proportion of released NE that enters the venous drainage.33 34 Thus, decreased efficiency of NE reuptake in the failing heart could reflect changes of cardiac ultrastructure, microvascular hemodynamics, or density of sympathetic nerve endings and does not necessarily imply abnormal function of the membrane transporter.
Most CHF patients in the present study remained medicated during the investigation. Cardiac spillovers of NE are much higher in untreated5 6 than in treated CHF patients,7 probably reflecting more sympathetic recruitment in untreated patients. Thus, although decreased efficiency of NE reuptake contributed substantially to increased cardiac adrenergic drive in the treated CHF patients of the present study, increased NE release might contribute more to elevated cardiac NE spillovers in untreated patients.5 6
Vesicular Leakage of NE
Comparison of the desipramine-sensitive cardiac neuronal
removal of [3H]NE and spillover of
[3H]DHPG (Table 4) indicates that in control subjects,
18.1-fold more NE enters the cardiac sympathetic axoplasm than is
released into plasma as DHPG, compared with 14.0-fold more in patients
with CHF. Thus, from the cardiac spillovers of
endogenous DHPG (Table 2), rates of entry of NE into the
cardiac sympathetic axoplasm can be estimated to be 12 761 pmol/min
(18.1x705) in control subjects and 9296 pmol/min (14x664) in CHF
patients. Subtraction of the corresponding neuronal reuptake rates
shows that vesicular leakage of NE is higher in control subjects than
in patients with CHF (10 330 versus 5967 pmol/min). Thus, although
rates of neuronal release, reuptake, and spillover of NE are higher
in the failing than in the normal heart, the rate of leakage of
transmitter from cardiac storage vesicles is lower (Fig 5),
presumably reflecting depletion of cardiac NE
stores.10 11 12 13 14 15
Cardiac NE Stores
Reduced tissue stores of NE in the failing heart are reflected by
differences in the time-dependent increases in specific activity of
[3H]DHPG produced in the hearts of control subjects and
CHF patients (Fig 1). The linear time-dependent increase in
[3H]DHPG specific activity reflects the increase in the
specific activity of [3H]NE in vesicular stores secondary
to accumulation of infused [3H]NE.24 The
rate of increase varies directly with the rate of entry of
[3H]NE into vesicular stores and inversely with the
amount of endogenous NE available to dilute the sequestered
[3H]NE. The amount of NE in vesicular stores may
therefore be estimated by dividing the rate of vesicular sequestration
of [3H]NE by the rate of increase in specific activity of
[3H]DHPG (Table 5). The NE content of the
normal human myocardium is between 4 and 8
nmol/g,12 13 or 1 to 2 µmol in a normal 250-g left
ventricle. The present estimates (Table 5) are close to this range;
however, they reflect the NE content of only that region of the
myocardium drained by the coronary sinus. The 50%
lower cardiac NE content in the failing heart agrees with previous
findings.10 11 12 13 14 15
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Cardiac NE Turnover
As illustrated in Fig 5, NE turnover depends much less on neuronal
release of NE than on leakage of NE from storage vesicles. The
present data show that the contributions of neuronal release and
vesicular leakage to NE turnover are altered reciprocally in CHF; thus,
the overall net increase in NE turnover is small. However, in keeping
with other findings,35 the rate constant for NE turnover
is increased substantially in CHF, resulting in considerable reduction
of the half-life of cardiac NE stores (Table 5).
The calculated rate constants for NE leakage (Table 5) are close to
that of 0.018 min-1 calculated by Ulli
Trendelenburg, MD, PhD (unpublished data, 1993), from fractional rates
of loss of NE in the isolated rat vas deferens.36
Similar rate constants for vesicular leakage in control subjects and
CHF patients indicate that the decreased rate of NE leakage in the
failing heart reflects the depleted state of NE stores. Furthermore,
the similar rate constants for vesicular leakage indicate that the
greater rate constant for cardiac NE turnover in CHF must be due to
greater neuronal release of NE in the failing heart. Less efficient NE
reuptake (85% versus 92%) and vesicular sequestration (88%
versus 92%) in the failing than in the normal heart could also
contribute to the increased rate constant for cardiac NE turnover in
CHF.
Cardiac NE Synthesis
Results of previous studies in animal models of CHF suggested that
reduced tyrosine hydroxylase activity11 37 or impaired
conversion of DA to NE14 could contribute to depletion of
NE stores in the failing heart. In contrast, the present results
suggest that depletion of NE stores may reflect attainment of a new
steady state in response to chronic alterations in the determinants of
NE turnover. Reduced cardiac tissue stores of NE lessen the
contribution of vesicular leakage to the increase in NE turnover and
thus minimize the increase in catecholamine biosynthesis
required to maintain constant stores of transmitter. Thus, the small
31% increase in the overall rate of NE turnover in the failing heart
was matched closely by the 32% increase in dopa spillover (Table 2), indicating that the activity of tyrosine hydroxylase was increased
to a level adequate to maintain cardiac NE stores at their lowered
level.
Lack of cardiac dopa production in patients with heart
transplants38 or pure autonomic failure,39
and positive relationships between cardiac NE turnover and cardiac dopa
spillover25 40 support the view that cardiac dopa
spillover reliably reflects cardiac tyrosine hydroxylase activity.
This is also supported in the present study by the magnitude of the
increases in cardiac dopa spillover during exercise that matched
closely those in NE turnover (Fig 4). Similar relative increases in
cardiac dopa spillover to NE turnover in both groups indicate
adequate capacity of tyrosine hydroxylase to respond to increased NE
turnover in the failing heart.
Conclusions
Increased neuronal release of NE and decreased efficiency of
NE reuptake both contribute to cardiac adrenergic activation in CHF.
Decreased vesicular leakage of NE in the failing heart due to depleted
cardiac NE stores limits the increase in cardiac NE turnover that
results from increased NE release. Chronically increased NE release
combined with reduced efficiency of NE reuptake and storage may
contribute to depletion of NE stores in CHF.
|
Selected Abbreviations and Acronyms |
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Acknowledgments |
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The authors gratefully acknowledge the expert technical assistance of Anneli Ambring, Helen Cox, Douglas Hooper, and Andrea Turner.
Received August 31, 1995; revision received October 25, 1995; accepted November 3, 1995.
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References |
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 I. A. Sharpe, E. Palant, C. I. Schroeder, D. M. Kaye, D. J. Adams, P. F. Alewood, and R. J. Lewis Inhibition of the Norepinephrine Transporter by the Venom Peptide {chi}-MrIA: SITE OF ACTION, Na+ DEPENDENCE, AND STRUCTURE-ACTIVITY RELATIONSHIP J. Biol. Chem., October 10, 2003; 278(41): 40317 - 40323. [Abstract] [Full Text] [PDF]
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S.-T. Li, C. Holmes, I. J. Kopin, and D. S. Goldstein Aging-Related Changes in Cardiac Sympathetic Function in Humans, Assessed by 6-18F-Fluorodopamine PET Scanning J. Nucl. Med., October 1, 2003; 44(10): 1599 - 1603. [Abstract] [Full Text] [PDF]
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H. Terai, M. Shimizu, H. Ino, M. Yamaguchi, K. Uchiyama, K. Oe, K. Nakajima, J. Taki, M. Kawano, and H. Mabuchi Changes in Cardiac Sympathetic Nerve Innervation and Activity in Pathophysiologic Transition from Typical to End-Stage Hypertrophic Cardiomyopathy J. Nucl. Med., October 1, 2003; 44(10): 1612 - 1617. [Abstract] [Full Text] [PDF]
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K. Mardon, O. Montagne, N. Elbaz, Z. Malek, A. Syrota, J.-L. Dubois-Rande, M. Meignan, and P. Merlet Uptake-1 Carrier Downregulates in Parallel with the {beta}-Adrenergic Receptor Desensitization in Rat Hearts Chronically Exposed to High Levels of Circulating Norepinephrine: Implications for Cardiac Neuroimaging in Human Cardiomyopathies J. Nucl. Med., September 1, 2003; 44(9): 1459 - 1466. [Abstract] [Full Text] [PDF]
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K. Morita, Y. Kuge, and N. Tamaki What Is the Clinical Role of Neuronal Imaging? J. Nucl. Med., September 1, 2003; 44(9): 1467 - 1468. [Full Text] [PDF]
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 J. A L Calbet Chronic hypoxia increases blood pressure and noradrenaline spillover in healthy humans J. Physiol., August 15, 2003; 551(1): 379 - 386. [Abstract] [Full Text] [PDF]
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A. Igawa, T. Nozawa, N. Fujii, B.-i. Kato, H. Asanoi, and H. Inoue Long-term treatment with Low-Dose, but not High-Dose, guanethidine improves ventricular function and survival of rats with heart failure after myocardial infarction J. Am. Coll. Cardiol., August 6, 2003; 42(3): 541 - 548. [Abstract] [Full Text] [PDF]
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 G. Horvath, A. Torbati, G. E. Conner, M. Salathe, and A. Wanner Systemic Ovalbumin Sensitization Downregulates Norepinephrine Uptake by Rabbit Aortic Smooth Muscle Cells Am. J. Respir. Cell Mol. Biol., December 1, 2002; 27(6): 746 - 751. [Abstract] [Full Text] [PDF]
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 D. S. Goldstein, D. Robertson, M. Esler, S. E. Straus, and G. Eisenhofer Dysautonomias: Clinical Disorders of the Autonomic Nervous System Ann Intern Med, November 5, 2002; 137(9): 753 - 763. [Abstract] [Full Text] [PDF]
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C.-S. Liang, Y. Himura, M. Kashiki, and S. Y. Stevens Differential pre- and postsynaptic effects of desipramine on cardiac sympathetic nerve terminals in RHF Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1863 - H1872. [Abstract] [Full Text] [PDF]
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K. Leineweber, T. Wangemann, C. Giessler, H. Bruck, S. Dhein, M. Kostelka, F.-W. Mohr, R.-E. Silber, and O.-E. Brodde Age-dependent changes of cardiac neuronal noradrenaline reuptake transporter (uptake1) in the human heart J. Am. Coll. Cardiol., October 16, 2002; 40(8): 1459 - 1465. [Abstract] [Full Text] [PDF]
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 P G Camici Imaging of cardiac adrenergic innervation Heart, September 1, 2002; 88(3): 209 - 210. [Full Text] [PDF]
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M. Esler, J. Hastings, G. Lambert, D. Kaye, G. Jennings, and D. R. Seals The influence of aging on the human sympathetic nervous system and brain norepinephrine turnover Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2002; 282(3): R909 - R916. [Abstract] [Full Text] [PDF]
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S. C. Malpas Neural influences on cardiovascular variability: possibilities and pitfalls Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H6 - H20. [Abstract] [Full Text] [PDF]
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D. L. Jardine, C. J. Charles, I. C. Melton, C. N. May, M. D. Forrester, C. M. Frampton, S. I. Bennett, and H. Ikram Continual recordings of cardiac sympathetic nerve activity in conscious sheep Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H93 - H99. [Abstract] [Full Text] [PDF]
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T. Wakabayashi, T. Nakata, A. Hashimoto, S. Yuda, K. Tsuchihashi, M. I. Travin, and K. Shimamoto Assessment of Underlying Etiology and Cardiac Sympathetic Innervation to Identify Patients at High Risk of Cardiac Death J. Nucl. Med., December 1, 2001; 42(12): 1757 - 1767. [Abstract] [Full Text] [PDF]
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 F.M. Bengel, B. Permanetter, M. Ungerer, S.G. Nekolla, and M. Schwaiger Relationship between altered sympathetic innervation, oxidative metabolism and contractile function in the cardiomyopathic human heart; a non-invasive study using positron emission tomography Eur. Heart J., September 1, 2001; 22(17): 1594 - 1600. [Abstract] [PDF]
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F. Qin, N. K. Rounds, W. Mao, K. Kawai, and C.-s. Liang Antioxidant vitamins prevent cardiomyocyte apoptosis produced by norepinephrine infusion in ferrets Cardiovasc Res, September 1, 2001; 51(4): 736 - 748. [Abstract] [Full Text] [PDF]
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H.P Brunner-La Rocca, M.D Esler, G.L Jennings, and D.M Kaye Effect of cardiac sympathetic nervous activity on mode of death in congestive heart failure Eur. Heart J., July 1, 2001; 22(13): 1136 - 1143. [Abstract] [PDF]
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P Acar, P Merlet, L Iserin, D Bonnet, D Sidi, A Syrota, and J Kachaner Impaired cardiac adrenergic innervation assessed by MIBG imaging as a predictor of treatment response in childhood dilated cardiomyopathy Heart, June 1, 2001; 85(6): 692 - 696. [Abstract] [Full Text]
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U. Lotze, S. Kaepplinger, A. Kober, B. M. Richartz, D. Gottschild, and H. R. Figulla Recovery of the Cardiac Adrenergic Nervous System After Long-Term {beta}-Blocker Therapy in Idiopathic Dilated Cardiomyopathy: Assessment by Increase in Myocardial 123I-Metaiodobenzylguanidine Uptake J. Nucl. Med., January 1, 2001; 42(1): 49 - 54. [Abstract] [Full Text] [PDF]
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 C. F. Notarius and J. S. Floras Limitations of the use of spectral analysis of heart rate variability for the estimation of cardiac sympathetic activity in heart failure Europace, January 1, 2001; 3(1): 29 - 38. [Abstract] [PDF]
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E. Omerovic, E. Bollano, R. Mobini, V. Kujacic, B. Madhu, B. Soussi, M. Fu, A. Hjalmarson, F. Waagstein, and J. Isgaard Growth Hormone Improves Bioenergetics and Decreases Catecholamines in Postinfarct Rat Hearts Endocrinology, December 1, 2000; 141(12): 4592 - 4599. [Abstract] [Full Text] [PDF]
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A. Bottner, A. Haidan, G. Eisenhofer, K. Kristensen, A. L. Castle, W. A. Scherbaum, H. Schneider, G. P. Chrousos, and S. R. Bornstein Increased Body Fat Mass and Suppression of Circulating Leptin Levels in Response to Hypersecretion of Epinephrine in Phenylethanolamine-N-Methyltransferase (PNMT)-Overexpressing Mice Endocrinology, November 1, 2000; 141(11): 4239 - 4246. [Abstract] [Full Text] [PDF]
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J. Shite, E. Dong, H. Kawai, S. Y. Stevens, and C.-S. Liang Selegiline improves cardiac sympathetic terminal function and beta -adrenergic responsiveness in heart failure Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H1283 - H1290. [Abstract] [Full Text] [PDF]
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C.-s. Liang, N. K. Rounds, E. Dong, S. Y. Stevens, J. Shite, and F. Qin Alterations by Norepinephrine of Cardiac Sympathetic Nerve Terminal Function and Myocardial {beta}-Adrenergic Receptor Sensitivity in the Ferret : Normalization by Antioxidant Vitamins Circulation, July 4, 2000; 102(1): 96 - 103. [Abstract] [Full Text] [PDF]
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H. Kawai, A. Mohan, J. Hagen, E. Dong, J. Armstrong, S. Y. Stevens, and C.-S. Liang Alterations in cardiac adrenergic terminal function and beta -adrenoceptor density in pacing-induced heart failure Am J Physiol Heart Circ Physiol, May 1, 2000; 278(5): H1708 - H1716. [Abstract] [Full Text] [PDF]
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H. Senzaki, N. Paolocci, Y. A. Gluzband, M. L. Lindsey, J. S. Janicki, M. T. Crow, and D. A. Kass {beta}-Blockade Prevents Sustained Metalloproteinase Activation and Diastolic Stiffening Induced by Angiotensin II Combined With Evolving Cardiac Dysfunction Circ. Res., April 14, 2000; 86(7): 807 - 815. [Abstract] [Full Text] [PDF]
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K. P. Patel, K. Zhang, and P. K. Carmines Norepinephrine turnover in peripheral tissues of rats with heart failure Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2000; 278(3): R556 - R562. [Abstract] [Full Text] [PDF]
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A. Bottner, G. Eisenhofer, P. Friberg, B. Rundqvist, and S.R. Bornstein Serum leptin levels in heart failure patients may be altered differently according to clinical stage Eur. Heart J., February 2, 2000; 21(4): 334 - 335. [PDF]
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 C. A. Walker, F. A. Crawford Jr, and F. G. Spinale MYOCYTE CONTRACTILE DYSFUNCTION WITH HYPERTROPHY AND FAILURE: RELEVANCE TO CARDIAC SURGERY J. Thorac. Cardiovasc. Surg., February 1, 2000; 119(2): 388 - 400. [Full Text] [PDF]
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O.-E. Brodde and M. C. Michel Adrenergic and Muscarinic Receptors in the Human Heart Pharmacol. Rev., December 1, 1999; 51(4): 651 - 690. [Abstract] [Full Text] [PDF]
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L. Spinelli, M. Petretta, F. Marciano, G. Testa, M. A. E. Rao, M. Volpe, and D. Bonaduce Cardiac autonomic responses to volume overload in normal subjects and in patients with dilated cardiomyopathy Am J Physiol Heart Circ Physiol, October 1, 1999; 277(4): H1361 - H1368. [Abstract] [Full Text] [PDF]
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H. Kawai, T.-H. M. Fan, E. Dong, R. A. Siddiqui, A. Yatani, S. Y. Stevens, and C.-S. Liang ACE inhibition improves cardiac NE uptake and attenuates sympathetic nerve terminal abnormalities in heart failure Am J Physiol Heart Circ Physiol, October 1, 1999; 277(4): H1609 - H1617. [Abstract] [Full Text] [PDF]
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A. Cohen-Solal, Y. Esanu, D. Logeart, F. Pessione, C. Dubois, G. Dreyfus, R. Gourgon, and P. Merlet Cardiac metaiodobenzylguanidine uptake in patients with moderate chronic heart failure: relationship with peak oxygen uptake and prognosis J. Am. Coll. Cardiol., March 1, 1999; 33(3): 759 - 766. [Abstract] [Full Text] [PDF]
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J. R. Henegar, D. D. Schwartz, and J. S. Janicki ANG II-related myocardial damage: role of cardiac sympathetic catecholamines and beta -receptor regulation Am J Physiol Heart Circ Physiol, August 1, 1998; 275(2): H534 - H541. [Abstract] [Full Text] [PDF]
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I. J. Kopin, B. Rundqvist, P. Friberg, J. Lenders, D. S. Goldstein, and G. Eisenhofer Different relationships of spillover to release of norepinephrine in human heart, kidneys, and forearm Am J Physiol Regulatory Integrative Comp Physiol, July 1, 1998; 275(1): R165 - R173. [Abstract] [Full Text] [PDF]
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T. Nozawa, A. Igawa, N. Yoshida, M. Maeda, M. Inoue, Y. Yamamura, H. Asanoi, and H. Inoue Dual-Tracer Assessment of Coupling Between Cardiac Sympathetic Neuronal Function and Downregulation of ß-Receptors During Development of Hypertensive Heart Failure of Rats Circulation, June 16, 1998; 97(23): 2359 - 2367. [Abstract] [Full Text] [PDF]
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 G. Eisenhofer, H. Keiser, P. Friberg, E. Mezey, T.-T. Huynh, B. Hiremagalur, T. Ellingson, S. Duddempudi, A. Eijsbouts, and J. W. M. Lenders Plasma Metanephrines Are Markers of Pheochromocytoma Produced by Catechol-O-Methyltransferase Within Tumors J. Clin. Endocrinol. Metab., June 1, 1998; 83(6): 2175 - 2185. [Abstract] [Full Text]
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G. Eisenhofer, B. Rundqvist, and P. Friberg Determinants of cardiac tyrosine hydroxylase activity during exercise-induced sympathetic activation in humans Am J Physiol Regulatory Integrative Comp Physiol, March 1, 1998; 274(3): R626 - R634. [Abstract] [Full Text] [PDF]
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M. Ungerer, F. Hartmann, M. Karoglan, A. Chlistalla, S. Ziegler, G. Richardt, M. Overbeck, H. Meisner, A. Schomig, and M. Schwaiger Regional In Vivo and In Vitro Characterization of Autonomic Innervation in Cardiomyopathic Human Heart Circulation, January 20, 1998; 97(2): 174 - 180. [Abstract] [Full Text] [PDF]
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G. Grassi, M. Colombo, G. Seravalle, D. Spaziani, and G. Mancia Dissociation Between Muscle and Skin Sympathetic Nerve Activity in Essential Hypertension, Obesity, and Congestive Heart Failure Hypertension, January 1, 1998; 31(1): 64 - 67. [Abstract] [Full Text] [PDF]
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G. Eisenhofer, A. Aneman, P. Friberg, D. Hooper, L. Fandriks, H. Lonroth, B. Hunyady, and E. Mezey Substantial Production of Dopamine in the Human Gastrointestinal Tract J. Clin. Endocrinol. Metab., November 1, 1997; 82(11): 3864 - 3871. [Abstract] [Full Text] [PDF]
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 D. S. Goldstein, C. Holmes, R. O. Cannon, G. Eisenhofer, and I. J. Kopin Sympathetic Cardioneuropathy in Dysautonomias N. Engl. J. Med., March 6, 1997; 336(10): 696 - 702. [Abstract] [Full Text] [PDF]
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B. Rundqvist, G. Eisenhofer, M. Elam, and P. Friberg Attenuated Cardiac Sympathetic Responsiveness During Dynamic Exercise in Patients With Heart Failure Circulation, February 18, 1997; 95(4): 940 - 945. [Abstract] [Full Text]
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B. Rundqvist, M. Elam, Y. Bergmann-Sverrisdottir, G. Eisenhofer, and P. Friberg Increased Cardiac Adrenergic Drive Precedes Generalized Sympathetic Activation in Human Heart Failure Circulation, January 7, 1997; 95(1): 169 - 175. [Abstract] [Full Text]
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G. Bru-Mercier, E. Deroubaix, D. Rousseau, A. Coulombe, and J.-F. Renaud Depressed transient outward potassium current density in catecholamine-depleted rat ventricular myocytes Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1237 - H1247. [Abstract] [Full Text] [PDF]
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