Download 1 Norepinephrine Transporter Function and Human - AJP

Articles in PresS. Am J Physiol Heart Circ Physiol (September 28, 2012). doi:10.1152/ajpheart.00492.2012
1
2
Norepinephrine Transporter Function and Human Cardiovascular Disease
3
4
5
C Schroeder and J Jordan*
6
Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany
7
8
9
10
11
12
*Corresponding Author:
13
Jens Jordan, M.D.
14
Institute of Clinical Pharmacology
15
Hannover Medical School
16
Carl-Neuberg-Str. 1
17
30625 Hannover, Germany
18
Phone: +49-511-532 2821
19
Fax: +49-511-532 2750
20
Email: [email protected]
21
Copyright © 2012 by the American Physiological Society.
2
22
Abstract
23
Approximately 80-90% of the norepinephrine released in the brain or in peripheral
24
tissues is taken up again through the neuronal norepinephrine transporter (NET).
25
Pharmacological studies with NET inhibitors showed that NET has opposing effects
26
on cardiovascular sympathetic regulation in the brain and in the periphery.
27
Furthermore, NET is involved in the distribution of sympathetic activity between
28
vasculature, heart, and kidney. Genetic NET dysfunction is a rare cause of the
29
postural tachycardia syndrome.
30
adrenergic stimulation of the heart, particularly with standing.
31
inhibition may be beneficial in hypoadrenergic states, such as central autonomic
32
failure, or neurally mediated syncope, which results from acute sympathetic
33
withdrawal. Biochemical studies suggested reduced NET function in some patients
34
with essential hypertension.
35
reduced in common heart diseases, such as congestive heart failure, ischemic heart
36
disease, and stress-induced cardiomyopathy.
37
consequence or cause of progressive heart disease in human subjects requires
38
further study. However, studies with the non selective NET inhibitor sibutramine
39
suggest that reduced NET function could have an adverse effect on the
40
cardiovascular system. Given the widespread use of medications inhibiting NET, the
41
issue deserves more attention.
The condition is characterized by excessive
Conversely, NET
Furthermore, cardiac NET function appears to be
Whether NET dysfunction is a
42
43
Key words: norepinephrine, norepinephrine transporter, cardiovascular, autonomic
44
nervous system, blood pressure regulation
45
46
3
47
Introduction
48
With few exceptions, norepinephrine is the main neurotransmitter released from
49
postganglionic sympathetic neurons in peripheral tissues.
50
serves as an important neurotransmitter in the brain. Norepinephrine’s biological
51
effects are mediated through stimulation of pre- and postsynaptic adrenoceptors. In
52
the periphery, norepinephrine increases heart rate, cardiac contractility, vascular
53
tone, renin angiotensin system activity, and renal sodium reabsorption. In contrast,
54
in some brain areas, norepinephrine shuts off centrally generated sympathetic
55
activity.
56
through the neuronal norepinephrine transporter (NET, Figure 1) (32).
Norepinephrine also
Approximately 80-90% of the released norepinephrine is taken up again
NET belongs to the monoamine transporter superfamily and consists of 12
57
58
transmembrane domains (14).
59
active transport that is dependent on Na+ and Cl- ions. Uptake is driven by an
60
inwardly directed Na+ gradient maintained by the action of the Na+-K+-ATPase (14).
61
A smaller proportion of the released norepinephrine spills out of the synaptic cleft, is
62
taken
63
methyltransferase (COMT). Norepinephrine that has been taken up by NET is either
64
repackaged into vesicles via the vesicular monoamine transporter-2 (VMAT2) or
65
degraded
66
dihydroxyphenylglycol (DHPG).
up
by
by
extraneuronal
Norepinephrine reuptake by NET is a secondary
tissues,
monoaminooxidase
and
is
metabolized
(MAO).
The
main
by
catechol-O-
metabolite
is
67
The role of catecholamine biosynthesis, release, and metabolism for the
68
regulation of sympathetic tone and blood pressure has received increasing attention
69
recently (26). Given the central role of NET in the regulation of central nervous
70
system
71
norepinephrine transporter function could have important effects on the human body,
72
particularly the cardiovascular system. Indeed, altered NET has been implicated in a
and
peripheral
norepinephrine
turnover,
even
subtle
changes
in
4
73
number of cardiovascular disorders that will be reviewed in the following sections.
74
The fact that altered NET function induces changes in cardiovascular regulation is
75
well documented.
76
cardiovascular structure. Studies in patients with the postural tachycardia syndrome
77
(POTS) suggest that changes in NET function can occur through genetic
78
mechanisms.
79
antidepressants, inhibit NET. Pharmacological NET inhibition may not be without
80
risk as indicated by a recently completed placebo-controlled study with the weight
81
loss drug sibutramine.
However, chronic changes in NET function may also affect
Moreover,
commonly
prescribed
medications,
particularly
82
83
Genetic influences on norepinephrine transporter function and familial
84
norepinephrine transporter deficiency
85
The postural tachycardia syndrome (POTS) is a relatively common condition
86
primarily affecting women in their reproductive years (57; 62; 63). POTS is defined
87
as an exaggerated increase in heart rate of >30 bpm upon standing without
88
orthostatic hypotension, together with orthostatic symptoms persisting for more than
89
3 months (38).
90
these patients (57; 62).
91
extensive physiological, biochemical, and pharmacological testing suggested
92
reduced neuronal norepinephrine uptake. The systemic clearance of radioactively
93
labeled norepinephrine was substantially reduced. Furthermore, the patient showed
94
attenuated norepinephrine release during tyramine infusion. Tyramine requires a
95
functioning norepinephrine transporter to enter adrenergic neurons and to release
96
norepinephrine. Together, these findings suggested that hyperadrenergic symptoms
97
in the twin pair may have been secondary to impaired norepinephrine uptake.
98
Elevated plasma norepinephrine concentrations are common in
In a POTS patient and her monozygotic twin sister,
The human NET gene (SLC6A2, NET-1) was isolated and cloned in 1991
5
99
(97). The gene is located on chromosome 16q12.2 and encodes a 617 amino acids
100
protein (16).
The patient was heterozygous for a previously unknown mutation
101
(g237c) of the NET gene. The g237c mutation is associated with an alanine to
102
proline (A457P) amino acid exchange. The patient and family members who were
103
heterozygous for A457P showed increased upright heart rate and plasma
104
norepinephrine
105
homozygous for wild type NET. The DHPG to norepinephrine ratio, which provides a
106
crude biochemical estimate of norepinephrine uptake and metabolism, was reduced
107
in A457P heterozygous family members. Chinese hamster ovary cells transiently
108
transfected with the mutated NET showed <2 % norepinephrine uptake activity
109
compared with cells expressing wild type NET (106; 116).
110
revealed impairment in processing of NET-A457P and a decrease in cell surface
111
expression to approximately 30% compared with the wild type (45).
112
mutated NET was coexpressed with wild type NET, norepinephrine uptake remained
113
profoundly reduced. Apparently, mutated NET oligomerizes with wild type NET
114
thereby decreasing NET expression at the cell surface as well as norepinephrine
115
uptake (45).
116
mutated gene is sufficient to cause symptoms of the postural tachycardia syndrome.
117
However, we and others failed to identify additional families carrying the NET-
118
A457P mutation (92). Yet, POTS patients not carrying the A457P mutation showed
119
decreased NET protein expression compared to healthy subjects in leukocytes (8)
120
and forearm veins (72).
measurements
compared
with
family
members
who
were
Subsequent studies
When the
This dominant negative effect explains why heterozygosity of the
121
A number of more common polymorphisms in the NET gene have been
122
identified (14; 46; 108; 125). Most of the functional polymorphisms code for NET
123
variants with decreased norepinephrine affinity (14) (R121Q, N292T, A369P, Y548H
124
(45), A457P (106; 116)). However, genetic variants associated with increased NET
6
125
function in vitro have been described as well (F528C (45)). Hahn et al. studied
126
protein expression, trafficking, and norepinephrine reuptake function in a number of
127
NET polymorphisms leading to an amino acid exchange (45). The investigators also
128
tested whether or not these polymorphisms responded normally to proteinkinase C
129
and to pharmacological inhibition with the prototypical tricyclic antidepressant
130
desipramine.
131
polymorphism was retained intracellularly and lacked norepinephrine transport
132
activity much like the A457P mutation in patients with NET deficiency. A369P and
133
N292T polymorphisms exerted a dominant negative effect on wild type NET. In
134
contrast, the F528C polymorphism increased norepinephrine uptake by 30%.
135
Remarkably, norepinephrine uptake through the F528C NET variant was not blocked
136
by desipramine and was insensitive to proteinkinase C-mediated down-regulation.
137
Allele frequencies as high as 5% for A369P and 10% for N292T and F528C have
138
been identified in the literature (45). However, these numbers are controversial.
139
Recently, the frequency of two other NET gene variants (T182C and A3081T) that
140
alter NET promoter activity has been reported as 44 % and 59 %, respectively, in a
141
sample of 145 healthy volunteers (67).
142
associated with the pressor response during exercise, but not with heart rate or
143
plasma catecholamine changes. Splice variants for the NET gene product have also
144
been described (66; 124).
Six out of ten polymorphisms altered NET function.
The A369P
These NET variants were significantly
145
Finally, the NET gene may be subject to epigenetic modification (7; 48).
146
Recently, Bayles et al. reported reduced NET expression in leukocytes from POTS
147
patients that could not be explained by genetic variation of the NET gene (8). NET
148
promoter methylation did not differ between groups.
149
chromatinization differed markedly between POTS patients and healthy subjects,
150
indicating extensive histone modification that might explain differences in NET
However, NET gene
7
151
expression (8).
152
Given the known efficacy of medications inhibiting NET in the treatment of
153
depression, several groups tested the hypothesis that common NET polymorphisms
154
are associated with psychiatric disorders.
155
results with some indicating an association with depression (44; 109), panic disorder
156
(19; 73), attention deficit disorder (12; 47), and social phobia (40), while others did
157
not (96; 105). However, increased sympathetic tone has been identified as a likely
158
contributor to the increased cardiovascular risk in various psychiatric diseases (33),
159
particularly depression (41). Biochemical data suggests that reduced cardiac NET
160
function might be present at least in some patients with major depression (6). It is
161
tempting to speculate that disordered NET function in depression is due to altered
162
physiological regulation of epigenetic mechanisms rather than genetics. If so, these
163
mechanisms could provide yet another target for treating depression as well as the
164
associated disordered sympathetic regulation.
These studies yielded controversial
165
Studies on NET genetics and cardiovascular disease are scarce. However,
166
an association between a polymorphism in the promoter 3 region of the NET gene
167
and hypertension has been found in Japanese and Caucasian populations (95; 136).
168
In another study, a different NET polymorphism was associated with hypertension in
169
patients with type 2 diabetes (70). Since many association studies have not been
170
replicated, these observations should be interpreted cautiously.
171
biochemical and pharmacological studies suggesting reduction in neuronal
172
norepinephrine uptake in some patients with essential arterial hypertension are
173
reassuring (31; 111).
However,
174
175
Pharmacological NET inhibition – insight in human physiology
176
Genetic studies, particularly studies in patients with NET deficiency, strongly
8
177
suggested that NET may contribute to human cardiovascular disease. However,
178
much of the information on how NET affects the human cardiovascular system has
179
been obtained in pharmacological studies with selective and non selective NET
180
inhibitors. Together, these studies suggest that NET regulates the cardiovascular
181
system through actions in both, peripheral tissues and the brain.
182
In healthy subjects, short-term pharmacological NET inhibition increases
183
resting blood pressure and heart rate in the supine position (114). Paradoxically, the
184
pressor response to sympathetic stimuli, such as the cold pressor test, is decreased
185
with NET inhibition (114).
186
inhibitor sibutramine, an adjunctive obesity treatment, elicits similar acute
187
hemodynamic responses, both, in healthy subjects (10) and in obese patients (11;
188
52). Thus, NET inhibition can inhibit as well as stimulate sympathetic responses.
The combined serotonin and norepinephrine uptake
189
When NET inhibitors are infused intra-arterially into the forearm in doses
190
insufficient to cause a systemic response, norepinephrine in forearm veins is
191
increased (21).
192
responses.
193
concentrations in the supine position (113) as well as systemic norepinephrine
194
spillover (34).
195
activity (Figure 2) (34; 128). Finally, NET inhibition shifts the sympathetic baroreflex
196
curve towards a higher blood pressure without affecting its slope (128).
197
changes in norepinephrine turnover and sympathetic nerve traffic are consistent with
198
central nervous sympathetic inhibition.
199
inhibition elicited by NET blockade may be mediated through alpha2-adrenoceptor
200
stimulation in the brain (30).
This peripheral mechanism tends to increase sympathetic
In contrast, systemic NET inhibition reduces venous norepinephrine
NET inhibition profoundly decreases resting sympathetic nerve
These
Animal studies suggest that sympathetic
201
Taken together, effect of NET inhibition on blood pressure results from a
202
sympatholytic actions in the brain, which tends to lower pressure, and a stimulatory
9
203
effect in the periphery, which tends to raise pressure. The idea is supported by the
204
observation that patients with increased centrally generated sympathetic activity
205
experience a lesser increase in blood pressure than patients with lower sympathetic
206
activity when treated with a NET inhibitor (51).
207
sympathetic activity, the sympatholytic effect opposes peripheral actions of the NET
208
inhibitor. In contrast, in patients with low sympathetic activity, sympathetic activity
209
cannot be decreased further, such that the peripheral NET inhibitor action prevails.
210
In accordance with this concept, selective NET blockade with atomoxetine induced a
211
substantial increase in blood pressure in patients with central autonomic failure
212
(119). In this condition, peripheral adrenergic neurons are disconnected from
213
brainstem input (117) such that the peripheral stimulatory effect of NET inhibition is
214
unmasked.
In patients with increased
215
NET inhibition changes norepinephrine turnover in an organ specific fashion.
216
Studies with the non-selective NET inhibitor desipramine showed reductions in
217
forearm and renal norepinephrine spillover (34). In contrast, cardiac norepinephrine
218
spillover increased with desipramine (34).
219
adrenergic activity between organs lead to corresponding changes in organ function.
220
For example, NET inhibition attenuates supine and upright plasma renin activity and
221
angiotensin II concentrations (80).
222
vasoconstriction with standing (80).
223
increase in plasma norepinephrine during orthostatic stress (113) and profoundly
224
increases upright heart rate thus, mimicking the hemodynamic abnormalities in
225
POTS patients (Figure 3) (114). NET inhibition also raises heart rate with exposure
226
to gravitational stress in a human centrifuge (126). Yet, NET inhibition prevents
227
neurally mediated presyncope and syncope during head-up tilt testing (Figure 4),
228
which are characterized by acute sympathetic withdrawal (113).
These changes in the distribution of
NET inhibition also attenuates renal
In contrast, NET inhibition augments the
10
229
We observed considerable gender differences in the hemodynamic response
230
to short-term NET inhibition. The increase in resting blood pressure, which was
231
mainly due to an increase in cardiac output, was three-fold larger in men than in
232
women.
233
extent in men than in women, which could indicate reduced cardiac NET activity in
234
women (112).
235
hormones during the menstrual cycle are associated with changes in the
236
cardiovascular response to NET inhibition (85).
Furthermore, NET inhibition augmented upright heart rate to a greater
A subsequent study indicated that fluctuations in female sex
237
238
NET dysfunction and chronic heart disease
239
Recent studies suggest an association between chronically altered NET function and
240
heart disease.
241
norepinephrine uptake from the synaptic cleft through NET is an active, energy-
242
dependent process (14) which could be altered in conditions characterized by limited
243
oxygen and substrate supply. It is also possible that altered norepinephrine uptake
244
promotes heart disease.
245
correlations, cause and effect are difficult to distinguish from each other.
Heart diseases may alter norepinephrine uptake.
Indeed,
Since many clinical investigations in this field rely on
246
The idea that excessive synaptic norepinephrine concentrations may promote
247
heart disease through NET dysfunction is not new. More than two decades ago,
248
profoundly diminished norepinephrine uptake was described in hypertrophic
249
cardiomyopathy patients (15). Excessive catecholamine concentrations can acutely
250
damage the heart (79) and contribute to myocardial electrical instability, thereby
251
predisposing to cardiac dysrhythmias (122).
252
release in patients with pheochromocytoma can induce a cardiac myopathy (42).
253
Evidence for excessive adrenergic activity in the heart has been reported in
254
myocardial infarction (1), unstable ischemic heart disease (81), stress-induced
Indeed, excessive catecholamine
11
255
cardiomyopathy (71), and congestive heart failure (104). In patients with myocardial
256
infarction, norepinephrine spillover was increased in those who subsequently
257
developed heart failure (1). Excessive plasma norepinephrine concentrations predict
258
a poor prognosis in patients with severe congestive heart failure (98). Yet, the most
259
persuasive finding linking excessive cardiac sympathetic activity with heart disease
260
progression is the beneficial effect of beta-adrenoceptor blockers in congestive heart
261
failure (36; 58) and after acute myocardial infarction (39). Beta-adrenergic blockade
262
does not seem to decrease cardiac sympathetic tone itself (5), but rather block its
263
deleterious effects on the myocardium.
264
Excessive sympathetic neural drive to the heart appears to be the dominant
265
mechanism leading to adrenergic overactivation in heart failure. However, NET
266
dysfunction could further exacerbate sympathetically mediated heart disease. In
267
addition, NET dysfunction could limit the physiological adjustment in cardiac
268
sympathetic through depletion of norepinephrine stores. Cardiac tracers applied in
269
clinical imaging such as [123I]-MIBG, [18F]-fluorodopamine, [11C]-hydroxyephedrine,
270
and [3H]-norepinephrine, are all dependent on uptake into cardiac adrenergic nerve
271
terminals through NET. Decreased tracer uptake has been observed in patients with
272
myocardial infarction (68; 120; 121), stress-induced cardiomyopathy (17; 23; 56; 88;
273
100; 101; 110; 127; 135), and congestive heart failure (2; 84). In a small study in
274
patients with arrhythmogenic right ventricle cardiomyopathy cardiac uptake of [11C]-
275
hydroxyephedrine tended to be attenuated (133). Finally, in idiopathic ventricular
276
arrhythmia patients, the NET gene expression was downregulated in the septal wall
277
of the right ventricular outflow tract (49). Decreased cardiac radiotracer uptake is
278
associated with a poor prognosis in patients with ischemic heart disease as well as
279
in patients with dilated or hypertrophic cardiomyopathy (90).
280
Stress-induced cardiomyopathy has been reported after overdosing with the
12
281
unspecific NET inhibitor nortriptyline (27), the combined selective NET/SERT
282
inhibitors venlafaxine (22; 91; 130), and milnacipran (74), as well as with
283
amphetamines which also exert NET inhibition (3). Among other pharmacological
284
actions, cocaine inhibits NET function (37).
285
cardiomyopathies (4).
Cocaine abuse can induce
286
Excessive cardiac norepinephrine release in congestive heart failure is not
287
adequately matched by norepinephrine reuptake, due to either down-regulation of
288
NET (13; 65; 75) or decreased NET efficiency (29).
289
reduction in [123I]-MIBG uptake in these patients also indicates an impaired
290
norepinephrine reuptake and storage system (2; 84). Impaired [123I]-MIBG uptake
291
occurs early in the course of congestive heart failure regardless of underlying
292
etiologies and affects both, prognosis (55) and treatment (64). An eight-fold increase
293
in cardiac norepinephrine spillover was associated with moderately reduced
294
norepinephrine clearance in congestive heart failure patients (83). In human cardiac
295
tissue obtained during cardiac transplantation, NET expression and norepinephrine
296
reuptake were reduced (9; 13).
297
adenoviral transfer of NET gene in an animal model of heart failure increased
298
cardiac norepinephrine content and improved heart function (89). Interestingly, the
299
treatment response in dilated cardiomyopathy is dependent on NET polymorphisms,
300
with patients exhibiting the T182C genotype being resistant to beta-adrenoceptor
301
blocker therapy (93).
The previously mentioned
Finally, preventing NET down regulation by
302
Moreover, together with two distinct adrenoceptor genotypes the T182C
303
genotype may negatively affect the outcome in dilated cardiomyopathy patients (94).
304
Given the high prevalence of the T182C genotype (67), this finding might be of
305
importance for a large number of heart failure patients. Recent findings suggest that
306
treatment for heart failure by both, combined ß- and a1-adrenergic blockade with
13
307
carvedilol (78) or mechanical unloading by means of a left ventricular assist device
308
(28) may improve norepinephrine reuptake in patients with heart failure. Together,
309
these findings suggest that NET dysfunction may, indeed, play a major role in
310
cardiac disease. In fact, heart disease progression and recuperation may be
311
affected.
312
313
Long-term cardiovascular response to pharmacological NET inhibition
314
Numerous drugs inhibit NET function.
315
antidepressants, rather unselectively inhibit a range of monoamine transporters and
316
metabolizing enzymes. Newer agents are more selective for NET and/or other
317
monoamine transporter, such as the serotonin transporter (SERT). Most NET and
318
combined NET/SERT inhibitors are approved as antidepressants and are among the
319
most frequently prescribed drugs. Recently, more than 10% of U.S. Americans aged
320
12 or older reported antidepressant use with a clear preponderance in females (102).
321
Some NET inhibitors are approved for other indications: atomoxetine is licensed for
322
use in patients with attention deficit syndrome, while duloxetine is prescribed in
323
painful diabetic neuropathies, a condition associated with increased cardiovascular
324
risk, and in fibromyalgia (50). Finally, the NET/SERT inhibitor sibutramine has been
325
utilized in the treatment of obesity.
Older substances, such as tricyclic
326
Theoretically, NET inhibition could damage the cardiovascular system directly
327
through actions within the target tissues and indirectly by increasing blood pressure.
328
Recent data suggests that the use of tricyclic antidepressants as well as NET
329
inhibitors is associated with increases in blood pressure (76). Data on long-term
330
influences of pharmacological NET inhibition on blood pressure have been obtained
331
with a combined NET/SERT inhibitor, the weight loss drug sibutramine. For example,
332
combined analysis of two placebo-controlled trials showed no significant change in
14
333
systolic blood pressure over a 48-week period (61). Diastolic blood pressure was
334
1.1 mmHg increased with sibutramine.
335
exacerbated in patients with grade 1 or 2 hypertension or in patients with isolated
336
systolic hypertension and the pressure response to sibutramine treatment varied
337
substantially between patients.
338
influences of sibutramine on cardiovascular morbidity. In the recent Sibutramine
339
Cardiovascular Outcome Trial (SCOUT) (59) overweight or obese patients with type
340
2 diabetes mellitus and/or a medical history of cardiovascular disease were
341
randomized to treatment with sibutramine or placebo. Based on study results of an
342
increased risk for non-fatal heart attack and stroke with sibutramine, the European
343
Medicines Agency (EMA) recommended suspending its license in Europe (35).
The blood pressure response was not
Nonetheless there is evidence for adverse
344
The interpretation of cardiovascular morbidity data in NET inhibitor treated
345
patients is complicated by the fact that the disease leading to NET inhibitor
346
prescription may associated with altered cardiovascular disease risk. For example,
347
depression is an independent risk factor for cardiovascular disease (53).
348
Conversely, patients with heart disease are prone to experience depression (20).
349
Most studies investigating whether antidepressants affect cardiovascular risk
350
involved tricyclic antidepressants, which interact with many monoamine transporters
351
and receptors, and selective serotonin reuptake inhibitors (SSRI). Some (24; 87;
352
118; 129; 134), but not all (82; 86), showed an increased risk particularly in patients
353
on tricyclic antidepressants. SSRIs, such as sertraline, are considered safe, even in
354
patients with preexisting cardiovascular disease (60; 99).
355
Considering the widespread use of NET inhibitors including in populations at
356
high cardiovascular risk, data on long-term cardiovascular safety is surprisingly
357
scarce. The issue of possible negative effects of NET inhibitors on cardiovascular
358
morbidity and mortality is not conclusively solved.
A number of epidemiological
15
359
studies showed an association between antidepressant use and cardiovascular risk
360
(69; 123; 131; 132). Discrepancies in populations and methodological approaches
361
may explain why other studies did not find such association (25; 43). Recently, a
362
disproportionality analysis failed to show an association between the antidepressants
363
inhibiting NET and cardiomyopathy risk (103). However, findings from cases of drug
364
overdosing suggest that both, NET inhibition with or without additional SERT
365
inhibition can be cardiotoxic, with tachycardia and increases of blood pressure being
366
the most frequent findings (54; 77).
367
normal doses (107; 115) of NET/SERT inhibitors have been linked with frank
368
cardiomyopathy (22; 27; 74; 91; 130).
369
In case reports, overdosing and - rarely –
NET inhibitors may also interfere with the reuptake of other biogenic amines,
370
such as dopamine, which could affect toxicity.
Furthermore, older unselective
371
medications like tricyclic antidepressants are well-known for their cardiac side effects
372
likely through inhibition of cardiac ion channels rather than NET inhibition. However,
373
newer NET inhibitors are much more selective and less likely to affect other ion
374
channels or other monoamine transporters. Norepinephrine’s cardiotoxic potential
375
compared with other biogenic amines (18) suggests that excessive local
376
norepinephrine concentrations could play an important role in NET inhibitor mediated
377
cardiotoxicity.
378
379
Conclusions
380
NET has a pivotal role in the regulation of synaptic norepinephrine in the brain and in
381
peripheral tissues. Pharmacological studies with NET inhibitors showed that NET
382
has opposing effects on cardiovascular sympathetic regulation in the brain and in the
383
periphery. Furthermore, NET is involved in the distribution of sympathetic activity
384
between vasculature, heart, and kidney.
There is evidence that genetic NET
16
385
dysfunction
386
“hyperadrenergic” postural tachycardia syndrome. Conversely, NET inhibition may
387
be beneficial in “hypoadrenergic” states such as central autonomic failure or neurally
388
mediated syncope. Evidence for impaired cardiac NET function has been obtained
389
in a range of cardiac conditions, both common and chronic, e.g. congestive heart
390
failure, and less frequent but acute, such as stress-induced cardiomyopathy.
391
Whether NET dysfunction is the cause or merely a consequence of heart disease in
392
humans requires further study. However, there is compelling evidence that reduced
393
NET function could have an adverse effect on the cardiovascular system, either
394
through direct norepinephrine-mediated cardiotoxicity or indirectly through changes
395
in blood pressure. Given the widespread use of medications inhibiting NET, the
396
issue deserves more attention.
397
398
is
pathophysiologically
involved
at
least
in
some
cases
of
17
399
Figure legends
400
Figure 1. Schematic diagram of norepinephrine biosynthesis, release, reuptake, and
401
degradation. For details see text. COMT: catechol-methyl-O-transferase, DHPG:
402
dihydroxyphenylglycol,
403
monoaminooxidase, VMAT2: vesicular monoamine transporter-2.
NET:
norepinephrine
reuptake
transporter,
MAO:
404
405
Figure 2. Reboxetine plasma concentrations (upper panel, closed squares), systolic
406
and diastolic blood pressure (middle panel, closed triangles), heart rate (middle
407
panel, open circles) and muscle sympathetic nerve activity (MSNA, lower panel,
408
closed circles) in the supine position in six healthy male controls after a single oral
409
dose of 8 mg reboxetine (*=p<.05, **=p<.01, repeated measures ANOVA, Dunnett´s
410
post test). Selective NET inhibition by reboxetine increases systolic blood pressure
411
and heart rate after 90 min. MSNA is profoundly decreased 60 min after reboxetine
412
ingestion. Figure redrawn from previously published work (128).
413
414
Figure 3. Heart rate in the supine position (0°) and with increasing orthostatic stress
415
during incremental head-up tilt in 18 healthy controls with placebo (open circles), and
416
selective pharmacological NET inhibition with reboxetine (closed circles).
417
inhibition increased heart rate in the supine position (#= p<.001, paired t test). More
418
strikingly, the increase in heart rate during incremental orthostatic stress was
419
profoundly augmented with NET inhibition (***=p<.001, ANOVA). Figure redrawn
420
from previously published work (114).
NET
421
422
Figure 4.
Individual differences in tilt tolerance measured as the tolerated time
423
during head-up tilt testing between pharmacological NET inhibition and placebo in 51
424
healthy controls. In subjects who tolerated the full tilt test protocol, both on placebo
18
425
and with NET inhibition, the difference is 0. The solid vertical lines indicate the mean
426
values and the boundaries of the 95% confidence interval. Figure redrawn from
427
previously published work (113).
428
19
429
References
430
431
432
433
434
1. Adamopoulos S, Kemp GJ, Thompson CH, Arnolda L, Brunotte F, Stratton JR,
Radda GK, Rajagopalan B, Kremastinos DT and Coats AJ. The time course of
haemodynamic, autonomic and skeletal muscle metabolic abnormalities following
first extensive myocardial infarction in man. J Mol Cell Cardiol 31: 1913-1926, 1999.
435
436
437
438
2. Agostini D, Babatasi G, Scanu P, Lecluse E, Belin A, Quennelle F, Grollier G, Potier
JC and Bouvard G. Value of cardiac scintigraphy with I123 metaiodobenzylguanidine in congestive heart failure. A review. Ann Cardiol Angeiol
(Paris) 46: 293-302, 1997.
439
440
3. Alsidawi S, Muth J and Wilkin J. Adderall induced inverted-Takotsubo
cardiomyopathy. Catheter Cardiovasc Interv 78: 910-913, 2011.
441
442
443
4. Arora S, Alfayoumi F and Srinivasan V. Transient left ventricular apical ballooning
after cocaine use: is catecholamine cardiotoxicity the pathologic link? Mayo Clin Proc
81: 829-832, 2006.
444
445
446
447
5. Azevedo ER, Kubo T, Mak S, Al-Hesayen A, Schofield A, Allan R, Kelly S, Newton
GE, Floras JS and Parker JD. Nonselective versus selective beta-adrenergic
receptor blockade in congestive heart failure: differential effects on sympathetic
activity. Circulation 104: 2194-2199, 2001.
448
449
450
451
6. Barton DA, Dawood T, Lambert EA, Esler MD, Haikerwal D, Brenchley C, Socratous
F, Kaye DM, Schlaich MP, Hickie I and Lambert GW. Sympathetic activity in major
depressive disorder: identifying those at increased cardiac risk? J Hypertens 25:
2117-2124, 2007.
452
453
7. Bayles R, Baker E, Eikelis N, El-Osta A and Lambert G. Histone modifications
regulate the norepinephrine transporter gene. Cell Cycle 9: 4600-4601, 2010.
454
455
456
8. Bayles R, Kn H, Lambert E, Baker EK, Agrotis A, Guo L, Jowett JB, Esler M, Lambert
G and El-Osta A. Epigenetic modification of the norepinephrine transporter gene in
postural tachycardia syndrome. Arterioscler Thromb Vasc Biol 32: 1910-1916, 2012.
457
458
9. Beau SL and Saffitz JE. Transmural heterogeneity of norepinephrine uptake in failing
human hearts. J Am Coll Cardiol 23: 579-585, 1994.
459
460
461
10. Birkenfeld AL, Schroeder C, Boschmann M, Tank J, Franke G, Luft FC, Biaggioni I,
Sharma AM and Jordan J. Paradoxical effect of sibutramine on autonomic
cardiovascular regulation. Circulation 106: 2459-2465, 2002.
462
463
11. Birkenfeld AL, Schroeder C, Pischon T, Tank J, Luft FC, Sharma AM and Jordan J.
Paradoxical effect of sibutramine on autonomic cardiovascular regulation in obese
20
464
465
hypertensive patients--sibutramine and blood pressure. Clin Auton Res 15: 200-206,
2005.
466
467
468
469
470
12. Bobb AJ, Addington AM, Sidransky E, Gornick MC, Lerch JP, Greenstein DK, Clasen
LS, Sharp WS, Inoff-Germain G, Wavrant-De VF, Arcos-Burgos M, Straub RE, Hardy
JA, Castellanos FX and Rapoport JL. Support for association between ADHD and
two candidate genes: NET1 and DRD1. Am J Med Genet B Neuropsychiatr Genet
134B: 67-72, 2005.
471
472
473
13. Bohm M, La RK, Schwinger RH and Erdmann E. Evidence for reduction of
norepinephrine uptake sites in the failing human heart. J Am Coll Cardiol 25: 146153, 1995.
474
475
476
14. Bonisch H, Runkel F, Roubert C, Giros B and Bruss M. The human desipraminesensitive noradrenaline transporter and the importance of defined amino acids for its
function. J Auton Pharmacol 19: 327-333, 1999.
477
478
479
15. Brush JE, Jr., Eisenhofer G, Garty M, Stull R, Maron BJ, Cannon RO, III, Panza JA,
Epstein SE and Goldstein DS. Cardiac norepinephrine kinetics in hypertrophic
cardiomyopathy. Circulation 79: 836-844, 1989.
480
481
482
16. Bruss M, Kunz J, Lingen B and Bonisch H. Chromosomal mapping of the human
gene for the tricyclic antidepressant-sensitive noradrenaline transporter. Hum Genet
91: 278-280, 1993.
483
484
485
17. Burgdorf C, von HK, Schunkert H and Kurowski V. Regional alterations in myocardial
sympathetic innervation in patients with transient left-ventricular apical ballooning
(Tako-Tsubo cardiomyopathy). J Nucl Cardiol 15: 65-72, 2008.
486
487
488
18. Burniston JG, Ellison GM, Clark WA, Goldspink DF and Tan LB. Relative toxicity of
cardiotonic agents: some induce more cardiac and skeletal myocyte apoptosis and
necrosis in vivo than others. Cardiovasc Toxicol 5: 355-364, 2005.
489
490
491
492
19. Buttenschon HN, Kristensen AS, Buch HN, Andersen JH, Bonde JP, Grynderup M,
Hansen AM, Kolstad H, Kaergaard A, Kaerlev L, Mikkelsen S, Thomsen JF, Koefoed
P, Erhardt A, Woldbye DP, Borglum AD and Mors O. The norepinephrine transporter
gene is a candidate gene for panic disorder. J Neural Transm 118: 969-976, 2011.
493
494
20. Carney RM and Freedland KE. Depression in patients with coronary heart disease.
Am J Med 121: S20-S27, 2008.
495
496
497
21. Chang PC, van der Krogt JA and van BP. Demonstration of neuronal and
extraneuronal uptake of circulating norepinephrine in the forearm. Hypertension 9:
647-653, 1987.
21
498
499
500
501
22. Christoph M, Ebner B, Stolte D, Ibrahim K, Kolschmann S, Strasser RH and Schon
S. Broken heart syndrome: Tako Tsubo cardiomyopathy associated with an overdose
of the serotonin-norepinephrine reuptake inhibitor Venlafaxine. Eur
Neuropsychopharmacol 20: 594-597, 2010.
502
503
504
23. Cimarelli S, Sauer F, Morel O, Ohlmann P, Constantinesco A and Imperiale A.
Transient left ventricular dysfunction syndrome: patho-physiological bases through
nuclear medicine imaging. Int J Cardiol 144: 212-218, 2010.
505
506
507
24. Cohen HW, Gibson G and Alderman MH. Excess risk of myocardial infarction in
patients treated with antidepressant medications: association with use of tricyclic
agents. Am J Med 108: 2-8, 2000.
508
509
510
511
25. Cooper WO, Habel LA, Sox CM, Chan KA, Arbogast PG, Cheetham TC, Murray KT,
Quinn VP, Stein CM, Callahan ST, Fireman BH, Fish FA, Kirshner HS, O'Duffy A,
Connell FA and Ray WA. ADHD drugs and serious cardiovascular events in children
and young adults. N Engl J Med 365: 1896-1904, 2011.
512
513
514
26. Currie G, Freel EM, Perry CG and Dominiczak AF. Disorders of blood pressure
regulation-role of catecholamine biosynthesis, release, and metabolism. Curr
Hypertens Rep 14: 38-45, 2012.
515
516
517
27. De RS, Beauloye C, De B, I, Vancraynest D, Gurne O, Gerber B and Hantson P.
Tako-tsubo syndrome following nortriptyline overdose. Clin Toxicol (Phila) 46: 475478, 2008.
518
519
520
521
28. Drakos SG, Athanasoulis T, Malliaras KG, Terrovitis JV, Diakos N, Koudoumas D,
Ntalianis AS, Theodoropoulos SP, Yacoub MH and Nanas JN. Myocardial
sympathetic innervation and long-term left ventricular mechanical unloading. JACC
Cardiovasc Imaging 3: 64-70, 2010.
522
523
524
29. Eisenhofer G, Friberg P, Rundqvist B, Quyyumi AA, Lambert G, Kaye DM, Kopin IJ,
Goldstein DS and Esler MD. Cardiac sympathetic nerve function in congestive heart
failure. Circulation 93: 1667-1676, 1996.
525
526
527
30. Eisenhofer G, Saigusa T, Esler MD, Cox HS, Angus JA and Dorward PK. Central
sympathoinhibition and peripheral neuronal uptake blockade after desipramine in
rabbits. Am J Physiol 260: R824-R832, 1991.
528
529
530
31. Esler M, Jackman G, Bobik A, Leonard P, Kelleher D, Skews H, Jennings G and
Korner P. Norepinephrine kinetics in essential hypertension. Defective neuronal
uptake of norepinephrine in some patients. Hypertension 3: 149-156, 1981.
531
532
533
32. Esler M, Jennings G, Lambert G, Meredith I, Horne M and Eisenhofer G. Overflow of
catecholamine neurotransmitters to the circulation: source, fate, and functions.
Physiol Rev 70: 963-985, 1990.
22
534
535
536
33. Esler M and Kaye D. Sympathetic nervous system activation in essential
hypertension, cardiac failure and psychosomatic heart disease. J Cardiovasc
Pharmacol 35: S1-S7, 2000.
537
538
539
34. Esler MD, Wallin G, Dorward PK, Eisenhofer G, Westerman R, Meredith I, Lambert
G, Cox HS and Jennings G. Effects of desipramine on sympathetic nerve firing and
norepinephrine spillover to plasma in humans. Am J Physiol 260: R817-R823, 1991.
540
541
542
543
544
545
546
547
548
35. European Medicines Agency (EMA). European Medicines Agency recommends
suspension of marketing authorisations for sibutramine. 1-21-2010. (Internet
Communication)
36. Fauchier L, Pierre B, de LA and Babuty D. Comparison of the beneficial effect of
beta-blockers on mortality in patients with ischaemic or non-ischaemic systolic heart
failure: a meta-analysis of randomised controlled trials. Eur J Heart Fail 9: 11361139, 2007.
549
550
551
37. Fleckenstein AE, Gibb JW and Hanson GR. Differential effects of stimulants on
monoaminergic transporters: pharmacological consequences and implications for
neurotoxicity. Eur J Pharmacol 406: 1-13, 2000.
552
553
554
555
556
557
38. Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, Cheshire
WP, Chelimsky T, Cortelli P, Gibbons CH, Goldstein DS, Hainsworth R, Hilz MJ,
Jacob G, Kaufmann H, Jordan J, Lipsitz LA, Levine BD, Low PA, Mathias C, Raj SR,
Robertson D, Sandroni P, Schatz I, Schondorff R, Stewart JM and van Dijk JG.
Consensus statement on the definition of orthostatic hypotension, neurally mediated
syncope and the postural tachycardia syndrome. Clin Auton Res 21: 69-72, 2011.
558
559
560
39. Freemantle N, Cleland J, Young P, Mason J and Harrison J. beta Blockade after
myocardial infarction: systematic review and meta regression analysis. BMJ 318:
1730-1737, 1999.
561
562
563
40. Gelernter J, Page GP, Stein MB and Woods SW. Genome-wide linkage scan for loci
predisposing to social phobia: evidence for a chromosome 16 risk locus. Am J
Psychiatry 161: 59-66, 2004.
564
565
566
567
568
41. Gold PW, Wong ML, Goldstein DS, Gold HK, Ronsaville DS, Esler M, Alesci S,
Masood A, Licinio J, Geracioti TD, Jr., Perini G, DeBellis MD, Holmes C, Vgontzas
AN, Charney DS, Chrousos GP, McCann SM and Kling MA. Cardiac implications of
increased arterial entry and reversible 24-h central and peripheral norepinephrine
levels in melancholia. Proc Natl Acad Sci U S A 102: 8303-8308, 2005.
569
570
571
42. Gujja KR, Aslam AF, Privman V, Tejani F and Vasavada B. Initial presentation of
pheochromocytoma with Takotsubo cardiomyopathy: a brief review of literature. J
Cardiovasc Med (Hagerstown ) 11: 49-52, 2010.
23
572
573
574
575
576
43. Habel LA, Cooper WO, Sox CM, Chan KA, Fireman BH, Arbogast PG, Cheetham
TC, Quinn VP, Dublin S, Boudreau DM, Andrade SE, Pawloski PA, Raebel MA,
Smith DH, Achacoso N, Uratsu C, Go AS, Sidney S, Nguyen-Huynh MN, Ray WA
and Selby JV. ADHD medications and risk of serious cardiovascular events in young
and middle-aged adults. JAMA 306: 2673-2683, 2011.
577
578
579
580
581
44. Haenisch B, Linsel K, Bruss M, Gilsbach R, Propping P, Nothen MM, Rietschel M,
Fimmers R, Maier W, Zobel A, Hofels S, Guttenthaler V, Gothert M and Bonisch H.
Association of major depression with rare functional variants in norepinephrine
transporter and serotonin1A receptor genes. Am J Med Genet B Neuropsychiatr
Genet 150B: 1013-1016, 2009.
582
583
584
585
45. Hahn MK, Mazei-Robison MS and Blakely RD. Single nucleotide polymorphisms in
the human norepinephrine transporter gene affect expression, trafficking,
antidepressant interaction, and protein kinase C regulation. Mol Pharmacol 68: 457466, 2005.
586
587
588
46. Hahn MK, Robertson D and Blakely RD. A mutation in the human norepinephrine
transporter gene (SLC6A2) associated with orthostatic intolerance disrupts surface
expression of mutant and wild-type transporters. J Neurosci 23: 4470-4478, 2003.
589
590
591
47. Hahn MK, Steele A, Couch RS, Stein MA and Krueger JJ. Novel and functional
norepinephrine transporter protein variants identified in attention-deficit hyperactivity
disorder. Neuropharmacology 57: 694-701, 2009.
592
593
594
595
48. Harikrishnan KN, Bayles R, Ciccotosto GD, Maxwell S, Cappai R, Pelka GJ, Tam PP,
Christodoulou J and El-Osta A. Alleviating transcriptional inhibition of the
norepinephrine slc6a2 transporter gene in depolarized neurons. J Neurosci 30: 14941501, 2010.
596
597
598
599
49. Hasdemir C, Aydin HH, Celik HA, Simsek E, Payzin S, Kayikcioglu M, Aydin M,
Kultursay H and Can LH. Transcriptional profiling of septal wall of the right ventricular
outflow tract in patients with idiopathic ventricular arrhythmias. Pacing Clin
Electrophysiol 33: 159-167, 2010.
600
601
602
50. Hauser W, Wolfe F, Tolle T, Uceyler N and Sommer C. The role of antidepressants in
the management of fibromyalgia syndrome: a systematic review and meta-analysis.
CNS Drugs 26: 297-307, 2012.
603
604
605
51. Heusser K, Engeli S, Tank J, Diedrich A, Wiesner S, Janke J, Luft FC and Jordan J.
Sympathetic vasomotor tone determines blood pressure response to long-term
sibutramine treatment. J Clin Endocrinol Metab 92: 1560-1563, 2007.
606
607
608
52. Heusser K, Tank J, Diedrich A, Engeli S, Klaua S, Kruger N, Strauss A, Stoffels G,
Luft FC and Jordan J. Influence of sibutramine treatment on sympathetic vasomotor
tone in obese subjects. Clin Pharmacol Ther 79: 500-508, 2006.
24
609
610
611
53. Hippisley-Cox J, Pringle M, Hammersley V, Crown N, Wynn A, Meal A and Coupland
C. Antidepressants as risk factor for ischaemic heart disease: case-control study in
primary care. BMJ 323: 666-669, 2001.
612
613
614
54. Howell C, Wilson AD and Waring WS. Cardiovascular toxicity due to venlafaxine
poisoning in adults: a review of 235 consecutive cases. Br J Clin Pharmacol 64: 192197, 2007.
615
616
617
618
55. Imamura Y, Fukuyama T, Mochizuki T, Miyagawa M and Watanabe K. Prognostic
value of iodine-123-metaiodobenzylguanidine imaging and cardiac natriuretic peptide
levels in patients with left ventricular dysfunction resulting from cardiomyopathy. Jpn
Circ J 65: 155-160, 2001.
619
620
621
622
56. Ito K, Sugihara H, Kinoshita N, Azuma A and Matsubara H. Assessment of
Takotsubo cardiomyopathy (transient left ventricular apical ballooning) using 99mTctetrofosmin, 123I-BMIPP, 123I-MIBG and 99mTc-PYP myocardial SPECT. Ann Nucl
Med 19: 435-445, 2005.
623
624
625
57. Jacob G, Shannon JR, Black B, Biaggioni I, Mosqueda-Garcia R, Robertson RM and
Robertson D. Effects of volume loading and pressor agents in idiopathic orthostatic
tachycardia. Circulation 96: 575-580, 1997.
626
627
58. Jafri SM. The effects of beta blockers on morbidity and mortality in heart failure.
Heart Fail Rev 9: 115-121, 2004.
628
629
630
631
59. James WP, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP, TorpPedersen C, Sharma AM, Shepherd GM, Rode RA and Renz CL. Effect of
sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J
Med 363: 905-917, 2010.
632
633
60. Jiang W and Davidson JR. Antidepressant therapy in patients with ischemic heart
disease. Am Heart J 150: 871-881, 2005.
634
635
636
61. Jordan J, Scholze J, Matiba B, Wirth A, Hauner H and Sharma AM. Influence of
Sibutramine on blood pressure: evidence from placebo-controlled trials. Int J Obes
(Lond) 29: 509-516, 2005.
637
638
62. Jordan J, Shannon J and Robertson D. The physiological conundrum of
hyperadrenergic orthostatic intolerance. Chin J Physiol 40: 1-8, 1997.
639
640
641
63. Jordan J, Shannon JR, Black BK, Paranjape SY, Barwise J and Robertson D. Raised
cerebrovascular resistance in idiopathic orthostatic intolerance: evidence for
sympathetic vasoconstriction. Hypertension 32: 699-704, 1998.
642
64. Kakuchi H, Sasaki T, Ishida Y, Komamura K and Miyatake K. Clinical usefulness of
25
643
644
645
123I meta-iodobenzylguanidine imaging in predicting the effectiveness of beta
blockers for patients with idiopathic dilated cardiomyopathy before and soon after
treatment. Heart 81: 148-152, 1999.
646
647
648
649
65. Kawai H, Mohan A, Hagen J, Dong E, Armstrong J, Stevens SY and Liang CS.
Alterations in cardiac adrenergic terminal function and beta-adrenoceptor density in
pacing-induced heart failure. Am J Physiol Heart Circ Physiol 278: H1708-H1716,
2000.
650
651
66. Kitayama S and Dohi T. Norepinephrine transporter splice variants and their
interaction with substrates and blockers. Eur J Pharmacol 479: 65-70, 2003.
652
653
654
655
67. Kohli U, Hahn MK, English BA, Sofowora GG, Muszkat M, Li C, Blakely RD, Stein
CM and Kurnik D. Genetic variation in the presynaptic norepinephrine transporter is
associated with blood pressure responses to exercise in healthy humans.
Pharmacogenet Genomics 21: 171-178, 2011.
656
657
658
68. Kozlovskaia II, Shitov VN, Samoilenko LE, Merkulova IN, Staroverov II and
Sergienko VB. Impairment of cardiac sympathetic function in patients with acute
myocardial infarction and unstable angina. Kardiologiia 44: 46-52, 2004.
659
660
661
662
663
69. Krantz DS, Whittaker KS, Francis JL, Rutledge T, Johnson BD, Barrow G, McClure
C, Sheps DS, York K, Cornell C, Bittner V, Vaccarino V, Eteiba W, Parashar S, Vido
DA and Merz CN. Psychotropic medication use and risk of adverse cardiovascular
events in women with suspected coronary artery disease: outcomes from the
Women's Ischemia Syndrome Evaluation (WISE) study. Heart 95: 1901-1906, 2009.
664
665
666
70. Ksiazek P, Buraczynska K and Buraczynska M. Norepinephrine transporter gene
(NET) polymorphism in patients with type 2 diabetes. Kidney Blood Press Res 29:
338-343, 2006.
667
668
669
670
71. Kume T, Kawamoto T, Okura H, Toyota E, Neishi Y, Watanabe N, Hayashida A,
Okahashi N, Yoshimura Y, Saito K, Nezuo S, Yamada R and Yoshida K. Local
release of catecholamines from the hearts of patients with tako-tsubo-like left
ventricular dysfunction. Circ J 72: 106-108, 2008.
671
672
673
674
72. Lambert E, Eikelis N, Esler M, Dawood T, Schlaich M, Bayles R, Socratous F, Agrotis
A, Jennings G, Lambert G and Vaddadi G. Altered sympathetic nervous reactivity
and norepinephrine transporter expression in patients with postural tachycardia
syndrome. Circ Arrhythm Electrophysiol 1: 103-109, 2008.
675
676
677
678
679
73. Lee YJ, Hohoff C, Domschke K, Sand P, Kuhlenbaumer G, Schirmacher A, Freitag
CM, Meyer J, Stober G, Franke P, Nothen MM, Fritze J, Fimmers R, Garritsen HS,
Stogbauer F and Deckert J. Norepinephrine transporter (NET) promoter and 5'-UTR
polymorphisms: association analysis in panic disorder. Neurosci Lett 377: 40-43,
2005.
26
680
681
74. Levine M, Truitt CA and O'Connor AD. Cardiotoxicity and serotonin syndrome
complicating a milnacipran overdose. J Med Toxicol 7: 312-316, 2011.
682
683
684
75. Liang CS, Fan TH, Sullebarger JT and Sakamoto S. Decreased adrenergic neuronal
uptake activity in experimental right heart failure. A chamber-specific contributor to
beta-adrenoceptor downregulation. J Clin Invest 84: 1267-1275, 1989.
685
686
687
76. Licht CM, de Geus EJ, Seldenrijk A, van Hout HP, Zitman FG, van DR and Penninx
BW. Depression is associated with decreased blood pressure, but antidepressant
use increases the risk for hypertension. Hypertension 53: 631-638, 2009.
688
689
77. Lovecchio F and Kashani J. Isolated atomoxetine (Strattera) ingestions commonly
result in toxicity. J Emerg Med 31: 267-268, 2006.
690
691
692
78. Machida M, Takechi S, Fujimoto T, Kakinoki S and Nomura A. Carvedilol improves
uptake-1 in patients with systolic congestive heart failure. J Cardiovasc Pharmacol
59: 175-181, 2012.
693
694
79. Mann DL, Kent RL, Parsons B and Cooper G. Adrenergic effects on the biology of
the adult mammalian cardiocyte. Circulation 85: 790-804, 1992.
695
696
697
80. Mayer AF, Schroeder C, Heusser K, Tank J, Diedrich A, Schmieder RE, Luft FC and
Jordan J. Influences of norepinephrine transporter function on the distribution of
sympathetic activity in humans. Hypertension 48: 120-126, 2006.
698
699
700
81. McCance AJ, Thompson PA and Forfar JC. Increased cardiac sympathetic nervous
activity in patients with unstable coronary heart disease. Eur Heart J 14: 751-757,
1993.
701
702
703
82. Meier CR, Schlienger RG and Jick H. Use of selective serotonin reuptake inhibitors
and risk of developing first-time acute myocardial infarction. Br J Clin Pharmacol 52:
179-184, 2001.
704
705
706
707
83. Meredith IT, Eisenhofer G, Lambert GW, Dewar EM, Jennings GL and Esler MD.
Cardiac sympathetic nervous activity in congestive heart failure. Evidence for
increased neuronal norepinephrine release and preserved neuronal uptake.
Circulation 88: 136-145, 1993.
708
709
710
84. Merlet P, Piot O, Dubois-Rande JL, Loisance D, Castaigne A and Syrota A. Clinical
use of metaiodobenzylguanidine imaging in cardiology. Q J Nucl Med 39: 29-39,
1995.
711
712
713
85. Moldovanova I, Schroeder C, Jacob G, Hiemke C, Diedrich A, Luft FC and Jordan J.
Hormonal influences on cardiovascular norepinephrine transporter responses in
healthy women. Hypertension 51: 1203-1209, 2008.
27
714
715
716
86. Monster TB, Johnsen SP, Olsen ML, McLaughlin JK and Sorensen HT.
Antidepressants and risk of first-time hospitalization for myocardial infarction: a
population-based case-control study. Am J Med 117: 732-737, 2004.
717
718
719
87. Monte S, Macchia A, Romero M, D'Ettorre A, Giuliani R and Tognoni G.
Antidepressants and cardiovascular outcomes in patients without known
cardiovascular risk. Eur J Clin Pharmacol 65: 1131-1138, 2009.
720
721
722
723
88. Morel O, Sauer F, Imperiale A, Cimarelli S, Blondet C, Jesel L, Trinh A, De PF,
Ohlmann P, Constantinesco A and Bareiss P. Importance of inflammation and
neurohumoral activation in Takotsubo cardiomyopathy. J Card Fail 15: 206-213,
2009.
724
725
726
89. Munch G, Rosport K, Bultmann A, Baumgartner C, Li Z, Laacke L and Ungerer M.
Cardiac overexpression of the norepinephrine transporter uptake-1 results in marked
improvement of heart failure. Circ Res 97: 928-936, 2005.
727
728
729
90. Nagamatsu H, Momose M, Kobayashi H, Kusakabe K and Kasanuki H. Prognostic
value of 123I-metaiodobenzylguanidine in patients with various heart diseases. Ann
Nucl Med 21: 513-520, 2007.
730
731
732
91. Neil CJ, Chong CR, Nguyen TH and Horowitz JD. Occurrence of Tako-Tsubo
cardiomyopathy in association with ingestion of serotonin/noradrenaline reuptake
inhibitors. Heart Lung Circ 21: 203-205, 2012.
733
734
735
92. Nickander KK, Carlson PJ, Urrutia RA, Camilleri M and Low PA. A screen of
candidate genes and influence of beta2-adrenergic receptor genotypes in postural
tachycardia syndrome. Auton Neurosci 120: 97-103, 2005.
736
737
738
739
93. Nonen S, Okamoto H, Fujio Y, Takemoto Y, Yoshiyama M, Hamaguchi T, Matsui Y,
Yoshikawa J, Kitabatake A and Azuma J. Polymorphisms of norepinephrine
transporter and adrenergic receptor alpha1D are associated with the response to
beta-blockers in dilated cardiomyopathy. Pharmacogenomics J 8: 78-84, 2008.
740
741
742
743
94. Ogimoto A, Okayama H, Nagai T, Suzuki J, Inoue K, Nishimura K, Shigematsu Y,
Tabara Y, Miki T and Higaki J. Impact of synergistic polymorphisms in adrenergic
receptor-related genes and cardiovascular events in patients with dilated
cardiomyopathy. Circ J 76: 2003-2008, 2012.
744
745
746
95. Ono K, Iwanaga Y, Mannami T, Kokubo Y, Tomoike H, Komamura K, Shioji K, Yasui
N, Tago N and Iwai N. Epidemiological evidence of an association between SLC6A2
gene polymorphism and hypertension. Hypertens Res 26: 685-689, 2003.
747
748
749
96. Owen D, Du L, Bakish D, Lapierre YD and Hrdina PD. Norepinephrine transporter
gene polymorphism is not associated with susceptibility to major depression.
Psychiatry Res 87: 1-5, 1999.
28
750
751
752
97. Pacholczyk T, Blakely RD and Amara SG. Expression cloning of a cocaine- and
antidepressant-sensitive human noradrenaline transporter. Nature 350: 350-354,
1991.
753
754
755
98. Packer M, Lee WH, Kessler PD, Gottlieb SS, Bernstein JL and Kukin ML. Role of
neurohormonal mechanisms in determining survival in patients with severe chronic
heart failure. Circulation 75: IV80-IV92, 1987.
756
757
758
99. Parissis J, Fountoulaki K, Paraskevaidis I and Kremastinos DT. Sertraline for the
treatment of depression in coronary artery disease and heart failure. Expert Opin
Pharmacother 8: 1529-1537, 2007.
759
760
761
100. Pessoa PM, Xavier SS, Lima SL, Mansur J, de Almeida AS, Carvalho PA, Gutfilen B
and da Fonseca BL. Assessment of takotsubo (ampulla) cardiomyopathy using
iodine-123 metaiodobenzylguanidine scintigraphy. Acta Radiol 47: 1029-1035, 2006.
762
763
101. Prasad A, Madhavan M and Chareonthaitawee P. Cardiac sympathetic activity in
stress-induced (Takotsubo) cardiomyopathy. Nat Rev Cardiol 6: 430-434, 2009.
764
765
102. Pratt LA, Brody DJ and Gu Q. Antidepressant use in persons aged 12 and over:
United States, 2005-2008. NCHS Data Brief 1-8, 2011.
766
767
768
103. Ratcliffe S, Younus M, Hauben M and Reich L. Antidepressants that inhibit neuronal
norepinephrine reuptake are not associated with increased spontaneous reporting of
cardiomyopathy. J Psychopharmacol 24: 503-511, 2010.
769
770
104. Recchia FA and Giacca M. Targeted uptake-1 carrier to rescue the failing heart. Circ
Res 97: 847-849, 2005.
771
772
773
774
105. Renner TJ, Nguyen TT, Romanos M, Walitza S, Roser C, Reif A, Schafer H, Warnke
A, Gerlach M and Lesch KP. No evidence for association between a functional
promoter variant of the Norepinephrine Transporter gene SLC6A2 and ADHD in a
family-based sample. Atten Defic Hyperact Disord 3: 285-289, 2011.
775
776
777
106. Robertson D, Flattem N, Tellioglu T, Carson R, Garland E, Shannon JR, Jordan J,
Jacob G, Blakely RD and Biaggioni I. Familial orthostatic tachycardia due to
norepinephrine transporter deficiency. Ann N Y Acad Sci 940: 527-543, 2001.
778
779
107. Rotondi F, Manganelli F, Carbone G and Stanco G. "Tako-tsubo" cardiomyopathy
and duloxetine use. South Med J 104: 345-347, 2011.
780
781
782
108. Runkel F, Bruss M, Nothen MM, Stober G, Propping P and Bonisch H.
Pharmacological properties of naturally occurring variants of the human
norepinephrine transporter. Pharmacogenetics 10: 397-405, 2000.
29
783
784
785
109. Ryu SH, Lee SH, Lee HJ, Cha JH, Ham BJ, Han CS, Choi MJ and Lee MS.
Association between norepinephrine transporter gene polymorphism and major
depression. Neuropsychobiology 49: 174-177, 2004.
786
787
788
110. Sakuragi S, Tokunaga N, Okawa K, Kakishita M and Ohe T. A case of takotsubo
cardiomyopathy associated with epileptic seizure: reversible left ventricular wall
motion abnormality and ST-segment elevation. Heart Vessels 22: 59-63, 2007.
789
790
791
792
111. Schlaich MP, Lambert E, Kaye DM, Krozowski Z, Campbell DJ, Lambert G, Hastings
J, Aggarwal A and Esler MD. Sympathetic augmentation in hypertension: role of
nerve firing, norepinephrine reuptake, and Angiotensin neuromodulation.
Hypertension 43: 169-175, 2004.
793
794
795
796
112. Schroeder C, Adams F, Boschmann M, Tank J, Haertter S, Diedrich A, Biaggioni I,
Luft FC and Jordan J. Phenotypical evidence for a gender difference in cardiac
norepinephrine transporter function. Am J Physiol Regul Integr Comp Physiol 286:
R851-R856, 2004.
797
798
799
113. Schroeder C, Birkenfeld AL, Mayer AF, Tank J, Diedrich A, Luft FC and Jordan J.
Norepinephrine transporter inhibition prevents tilt-induced pre-syncope. J Am Coll
Cardiol 48: 516-522, 2006.
800
801
802
114. Schroeder C, Tank J, Boschmann M, Diedrich A, Sharma AM, Biaggioni I, Luft FC
and Jordan J. Selective norepinephrine reuptake inhibition as a human model of
orthostatic intolerance. Circulation 105: 347-353, 2002.
803
804
115. Selke KJ, Dhar G and Cohn JM. Takotsubo cardiomyopathy associated with titration
of duloxetine. Tex Heart Inst J 38: 573-576, 2011.
805
806
807
116. Shannon JR, Flattem NL, Jordan J, Jacob G, Black BK, Biaggioni I, Blakely RD and
Robertson D. Orthostatic intolerance and tachycardia associated with
norepinephrine-transporter deficiency. N Engl J Med 342: 541-549, 2000.
808
809
810
117. Shannon JR, Jordan J, Diedrich A, Pohar B, Black BK, Robertson D and Biaggioni I.
Sympathetically mediated hypertension in autonomic failure. Circulation 101: 27102715, 2000.
811
812
813
814
118. Sherwood A, Blumenthal JA, Trivedi R, Johnson KS, O'Connor CM, Adams KF, Jr.,
Dupree CS, Waugh RA, Bensimhon DR, Gaulden L, Christenson RH, Koch GG and
Hinderliter AL. Relationship of depression to death or hospitalization in patients with
heart failure. Arch Intern Med 167: 367-373, 2007.
815
816
817
818
119. Shibao C, Raj SR, Gamboa A, Diedrich A, Choi L, Black BK, Robertson D and
Biaggioni I. Norepinephrine transporter blockade with atomoxetine induces
hypertension in patients with impaired autonomic function. Hypertension 50: 47-53,
2007.
30
819
820
821
822
120. Simoes MV, Barthel P, Matsunari I, Nekolla SG, Schomig A, Schwaiger M, Schmidt
G and Bengel FM. Presence of sympathetically denervated but viable myocardium
and its electrophysiologic correlates after early revascularised, acute myocardial
infarction. Eur Heart J 25: 551-557, 2004.
823
824
825
121. Simula S, Lakka T, Kuikka J, Laitinen T, Remes J, Kettunen R and Hartikainen J.
Cardiac adrenergic innervation within the first 3 months after acute myocardial
infarction. Clin Physiol 20: 366-373, 2000.
826
827
122. Slavikova J, Kuncova J and Topolcan O. Plasma catecholamines and ischemic heart
disease. Clin Cardiol 30: 326-330, 2007.
828
829
830
831
123. Smoller JW, Allison M, Cochrane BB, Curb JD, Perlis RH, Robinson JG, Rosal MC,
Wenger NK and Wassertheil-Smoller S. Antidepressant use and risk of incident
cardiovascular morbidity and mortality among postmenopausal women in the
Women's Health Initiative study. Arch Intern Med 169: 2128-2139, 2009.
832
833
834
835
124. Sogawa C, Mitsuhata C, Kumagai-Morioka K, Sogawa N, Ohyama K, Morita K, Kozai
K, Dohi T and Kitayama S. Expression and function of variants of human
catecholamine transporters lacking the fifth transmembrane region encoded by exon
6. PLoS One 5: e11945, 2010.
836
837
838
839
125. Stober G, Nothen MM, Porzgen P, Bruss M, Bonisch H, Knapp M, Beckmann H and
Propping P. Systematic search for variation in the human norepinephrine transporter
gene: identification of five naturally occurring missense mutations and study of
association with major psychiatric disorders. Am J Med Genet 67: 523-532, 1996.
840
841
842
126. Strempel S, Schroeder C, Hemmersbach R, Boese A, Tank J, Diedrich A, Heer M,
Luft FC and Jordan J. Norepinephrine transporter inhibition alters the hemodynamic
response to hypergravitation. J Appl Physiol 104: 756-760, 2008.
843
844
845
127. Tagawa M, Nakamura Y, Ishiguro M, Satoh K, Chinushi M, Kodama M and Aizawa Y.
Transient left ventricular apical ballooning developing after the Central Niigata
Prefecture Earthquake: two case reports. J Cardiol 48: 153-158, 2006.
846
847
848
128. Tank J, Schroeder C, Diedrich A, Szczech E, Haertter S, Sharma AM, Luft FC and
Jordan J. Selective impairment in sympathetic vasomotor control with norepinephrine
transporter inhibition. Circulation 107: 2949-2954, 2003.
849
850
851
852
129. Tata LJ, West J, Smith C, Farrington P, Card T, Smeeth L and Hubbard R. General
population based study of the impact of tricyclic and selective serotonin reuptake
inhibitor antidepressants on the risk of acute myocardial infarction. Heart 91: 465471, 2005.
853
854
130. Vinetti M, Haufroid V, Capron A, Classen JF, Marchandise S and Hantson P. Severe
acute cardiomyopathy associated with venlafaxine overdose and possible role of
31
855
CYP2D6 and CYP2C19 polymorphisms. Clin Toxicol (Phila) 49: 865-869, 2011.
856
857
858
859
860
131. Weeke P, Jensen A, Folke F, Gislason GH, Olesen JB, Andersson C, Fosbol EL,
Larsen JK, Lippert FK, Nielsen SL, Gerds T, Andersen PK, Kanters JK, Poulsen HE,
Pehrson S, Kober L and Torp-Pedersen C. Antidepressant Use and Risk of Out-ofHospital Cardiac Arrest: A Nationwide Case-Time-Control Study. Clin Pharmacol
Ther 2012.
861
862
863
864
132. Whang W, Kubzansky LD, Kawachi I, Rexrode KM, Kroenke CH, Glynn RJ, Garan H
and Albert CM. Depression and risk of sudden cardiac death and coronary heart
disease in women: results from the Nurses' Health Study. J Am Coll Cardiol 53: 950958, 2009.
865
866
867
868
869
870
133. Wichter T, Schafers M, Rhodes CG, Borggrefe M, Lerch H, Lammertsma AA,
Hermansen F, Schober O, Breithardt G and Camici PG. Abnormalities of cardiac
sympathetic innervation in arrhythmogenic right ventricular cardiomyopathy :
quantitative assessment of presynaptic norepinephrine reuptake and postsynaptic
beta-adrenergic receptor density with positron emission tomography. Circulation 101:
1552-1558, 2000.
871
872
873
874
134. Xiong GL, Jiang W, Clare R, Shaw LK, Smith PK, Mahaffey KW, O'Connor CM,
Krishnan KR and Newby LK. Prognosis of patients taking selective serotonin
reuptake inhibitors before coronary artery bypass grafting. Am J Cardiol 98: 42-47,
2006.
875
876
877
878
135. Yamabe H, Hanaoka J, Funakoshi T, Iwahashi M, Takeuchi M, Saito K, Kawashima
S and Yokoyama M. Deep negative T waves and abnormal cardiac sympathetic
image (123I-MIBG) after the Great Hanshin Earthquake of 1995. Am J Med Sci 311:
221-224, 1996.
879
880
881
882
883
136. Zolk O, Ott C, Fromm MF and Schmieder RE. Effect of the rs168924 singlenucleotide polymorphism in the SLC6A2 catecholamine transporter gene on blood
pressure in Caucasians. J Clin Hypertens (Greenwich ) 14: 293-298, 2012.