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Anxiolyticlike Effects of Atrial Natriuretic Peptide on Cholecystokinin Tetrapeptide–Induced Panic Attacks
Preliminary Findings
Klaus Wiedemann, MD;
Holger Jahn, MD;
Alexander Yassouridis, PhD;
Michael Kellner, MD
Arch Gen Psychiatry. 2001;58:371-377.
ABSTRACT
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Background Panic attacks induced by administration of cholecystokinin tetrapeptide
(CCK-4) have been evaluated as a valuable tool to investigate the neurobiological
mechanisms involved in panic anxiety. The rationale to study the effects of
natriuretic peptides on the CCK-4 response is derived from observations that
atrial natriuretic peptide (ANP) is released during panic attacks in humans
and has anxiolyticlike actions in various animal models.
Methods A double-blind, placebo-controlled design was conducted in 9 patients
with panic disorder and 9 similar healthy control subjects. After pretreatment
with an infusion of 150 µg of ANP or placebo in random order, each subject
received 50 µg of CCK-4. Psychopathological parameters as well as physiological
measures were sampled before and after CCK-4 administration.
Results After pretreatment with ANP, the number of CCK-4–induced panic
attacks decreased from 8 to 6 in patients and from 5 to 2 in controls. Acute
Panic Inventory ratings were significantly reduced in patients after ANP vs
placebo pretreatment. Infusion of ANP significantly curtailed the CCK-4–induced
release of corticotropin in patients. Heart rate variability analysis indicated
a sympathetic stimulation by CCK-4 that was inhibited by ANP in patients and
controls.
Conclusions The present study indicates that ANP exerts anxiolyticlike effects on
CCK-4–stimulated anxiety attacks in patients with panic disorder. In
addition, ANP produced an inhibition of the hypothalamopituitary-adrenocortical
system and sympatholytic effects.
INTRODUCTION
PANIC ATTACKS are characterized by paroxysmal episodes of intense anxiety
or discomfort combined with various autonomic symptoms. Some experimental
evidence supports the theory that panic attacks are generated by neuronal
discharges in the brainstem,1 which are caused
by a hypersensitive suffocation monitor that produces false alarms.2 Although several experimental provocation paradigms
for panic attacks have been developed,3 it
has recently been hypothesized that panic attacks are associated with an excessive
release of corticotropin-releasing hormone (CRH) within the central nervous
system (CNS). In rats, this hormone activates noradrenergic neurons in the
locus coeruleus,4 and direct infusion of CRH
into this structure causes significant behavioral arousal.5
Complementarily, anxiogenic effects are blocked by CRH receptor antagonists6; antisense targeting of CRH receptor messenger RNA7 elicits anxiolytic effects, and CRH-1 receptor–deficient
mice display considerably lower anxiety levels than wild-type control mice.8 In patients with panic disorder, the hypothalamopituitary-adrenocortical
(HPA) system shows changes that point to a temporary hypothalamic CRH hypersecretion.9
Surprisingly, although living through a panic attack represents an intense
stressor, most of the studies on naturally occurring attacks or those stimulated
by sodium lactate found no significant activation of the HPA system.10, 11, 12 In contrast to other
compounds,13 atrial natriuretic peptide (ANP)
is the only peptide that inhibits HPA activity in humans at all regulatory
levels of the system.14 In patients with panic
attacks, infusion of sodium lactate produces a more rapid and pronounced increase
in ANP11 in comparison with healthy control
subjects,15 which might in part explain the
frequently observed quiescence of the peripheral HPA system.
Sympathetic responses during the panicogenic challenge with sodium lactate
are also absent, which again can be explained by an inhibitory action of elevated
plasma ANP levels.16 Most importantly, ANP
and related peptides exert anxiolyticlike effects in rats.17
Hence, it can be surmised that ANP, which is found not only in the cardiac
atria but also in various brain regions, might serve as a humoral feedback
signal to confine the psychopathological and neuroendocrine sequelae of panic
anxiety, possibly via inhibition of CRH-mediated brain circuits.18
To investigate both processes, the panicogenic stimulus should activate
not only panic anxiety but also the HPA system, which is provided by cholecystokinin
tetrapeptide19 (CCK-4). In parallel with its
panicogenic actions, CCK-4 induces a significant release of corticotropin
and cortisol.20, 21
To test the hypothesis that ANP has an anxiolyticlike profile, the effect
of an infusion of ANP vs placebo during a CCK-4 stimulus was investigated
in patients with panic disorder and healthy controls in a prospective, randomized,
double-blind study. The aim of the study was to clarify in detail whether
peripherally administered ANP modulates the psychological, endocrine, and
autonomic responses to CCK-4.
SUBJECTS AND METHODS
SUBJECTS
Nine patients with a diagnosis of panic disorder with and without agoraphobia
(6 women and 3 men; mean ± SD age, 33 ± 9 years; DSM-III-R diagnoses 300.01/300.21) and 9 similar controls (6 women
and 3 men; mean ± SD age, 30 ± 5 years) were studied. Controls
were recruited by means of advertisement and informed about the protocol.
All patients and controls were given the Structured Clinical Interview for
the DSM-III-R (German version)22
by a trained rater (M.K.). None of the patients had other Axis I diagnoses,
and none of the controls had any psychiatric diagnosis. All subjects were
physically healthy and had been without prescription and nonprescription drugs
for at least 10 days. The subjects were given a thorough medical examination,
including urinary drug screening. Furthermore, all subjects were not sleep
deprived, they refrained from alcohol and nicotine (no more than 3 cigarettes
per day), and they had no additional stressful life events during the 3 months
before the study period (ascertained by interview). The protocol used was
approved by the Ethics Committee for Human Experiments, Max Planck Institute
of Psychiatry, Munich, Germany, and written informed consent was obtained
from each participant before the investigation.
PROCEDURE
All subjects were studied in a supine position under video observation
in a soundproof private room from 9 AM to 1 PM on 2 separate days. After subjects
had had a standardized breakfast without caffeine ingestion at 8 AM, an intravenous
cannula was inserted into a forearm vein of each arm at 9 AM. Each cannula
was connected to a long catheter that ran through a soundproof lock to the
adjacent laboratory. The cannulae were kept patent using isotonic sodium chloride
solution (the blood-sampling cannula at an infusion rate of 50 mL/h and the
infusion cannula at a rate of 1 mL/h). At 11 AM on both study days, each subject
received as bolus injection CCK-4 (Clinalfa, Läufelfingen, Switzerland),
50 µg, dissolved in 10 mL of isotonic sodium chloride solution. From
10:40 to 11:10 AM in a prospective, randomized, double-blind design, all participants
underwent infusion with isotonic sodium chloride solution, 30 mL (placebo
condition), or isotonic sodium chloride solution, 30 mL, containing human  -ANP
(Clinalfa), 150 µg. Four of 9 patients and 5 of 9 controls received
placebo on the first study day. Blood samples (8 mL each) were drawn at 10,
10:15, 10:30, 10:40, 10:50, 11, 11:05, 11:10, and 11:15 AM, and thereafter
every 30 minutes from 11:30 AM to 1 PM for the determination of hormonal concentrations.
These samples were placed on ice, plasma was immediately separated, and specimens
were stored at -80°C until analysis. Blood pressure was registered
at blood sampling times with an automatic device. An electrocardiogram (ECG)
was recorded continuously from 10:30 AM to 1 PM using commercially available
equipment (Spectra Scan Model 263; DelMar Avionics, Irvine, Calif) with a
standard cassette tape recorder.
ASSSESSMENT OF PANIC AND ANXIETY
The Acute Panic Inventory23 (API), a DSM-III-R panic symptom checklist,24
and a 100-mm visual analog scale (VAS) for anxiety were administered before
CCK-4 injection at 10:55 and then at 11:10 AM to determine post hoc the peak
level of provoked panic. The rater (M.K.) was unaware of the ANP or placebo
administration. The criterion for the presence of a panic attack was an API
total score exceeding 20 or an increment of at least 14 points above the preinfusion
score, the presence of at least 4 DSM-III-R panic
items, and an increase of at least 40 mm in the VAS. Furthermore, the patients
were asked whether they had had a panic attack, and they should have reported
similarities of at least 70% to their spontaneously occurring attacks. On
the second study day, all subjects were asked which investigation was less
frightening.
HORMONAL ASSESSMENTS
Plasma cortisol concentrations were determined using a commercially
available radioimmunoassay (ICN Biomedicals, Carson, Calif). The detection
limit was 0.8 nmol/L; intra-assay and interassay coefficients of variation
for 55.2- and 110.4-nmol/L levels were less than 7%. Corticotropin concentrations
were determined using an immunoradiometric assay (Nichols Institute, San Juan
Capistrano, Calif). The detection limit for plasma corticotropin was 0.8 pmol/L,
and the intra-assay and interassay coefficients of variation at 4.4 pmol/L
were less than 8%. To measure ANP level, we adjusted a radioimmunoassay (Nichols
Institute) to our requirements as described elsewhere.15
Minimum detectable amounts were 8 ng/L. The intra-assay coefficient of variation
was 8.5%, and the interassay coefficient was less than 10%, calculated at
plasma levels of 80 ng/L after extraction.
HEART RATE ANALYSES
Stored analog ECG data were digitalized at a rate of 128 samples per
second (R-R signal values, distance of 2 successive R spikes per second),
and an arrhythmia analysis was performed in a prospective user-interactive
mode (Stratascan; DelMar Avionics). All successive R-R intervals were sampled,
excluding ectopic beats and artifacts. Single missing events were interpolated
if no sinus reset had occurred; all other artifacts were rejected. The mean
location (ML; average of values in each time interval) of the R-R interval
values or average of heart rate (in beats per minute) was calculated for 1-minute
segments. For spectral domain parameters, the artifact-free R-R signal was
equidistantly scanned as a step function subtracting the mean signal values,
and a fast Fourier transformation was performed in overlapping 1- or 3-minute
segments. From the spectra, we calculated total power (PTOT) between 0.01
and 0.45 Hz (in milliseconds squared) as indicator of heart rate fluctuation
and low- (LF; 0.01-0.05 Hz), mid- (MF; 0.05-0.15 Hz), and high-frequency power
(HF; 0.15-0.45 Hz), each given as percentage of PTOT. The LF/HF ratios were
also calculated. Details of analysis are given elsewhere.16
STATISTICAL ANALYSES
Differences in the measured quantities (psychopathometric scores, hormonal
concentrations, and spectral parameters) between patients and controls, between
the placebo and ANP conditions, and among baseline, infusion (10:40-11 and
11-11:10 AM), and postinfusion intervals (11:10-11:30 AM) were tested for
significance by means of a multivariate analysis of variance (MANOVA) with
repeated-measures design. To compensate for baseline differences, all considered
quantities were normalized to their mean values at baseline before being used
in MANOVAs. The influential factors in the MANOVAs were group (a between-subjects
factor), treatment, and time (both within-subjects factors). For hormonal
concentrations, the ML (average of values in each time interval) and area
under the curve (AUC) values were used in this analysis. When significant
main and interaction effects were found in the MANOVA, univariate F tests
followed to identify variables that contributed significantly to these effects.
Tests with contrasts were also performed to locate pairs of time intervals
with significant differences in those variables, on which the factor time
showed significant main or interaction effects. For testing the frequency
distribution of panic attacks between both groups, Fisher exact tests were
performed. To differentiate the incidence of frightening in the postprovocation
interview between placebo and ANP conditions, McNemar tests were also performed.
Furthermore, the stability of the hormonal concentration curves, ie, whether
concentration curve values of one sample were continuously above those of
another sample, was tested for significance with the matched paired Wilcoxon
test by considering at each time the part of each sample with hormonal concentrations
above the common medians. As a nominal level of significance, .05 was accepted.
To keep the type I error at .05 or less, all post hoc tests (univariate F
tests and tests with contrasts) were performed at a reduced level of significance
(ie, adjusted according to the Bonferroni procedure). (After finding
a global effect of a factor, all subsequently performed post hoc tests concerning
simple effects of this factor were performed at a corrected level of significance
that was generally equal to .05 divided by the number of the corresponding
tests. If the P values of the underlying statistics
to these tests were less than the corrected level of significance, we declared
a statistical significance. However, we denoted significance using P<.05 because statistical statements have to be made at the nominal
level of significance, ie, = .05, and not at the corrected level,
which can differ from case to case and from effect to effect.) All measurements
are expressed as mean ± SEM.
RESULTS
ANXIETY SYMPTOMS AND PANIC ATTACKS
According to the DSM-III-R symptom checklist
and respective criteria in API and VAS scores, 8 of 9 patients and 5 of 9
controls experienced a panic attack during the placebo condition after CCK-4
administration (frequency distribution between patients and controls was nonsignificant
[P = .06], Fisher exact test). During the ANP condition,
the number of subjects with panic attacks was reduced from 8 to 6 patients
and 5 to 2 controls. A free postprovocation interview on the second study
day showed that 8 of 9 patients and 7 of 9 controls identified the ANP condition
as less frightening (McNemar test, P = .008 and P = .02 for patients and controls, respectively).
Analysis of variance with the normed scores of API and VAS revealed
a significant group (F15,2 = 8.67; P =
.003) and time effect (F15,2 = 54.40; P<.001)
and a marginally significant treatment x time effect. Variables API
and VAS scores contributed significantly to the aforementioned effects (univariate
F tests, P<.05). During placebo condition, API
scores increased in patients after CCK-4 administration from 9.7 ±
2.5 to 30.1 ± 3.7, and in controls from 2.2 ± 0.7 to 15.4 ±
2.7. Similarly, the VAS scores increased from 37 ± 6 to 89 ±
4 in patients and from 9 ± 3 to 58 ± 8 in controls. Between
patients and controls, the severity of symptoms after CCK-4 administration
was significantly different (tests with contrasts, API, F1,16 =
8.77 [P = .009]; VAS, F1,16 = 18.27 [P = .001]).
Concomitant with ANP infusion, the CCK-4–induced increase of API
scores in patients from 7.2 ± 2.8 to 24.2 ± 3.4 was significantly
curtailed compared with placebo condition (tests with contrasts, P = .02). In controls, no differences of CCK-4–mediated increases
of API scores between conditions were seen (14.2 ± 2.7 after ANP vs
15.4 ± 2.7 after placebo). After ANP administration, the VAS scores
were slightly curtailed compared with those for placebo (patients, 73 ±
7 vs 89 ± 4; controls, 53 ± 8 vs 58 ± 8).
HORMONAL MEASURES
Corticotropin and Cortisol
The AUC values of the normed corticotropin and cortisol concentrations
revealed a significant time effect (F2,16 = 21.84 [P<.001]), a marginal group effect (F2,16 = 3.09 [P = .07]), and a significant group x treatment x
time interaction effect (F2,16 = 5.52 [P
= .02]) caused by variables corticotropin and cortisol (univariate F tests, P<.05). Subsequent tests with contrasts showed that
in the interval 10:40 to 11 AM, no significant differences emerged between
the ANP and placebo conditions for the AUC and ML values of corticotropin
and cortisol secretion.
During the placebo condition, patients and controls showed a significant
increase in corticotropin and cortisol levels after injection of CCK-4 (tests
with contrasts, P<.05). The AUC and ML values
were elevated significantly, and the increase of corticotropin was blunted
in patients in comparison with controls (ML corticotropin at 11 to 11:20 vs
10:40 to 11 AM in patients, 7.0 ± 1.3 vs 4.5 ± 0.7 pmol/L; in
controls, 10.0 ± 2.4 vs 4.8 ± 0.8 pmol/L [tests with contrasts, P<.05]).
During the ANP condition, the increase of corticotropin and cortisol
levels was curtailed mainly in controls (ML corticotropin at 11-11:20 AM,
ANP vs placebo, 8.1 ± 1.6 vs 10.0 ± 2.4 pmol/L; ML cortisol
at 11-11:20 AM, ANP vs placebo, 350.4 ± 41.4 vs 433.2 ± 63.5
nmol/L). The secretion of corticotropin in patients was significantly lower
than in controls at 11 to 11:20 AM and 11:20 AM to 1 PM (Figure 1; tests with contrasts, P<.05).
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Figure 1. Mean normed (10:40 AM) corticotropin
plasma concentrations of patients with panic disorder (n = 9) and healthy
control subjects (n = 9) are given for infusions of 150 µg of atrial
natriuretic peptide (ANP) vs placebo (PLA). The box indicates the infusion
period; the arrow, the cholecystokinin tetrapeptide (CCK-4) injection (50
µg).
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After injection of CCK-4, plasma concentrations of corticotropin (Figure 1) and cortisol remained lowered in
patients until the end of the investigation. Addressing the stability hypothesis,
we found that levels of both hormones showed on average continuously lower
concentration values after infusion of ANP in patients and controls (Wilcoxon
matched paired test, P<.05).
Atrial Natriuretic Peptide
Atrial natriuretic peptide plasma concentrations were significantly
lower in patients than controls at 10:40 AM (P =
.04). After CCK-4 and concomitant placebo infusion, ANP plasma concentrations
in patients rose by 30% (from 37 ± 5 ng/L at 10:40 AM to 48 ±
4 ng/L at 11:10 AM), and in controls by 13% (from 67 ± 16 to 76 ±
15 ng/L). In contrast to controls, the ANP plasma concentrations within the
patient sample showed a significant time effect (F2,7 = 5.87 [P = .03]), which could be attributed mostly to differences
between the 10:40 and 11:10 AM samples (test with contrasts, P = .008).
Infusion of ANP resulted in similar increases in ANP plasma concentrations
in patients and controls with a 4- to 5-fold increase compared with baseline.
HEART RATE ANALYSES
Heart Rate
Analysis of the mean heart rates normalized to the baseline mean values
revealed a significant time (F3,10 = 24.81 [P<.001]) and interaction effect (treatment x time, F3,10 = 10.87 [P = .002]). After CCK-4 injection,
a short-lasting increase in heart rate occurred in patients and controls,
which was slightly but significantly enhanced in patients during coadministration
of ANP (tests with contrasts, P<.05).
Spectral Analysis
In patients, the spectral PTOT showed a fast decrease after CCK-4 and
concomitant ANP infusions (significant differences in the total power scores
between 10:40-11 and 11-11:10 AM) and a delayed decrease after CCK-4 administration
and placebo infusion (significant differences in the total power scores between
11-11:10 and 11:10-11:30 AM; tests with contrasts, P<.05).
Controls did not show any significant change of PTOT.
For LF, significant time effects emerged (F3,10 = 7.21 [P = .007]) with a significant decrease in the interval
10:40 to 11 AM compared with baseline and thereafter an increase after CCK-4
administration. The MF and HF values showed marginally significant time effects
(F3,10 = 3.15 [P = .07] and F3,10 = 3.13 [P = .07], respectively) and HF showed
a significant interaction effect (treatment x time, F3,10
= 6.14 [P = .01]).
Comparison of the LF/HF ratios (Figure
2) before and after CCK-4 administration demonstrated significant
changes over time only during placebo infusion in both patients and controls
(F3,10 = 3.60 [P = .05]). In the intervals
before (10:40-11 AM) and after CCK-4 injection (11-11:10 AM), a shift of HF
to LF occurred in patients during placebo infusion, indicating an enhancement
of sympathetic activity before CCK-4 administration. This shift was observed
in controls after CCK-4 administration (ie, 11-11:10 AM).
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Figure 2. Mean ratios of low- to high-frequency
power (LF/HF) before and after cholecystokinin tetrapeptide (CCK-4) administration
are given as indicated for the atrial natriuretic peptide (ANP) and the placebo
(PLA) condition in controls (n = 9; A) and patients (n = 9; B). During PLA
condition, significant changes occurred that were largely prevented by ANP
infusion.
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Concomitant infusion of ANP largely reduced the CCK-4 effects on the
LF/HF ratio, indicating an inhibitory effect of ANP on sympathetic activity.
When testing the stability of the LF/HF ratios over time, we found significant
differences between the 2 treatments (Wilcoxon matched paired test, P = .04), but not between patients and controls.
Blood Pressure
Infusion of ANP did not induce significant changes in diastolic or systolic
blood pressure in patients or controls. In addition, the injection of CCK-4
was without any detectable significant effect.
COMMENT
The first major result of our preliminary study is that administration
of ANP reduces the CCK-4–elicited panic reaction in patients with panic
disorder and to a lesser extent in healthy controls. Panicogenic effects of
CCK-4 have been confirmed in recent years to be consistent, reproducible,
and related to the dose administered with an enhanced sensitivity of panic
patients compared with healthy controls.19, 25
Accordingly, the dose of 50 µg of CCK-4 chosen for our investigation
is sufficient to elicit panic attacks in patients and controls. Cholecystokinin
tetrapeptide acts via cholecystokinin B-type (CCK-B) receptors in the CNS.26 In recent studies, the short-term administration
of benzodiazepines, ß-blockers, and CCK-B receptor antagonists27 and long-term treatment with imipramine hydrochloride
and serotonin reuptake inhibitors have been found to be effective21 for inhibiting CCK-4–mediated panic attacks.
Atrial natriuretic peptide and its corresponding receptors are found
within the CNS in areas known to regulate emotional states, such as the amygdala.28 Indirect support for the anxiolyticlike effects of
peripherally circulating ANP derives from studies during human pregnancy.
Here, plasma ANP concentrations increase 3-fold at term29
with a concomitant reduction in panic disorder symptoms and a postpartum reexacerbation.30 Furthermore, present and recent studies in patients
with panic disorder have consistently shown lower basal plasma ANP concentrations
in panickers than in nonpanickers.11, 15
Direct evidence of anxiolyticlike effects of ANP comes from preclinical
studies, despite their limited commensurability to human panic attacks. Intracerebroventricular
injection of ANP and related fragments into animals has revealed anxiolyticlike
effects in paradigms such as the elevated plus maze.31
Because central effects of peripherally released peptides on CNS functions
have been reproducibly found in man and animals,32, 33
the observation of anxiolyticlike effects after peripheral application corroborates
our findings.17 Direct effects of ANP on CCK-B
receptors can be excluded,6 but the level of
interaction of ANP with CCK-4–mediated effects remains unclear. Besides
an antagonism of the CCK-4–mediated CRH release,6, 34
a modulation by neural afferents also has to be considered.35
The second important finding of our preliminary study is that ANP inhibits
the CCK-4–induced rise of corticotropin and cortisol levels. In contrast
to most findings in spontaneous36, 37
and lactate-induced panic attacks,10, 11, 12
the heterogenous group of panicogenic agents consisting of fenfluramine hydrochloride,
yohimbine, and CCK-4 consistently activates the HPA axis.3
This activation has to be related to an acute hypothalamic release of CRH,
which can be inhibited by ANP.6, 13, 15, 38, 39
The finding of a blunted corticotropin release after CCK-4 administration
in patients compared with controls possibly has to be attributed to a chronic
hypersecretion of CRH as evidenced in depression, posttraumatic stress,40, 41 and panic disorder.9
In addition, the lowered increase of cortisol level in patients after CCK-4
treatment surmises an enhanced feedback regulation of the HPA system as shown
in posttraumatic stress disorder.41
As observed during lactate infusions, CCK-4 administration also induces
a pronounced increase of plasma ANP levels in patients. A cardiac or hypothalamic
release mediated by CRH6, 18, 42, 43
could contribute to this rise in plasma ANP level.
Besides the small sample size, a limitation of this study is that the
endocrine status of patients before study could have been further evaluated
to differentiate endocrine responsivity.
Another important finding of our study is the vegetative alterations
induced by CCK-4, as indicated by spectral analysis of heart rate. Patients
with panic disorder show an elevated baseline autonomic activity manifested
by an increased heart rate, which is in line with previous reports.44, 45 The elevated autonomic activity seems
to reflect an increased prechallenge arousal, since studies not performed
under laboratory conditions have revealed no abnormality in cardiovascular
parameters.46 Administration of CCK-4 led to
a very short and limited increase of heart rate in patients and controls,
as reported recently.9, 25 Despite
the increased basal activity in patients, a strong autonomic response to CCK-4–induced
panic does not occur, which has also been shown for lactate-induced panic
attacks.16, 46
Concerning spectral parameters, the increase in heart rate is followed
by a prolonged reduction of the PTOT, indicating a decrease in heart rate
variability. The analysis of the domain parameters showed an increase of sympathetic
activity in the time intervals before and after CCK-4 administration. These
findings provide further evidence of an increased prechallenge sympathetic
activity in patients but not in controls. The prechallenge and the CCK-4–mediated
sympathetic activation are almost entirely inhibited by ANP.
Our findings of vegetative alterations during panic are in line with
investigations using lactate44, 46
that reported a parasympathetic response in panickers in contrast to controls.
In humans during infusion of ANP,47 an inhibition
of sympathetic activity together with lowered total and HF power was found.
These inhibitory effects were also demonstrated in our present study and in
lactate-induced panic attacks.16
Preclinical data also support this idea. Sympathetic denervation and
chemical sympathectomy inhibited the ANP release in rats,48
whereas sympathetic activation increased ANP release in isolated hearts.49 Vice versa, ANP injections into the nucleus tractus
solitarii reduced the sympathetic tone.50, 51
Further support for mutual interactions between the autonomic nervous
system and ANP release is provided by the finding that fibers from the locus
coeruleus to hypothalamic ANP neurons can activate its release. Moreover,
considerable amounts of ANP have been found in the locus coeruleus.52 This structure appears to play a key role not only
in the regulation of the sympathetic nervous system but also in CRH release,
and links these regulatory circuits to ANP. If ANP release during a panic
attack contributes to the eventual termination of the attack via endocrine
and neural feedback loops between the heart, the hypothalamus, and the locus
coeruleus, it may prove worthwhile to develop and study long-acting ANP analogues
for their possible antipanic efficacy.
AUTHOR INFORMATION
Accepted for publication December 21, 2000.
The authors gratefully acknowledge the skillful technical assistance
of Kristina Knaudt and Gisela Gajewski.
From the Department of Psychiatry and Psychotherapy, University of
Hamburg, Hamburg (Drs Wiedemann, Jahn, and Kellner), and Max Planck Institute
of Psychiatry, Munich (Drs Wiedemann, Yassouridis, and Kellner), Germany.
Corresponding author and reprints: Klaus Wiedemann, Department of
Psychiatry and Psychotherapy, University of Hamburg, Martinistrasse 52, 20246
Hamburg, Germany (e-mail: wiedeman{at}uke.uni-hamburg.de).
REFERENCES
| |
1. Gorman JM, Battista D, Goetz RR, Dillon DJ, Liebowitz MR, Fyer AJ, Kahn JP, Sandberg D, Klein DF. A comparison of sodium bicarbonate and sodium lactate infusion in the
induction of panic attacks. Arch Gen Psychiatry. 1989;46:145-150.
FREE FULL TEXT
2. Klein DF. False suffocation alarms, spontaneous panics, and related conditions:
an integrative hypothesis. Arch Gen Psychiatry. 1993;50:306-317.
FREE FULL TEXT
3. Nutt DJ, Lawson CW. Panic attacks: a neurochemical overview of models and mechanisms. Br J Psychiatry. 1992;160:165-178.
FREE FULL TEXT
4. Curtis AL, Lechner SM, Pavcovich LA, Valentino RJ. Activation of the locus coeruleus noradrenergic system by intracoerulear
microinfusion of corticotropin-releasing factor: effects on discharge rate,
cortical norepinephrine levels and cortical electroencephalographic activity. J Pharmacol Exp Ther. 1997;281:163-172.
FREE FULL TEXT
5. Butler PD, Weiss JM, Stout JC, Nemeroff CB. Corticotropin-releasing factor produces fear-enhancing and behavioral
activating effects following infusion into the locus coeruleus. J Neurosci. 1990;10:176-180.
ABSTRACT
6. Biró E, Gardi J, Vecsernyés M, Julesz J, Tóth G, Telegdy G. The effects of atrial natriuretic peptide (ANP1-28) on corticotropin
releasing factor in brain of rats. Life Sci. 1996;59:1351-1356.
FULL TEXT
|
ISI
| PUBMED
7. Skutella T, Probst JC, Renner U, Holsboer F, Behl C. Corticotropin-releasing hormone receptor (type I) antisense targeting
reduces anxiety. Neuroscience. 1998;85:795-805.
FULL TEXT
|
ISI
| PUBMED
8. Timpl P, Spanagel R, Sillaber I, Kresse A, Reul JMHM, Stalla GK, Blanquet V, Steckler T, Holsboer F, Wurst W. Impaired stress response and reduced anxiety in mice lacking a functional
corticotropin-releasing hormone receptor 1. Nat Genet. 1998;19:162-166.
FULL TEXT
|
ISI
| PUBMED
9. Holsboer F, von Bardeleben U, Buller R, Heuser I, Steiger A. Stimulation response to corticotropin-releasing hormone (CRH) in patients
with depression, alcoholism and panic disorder. Horm Metab Res Suppl. 1987;16:80-88.
PUBMED
10. Liebowitz ML, Gorman JM, Fyer AJ, Levitt M, Dillon D, Levy G, Appleby IL, Anderson S, Palij M, Davies SO, Klein DF. Lactate provocation of panic attacks, II: biochemical and physiological
findings. Arch Gen Psychiatry. 1985;42:709-719.
FREE FULL TEXT
11. Kellner M, Herzog L, Yassouridis A, Holsboer F, Wiedemann K. Possible role of atrial natriuretic hormone in pituitary-adrenocortical
unresponsiveness in lactate-induced panic. Am J Psychiatry. 1995;152:1365-1367.
FREE FULL TEXT
12. Kellner M, Wiedemann K. Nonresponse of adrenocorticotropic hormone in first-ever lactate-induced
panic attacks in healthy volunteers. Arch Gen Psychiatry. 1998;55:85-86.
FREE FULL TEXT
13. Jessop DS. Central non-glucocorticoid inhibitors of the hypothalamo-pituitary-adrenal
axis. J Endocrinol. 1999;160:169-180.
FULL TEXT
|
ISI
| PUBMED
14. Kellner M, Wiedemann K, Holsboer F. Atrial natriuretic factor inhibits the CRH-stimulated secretion of
ACTH and cortisol in man. Life Sci. 1992;50:1835-1842.
FULL TEXT
|
ISI
| PUBMED
15. Kellner M, Knaudt K, Jahn H, Holsboer F, Wiedemann K. Atrial natriuretic hormone in lactate-induced panic attacks: mode of
release and endocrine and pathophysiological consequences. J Psychiatr Res. 1998;32:37-48.
FULL TEXT
|
ISI
| PUBMED
16. Seier FE, Kellner M, Yassouridis A, Heese R, Strian F, Wiedemann K. Autonomic reactivity and hormonal secretion in lactate-induced panic
attacks. Am J Physiol. 1997;272:H2630-H2638.
17. Ströhle A, Jahn H, Montkowski A, Liebsch G, Boll E, Landgraf R, Holsboer F, Wiedemann K. Central and peripheral administration of atriopeptin is anxiolytic
in rats. Neuroendocrinology. 1997;65:210-215.
ISI
| PUBMED
18. Wiedemann K, Jahn H, Kellner M. Effects of natriuretic peptides upon hypothalamo-pituitary-adrenocortical
system activity and anxiety behaviour. Exp Clin Endocrinol Diabetes. 2000;108:5-13.
ISI
| PUBMED
19. Bradwejn J, Koszycki D, Meteressian G. Cholecystokinin-tetrapeptide induces panic attacks in patients with
panic disorder. Can J Psychiatry. 1990;35:83-85.
ISI
| PUBMED
20. Kellner M, Yassouridis A, Jahn H, Wiedemann K. Influence of clonidine on psychopathological, endocrine and respiratory
effects of cholecystokinin tetrapeptide in patients with panic disorder. Psychopharmacology. 1997;133:55-61.
FULL TEXT
| PUBMED
21. Shlik J, Aluoja A, Vasar V, Vasar E, Podar T, Bradwejn J. Effects of citalopram on behavioral, cardiovascular and neuroendocrine
response to cholecystokinin tetrapeptide challenge in patients with panic
disorder. J Psychiatry Neurosci. 1997;22:332-340.
ISI
| PUBMED
22. Wittchen HU, Zaudig M, Schramm E, Spengler P, Mombour W, Klug J, Horn R. SKID: Strukturiertes klinisches Interview
für DSM-III-R. Weinheim, Germany: Beltz; 1991.
23. Dillon D, Gorman JM, Liebowitz MR, Fyer AJ, Klein DF. The measurement of lactate-induced panic anxiety. Psychiatry Res. 1987;20:97-105.
FULL TEXT
|
ISI
| PUBMED
24. Hiller W, von Bose M, Dichtl G, Agerer D. Reliability of checklist-guided diagnoses for DSM-III-R affective and anxiety disorders. J Affect Disord. 1990;20:235-247.
FULL TEXT
|
ISI
| PUBMED
25. Bradwejn J, Koszycki S, Shriqui C. Enhanced sensitivity to cholecystokinin-tetrapeptide in panic disorder. Arch Gen Psychiatry. 1991;48:603-610.
FREE FULL TEXT
26. Wank SA. Cholecystokinin receptors. Am J Physiol. 1995;269:G628-G646.
27. LeMellédo J-M, Bradwejn J, Koszycki D, Bichet DG, Bellavance F. The role of the ß-noradrenergic system in cholecystokinin-tetrapeptide–induced
panic symptoms. Biol Psychiatry. 1998;44:364-366.
FULL TEXT
|
ISI
| PUBMED
28. Langub MC, Watson RE, Herman JP. Distribution of natriuretic peptide precursor mRNAs in the rat brain. J Comp Neurol. 1995;356:183-199.
FULL TEXT
|
ISI
| PUBMED
29. Yoshimura T, Yoshimura M, Yasue H, Ito M, Okamura H, Mukoyama M, Nakao K. Plasma concentrations of atrial natriuretic peptide and brain natriuretic
peptide during normal human pregnancy and the postpartum period. J Endocrinol. 1994;140:393-397.
FREE FULL TEXT
30. Northcott EJ, Stein MB. Panic disorder in pregnancy. J Clin Psychiatry. 1994;55:539-542.
ISI
| PUBMED
31. Bidzseranova A, Gueron J, Toth G, Penke B, Varga J, Teledgy G. Behavioral effects of atrial natriuretic and brain natriuretic peptides
in rats. Neuroreport. 1992;3:283-285.
ISI
| PUBMED
32. Holsboer F, von Bardeleben U, Steiger A. Effects of intravenous corticotropin-releasing hormone upon sleep-related
growth hormone surge and sleep EEG in man. Neuroendocrinology. 1988;48:32-38.
ISI
| PUBMED
33. Banks WA, Kastin AJ. Differential permeability of the blood-brain barrier to two pancreatic
peptides: insulin and amylin. Peptides. 1998;19:883-889.
FULL TEXT
|
ISI
| PUBMED
34. Kamilaris TC, Johnson EO, Calogero AE, Kalogeras KT, Bernardini R, Chrousos GP, Gold PW. Cholecystokinin-octapeptide stimulates hypothalamic-pituitary-adrenal
function in rats: role of corticotropin-releasing hormone. Endocrinology. 1992;130:1764-1774.
FREE FULL TEXT
35. Atchison DJ, Ackermann U. The interaction between atrial natriuretic peptide and cardiac parasympathetic
function. J Auton Nerv Syst. 1993;42:81-88.
FULL TEXT
|
ISI
| PUBMED
36. Cameron OG, Lee MA, Curtiss GC, McCann DS. Endocrine and physiological changes during "spontaneous" panic attacks. Psychoneuroendocrinology. 1987;12:321-331.
FULL TEXT
|
ISI
| PUBMED
37. Curtis G, Buxton M, Lippmann D, Nesse R, Wrigth J. "Flooding in vivo" during the circadian phase of minimal cortisol secretion:
anxiety and therapeutic success without adrenal cortical activation. Biol Psychiatry. 1976;11:101-107.
ISI
| PUBMED
38. Bierwolf C, Burgemeister A, Luthke K, Born J, Fehm HL. Influence of exogenous atrial natriuretic peptide on the pituitary-adrenal
response to corticotropin-releasing hormone and vasopressin in healthy men. J Clin Endocrinol Metab. 1998;83:1151-1157.
FREE FULL TEXT
39. Franci CR, Anselmo-Franci JF, McCann SM. The role of endogenous atrial natriuretic peptide in resting and stress-induced
release of corticotropin, prolactin, growth hormone, and thyroid-stimulating
hormone. Proc Natl Acad Sci U S A. 1992;89:11391-11395.
FREE FULL TEXT
40. Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB. The role of corticotropin-releasing factor in depression and anxiety
disorders. J Endocrinol. 1999;160:1-12.
ABSTRACT
41. Kellner M, Yehuda R. Do panic disorder and posttraumatic stress disorder share a common
psychoneuroendocrinology? Psychoneuroendocrinology. 1999;24:485-504.
FULL TEXT
|
ISI
| PUBMED
42. Lim AT, Sheward WJ, Copolov D, Windmill D, Fink G. Atrial natriuretic factor is released into hypophysial portal blood:
direct evidence that atrial natriuretic factor may be a neurohormone involved
in hypothalamic pituitary control. J Neuroendocrinol. 1990;2:15-17.
FULL TEXT
|
ISI
| PUBMED
43. Colao A, Pivonello R, Ferone D, Faggiano A, Facciolli G, Di Somma C, Boudouresque F, Oliver C, Lombardi G. Effect of corticotrophin-releasing hormone on arginine vasopressin
and atrial natriuretic factor in patients with Cushing's disease. Clin Endocrinol (Oxf). 1998;49:77-84.
FULL TEXT
| PUBMED
44. Yeragani VK, Srinivasan K, Balon R, Ramesh C, Berchou R. Lactate sensitivity and cardiac cholinergic function in panic disorder. Am J Psychiatry. 1994;151:1226-1228.
FREE FULL TEXT
45. Yeragani VK, Srinivasan K, Pohl R, Berger R, Balon R, Berchou R. Sodium lactate increases sympathovagal ratios in normal control subjects:
spectral analysis of heart rate, blood pressure, and respiration. Psychiatry Res. 1994;54:97-114.
FULL TEXT
|
ISI
| PUBMED
46. George DT, Nutt DJ, Walker WV, Porges SW, Adinoff B, Linnoila M. Lactate and hyperventilation substantially attenuate vagal tone in
normal volunteers. Arch Gen Psychiatry. 1989;46:153-156.
FREE FULL TEXT
47. Butler GC, Beverley LS, Floras JS. Influence of atrial natriuretic factor on heart rate variability in
normal men. Am J Physiol. 1994;267:H500-H505.
48. Pettersson A, Ricksten SE, Towle AC, Hedner J, Hedner T. Effect of blood volume expansion and sympathetic denervation on plasma
levels of atrial natriuretic factor (ANF) in the rat. Acta Physiol Scand. 1985;124:309-311.
ISI
| PUBMED
49. Jiao JH, Baertschi AJ. Neural control of the endocrine heart. Proc Natl Acad Sci U S A. 1993;90:7799-7803.
FREE FULL TEXT
50. McKitrick DJ, Calaresu FR. Cardiovascular responses to microinjection of ANF into dorsal medulla
of rats. Am J Physiol. 1988;255:R182-R187.
51. Schultz HD, Steele MK, Gardner DG. Central administration of atrial natriuretic peptide decreases sympathetic
outflow in rats. Am J Physiol. 1990;258:R1250-R1256.
52. Geiger H, Bahner U, Palkovits M, Heidland A, Sterzel RB. Atrial natriuretic peptide in the locus coeruleus and its possible
role in the regulation of arterial blood pressure, fluid and electrolyte homeostasis. Life Sci. 1991;49:869-879.
FULL TEXT
|
ISI
| PUBMED
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