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256
Atrial Natriuretic Peptide in Chronic Heart Failure
in the Rat: A Correlation with Ventricular Dysfunction
KAZUO TSUNODA, G. PETER HODSMAN, ERIC SUMITHRAN, AND COLIN I. JOHNSTON
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To assess the relation between atrial natriuretic peptide and ventricular dysfunction, we simultaneously measured both atrial and plasma immunoreactive atrial natriuretic peptide concentrations in
rats 4 weeks after myocardial infarction induced by left coronary artery ligation. When compared to
controls (n = 39), rats with infarction (n = 16) had markedly elevated plasma immunoreactive atrial
natriuretic peptide concentrations (1205.8 ± 180.9 vs. 126.7 ± 8.9 pg/ml, p < 0.001) and reduced
immunoreactive atrial natriuretic peptide concentrations in right and left atria (31.4 ± 4.6 vs.
61.2 ± 3.2 ng/mg,p< 0.001; 14.9 ± 2.2 vs. 32.7 ± 2.4 ng/mg,p< 0.001, respectively). Right ventricular weight increased in proportion to infarct size, and both were correlated with plasma immunoreactive atrial natriuretic peptide levels (r = 0.825, p < 0.001 and r = 0.816, p<0.001, respectively). Right
atrial immunoreactive atrial natriuretic peptide content was significantly higher than left in both
controls and rats with infarction. Both right and left atrial immunoreactive atrial natriuretic peptide
concentrations were negatively correlated with both right ventricular weight as well as plasma immunoreactive atrial natriuretic peptide concentrations (right atrium: r = -0.816, p<0.001, r =
-0.708, p<0.01; left atrium: r = -0.687, p<0.01, r = -0.644, p<0.01, respectively). These results suggest that chronic stimulation of atrial natriuretic peptide release from both atria is associated
with increased turnover and depleted stores of atrial natriuretic peptide in atria in proportion to the
severity of heart failure. It also suggests that plasma atrial natriuretic peptide levels may be used as a
reliable index of cardiac decompensation in chronic heart failure. (Circulation Research 1986;59:
256-261)
F
LUID retention and inability to excrete a sodium load are cardinal features of chronic heart
failure. The sodium and water retention that
accompanies heart failure is associated with alterations
in total renal blood flow,' intrarenal redistribution of
blood flow,2 increased sympathetic tone, 3 activation of
the renin-angiotensin-aldosterone system,4 and increased levels of plasma vasopressin.5 In addition, the
influence of a putative natriuretic hormone has been
suspected for many years to be involved in the pathogenesis of abnormal sodium handling by the kidney in
heart failure.6
Mammalian cardiac atria contain granules that undergo changes in density under different conditions of
sodium and water load. 78 It is now known that these
granules contain a potent diuretic, natriuretic910 and
vasodilating" hormone, atrial natriuretic peptide
(ANP). Immunoreactive ANP (IR-ANP) has been
demonstrated both in rat and in human plasma,1213 and
concentrations have been shown to increase with salt12
and volume loading.14 Recent studies have shown both
high plasma IR-ANP concentrations in patients with
heart failure,1516 raising the possibility that ANP may
be important in the pathophysiology of this disease.
However, human studies are confounded by the diFrom the Monash University Department of Medicine, Prince
Henry's Hospital (K.T., G.P.H., C.I.J.), and Queen Victoria
Medical Centre (E.S.), Melbourne, Victoria, Australia.
Address for reprints: Professor C.I. Johnston, Melbourne University Department of Medicine, Austin Hospital, Heidelberg, Victoria 3084, Australia.
Received March 27, 1986; accepted May 20, 1986.
verse etiology of the disease, the varying severity of
heart failure, and concomitant therapy.
In the present study, a model of chronic ischemic
heart failure in the rat1718 has been used to study the
relation between ANP and ventricular dysfunction.
Furthermore, the concentrations of both atrial and
plasma IR-ANP have been measured simultaneously.
Materials and Methods
Induction of Myocardial Infarction
Left ventricular free-wall myocardial infarction was
produced in female normotensive Wistar rats aged
16-20 weeks by the method described by Pfeffer et al17
and Fletcher et al.18 Briefly, each rat is deeply anesthetized with ether, intubated, and ventilated with a respirator. A left thoracotomy is performed, the heart rapidly exteriorized, and a ligature inserted into the left
ventricular wall. The left coronary artery is not directly
visualized but is ligated by positioning the suture between the pulmonary artery out-flow tract and the left
atrium. The heart is then returned to its normal position, the lungs reinflated using positive end-expiratory
pressure, and the thorax immediately closed by a previously placed purse-string suture. The mortality rate
of this procedure is 40-60% within the first 24 hours
following the operation. Sham-operated rats are those
in which the operative procedure does not produce a
histologically detectable myocardial infarction as a result of failure to occlude the coronary artery. These
animals are used as controls.
Fifty-five surviving rats were maintained on standard rat feed and water ad libitum. Four weeks follow-
257
Tsunoda et al Atrlal Natriuretic Peptide in Heart Failure
ing ligation, a time by which necrotic myocardium has
been completely replaced by scar tissue,17 the rats were
sacrificed by decapitation. The heart, lungs, and liver •
were immediately removed and weighed. The right
and left atria were individually dissected, weighed,
frozen in liquid nitrogen, and stored at —70° C until
extraction. The right and left ventricles were dissected,
separated, and weighed. The left ventricles (including
intraventricular septum) were fixed in 10% buffered
formalin for histological study. The weights of ventricles, atria, livers, and lungs were corrected for body
weight. Blood was obtained by decapitation for the
measurement of plasma IR-ANP by radioimmunoassay. The infarct was quantitated histologically by projection and planimetry using the method of Pfeffer et
al.17
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Measurement of Atrial and Plasma IR-ANP
ANP was extracted from the atria by a method reported previously.19 The atria were boiled for 15 minutes in 10 volumes of 0.1 M acetic acid to inactivate
proteases and then homogenized with a polytron homogenizer. The homogenate was centrifuged at 5,000
rpm for 30 minutes at 4° C, and the supernatant was
stored at - 7 0 ° C until assay. Atrial ANP is expressed
as both concentration per milligram atrial weight and
as content per gram body weight.
Blood samples were taken into plastic tubes containing the following inhibitors: disodiumethylenediaminetetraacetic acid (EDTA-2Na, AJAX Chemicals
Ltd., Sydney, 1 mg/ml), aprotinin (Trasylol, Bayer,
500 kallikrein inhibitor units/ml), and soybean trypsin
inhibitor (SBTI, Sigma, 50 BAEE units/ml). Plasma
IR-ANP was extracted using Vycor glass beads. To 1
ml of plasma, 30 mg of Vycor glass (140 mesh, Society of the Association of Trade with America, Geneva)
was added and agitated for 30 minutes at 4°C. After 2
minutes centrifugation at 3500 rpm, the supernatant
was discarded and the glass powder was washed with 2
ml of distilled water. Adsorbed IR-ANP was eluted
from the glass powder with 1 ml of purified acetone-water mixture (60:40) containing 0.1% trifluoroacetic acid (TFA, BDH Ltd., Dorset, U.K.) during
30 minutes agitation at 4°C. The acetone was evaporated, the aqueous solution lyophilized and reconstituted in buffer for assay. Recovery of added synthetic
a-rat ANP (15-2000 pg, 28 amino acid, Peptide Institute Inc., Osaka, Japan) from rat plasma was 94.0
± 2.5% (mean ± SEM, n = 8). Serial dilution of the
atrial and plasma extracts showed parallelism to the
synthetic ANP standards. Results were not corrected
for recovery.
A 0.1 M Tris-acetate buffer, pH 7.4, containing
0.1% bovine serum albumin (Fraction V, Sigma),
aprotinin (500 kallikrein inhibitor units/ml), SBTI (50
BAEE units/ml), 0.1% iso-ocytlphenoxypolyethoxyethanol (Triton X-100, Packard Ins., 111.), EDTA-2Na
(1 mg/ml), and 0.02% sodium azide, was used to dissolve all reagents and to perform the radioimmunoassay. Fifty microliters of synthetic a-rat ANP or diluted
samples were incubated for 48 hours at 4°C with 450
yxl of buffer, 100 fi\ of antiserum (1:5000, rabbit antia-human ANP) and 100 ^1 of iodinated 125I-ANP
(~ 10,000 cpm). The separation of antibody-bound
and free peptide was performed using goat anti-rabbit
gamma globulin in the presence of normal rabbit serum. The sensitivity of the assay is 11 pg a-rat ANP
per tube. Intraassay and interassay variances were
5.3% (n = 10) and 16.3% (n = 10), respectively. The
anti-human ANP antibody cross-reacted 65% with arat ANP and was directed toward the ring of section of
ANP. Deletions at the N- or C-terminus had no effect
on the immunoreactivity, but disruption of the disulphide bond completely abolished immunoreactivity.
Statistical Analysis
The data were analyzed with a one-way analysis of
variance. Duncan's New Multiple-Range test, which
permits multiple testing among treatment means, was
then employed. Regression lines were fitted by the
method of least squares. P<0.05 was considered significant. Data are presented as mean ± SEM.
Results
Myocardial Infarct Size and Cardiac Weights
Healed myocardial infarcts were present in 16 of 55
surviving rats. There was marked thinning of the infarcted area, where muscle was replaced with fibrous
connective tissue. Right ventricular weight in infarcted
rats was progressively elevated in proportion to infarct
size (r = 0.864, p < 0 . 0 0 1 , Figure 1). Rats with infarcts were, therefore, divided arbitrarily into three
groups according to the ratio of right ventricular to
body weight (mg/g), namely, Group I, <1.0; Group
II, over 1.0 and under 1.4; Group III, >1.4.
Table 1 shows the body and the organ weights of
control rats and rats with infarcts. There was no significant difference in body weight between controls
and rats with infarction. Both right and left atrial
weights were progressively increased in the infarcted
rats; however, the values in Group I did not reach
statistical significance. Left atrial hypertrophy was
more marked than right. Increments in atrial weight
were significantly correlated with increasing right ventricular weight (right atria: r= 0.594, p < 0 . 0 5 ; left
atria: r = 0.832,p<0.001). Lung weight was progressively increased in the infarcted groups and correlated
significantly with right ventricular and left atrial
75 »f
FIGURE 1. Right ventricular weight (open bars) and infarct
size (closed bars) in controls (C) and rats with infarction. I, II,
and III indicate the subgroups described in "Results".
Circulation Research
258
Vol 59, No 3, September 1986
TABLE 1. Body and Organ Weights (mglg) in Controls and Rats with Infarction
I
Control
Numbers
Body wt. (g)
Organ wt. (mg/g b. wt.)
Left ventricle
Left atrium
Right atrium
Lungs
Liver
5
255±15
39
271 ± 4
2.40±0.04
0.15±0.01
0.15±0.01
5.3 + 0.1
32.1+0.5
2.76±0.08*
0.19 + 0.02
0.17±0.01
5.5±0.3
32.6±0.9
Myocardial Infarction Groups
III
II
5
269 ±10
2.74±0.13*
0.56±0.04t
0.24 + 0.03*
5.5±0.3
32.8±1.1
6
251 ±9
2.70±0.06*
0.56 + 0.04t
0.27±0.03*
14.8±1.5*
36.6+1.4
Total
16
258±6
2.73±0.08*
0.44±0.05*
0.23 ±0.02$
9.9±1.2*
34.3±0.8
Results are expressed as means ± SEM.
*p < 0.01, tp < 0.001, %p < 0.05, control vs. infarction group.
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weights (r = 0.873, p<0.001; r = 0.661, p<0.01;
respectively). Left ventricular weight was also slightly
but significantly increased despite marked thinning of
the ventricular free wall. There was no difference in
liver weight between controls and animals with infarction.
IR-ANP in Plasma and Atria
Figure 2 shows the mean values of plasma IR-ANP
in each group. Mean plasma ANP concentration in the
control sham-operated group was 126.7 ± 8.9 pg/ml,
similar to that of 10 nonoperated intact Wistar rats
(114.2 ±14.7 pg/ml). Mean plasma IR-ANP concentration in infarcted rats was tenfold higher
(1205.8 ± 180.9 pg/ml, p< 0.01) than that of the control group. Plasma IR-ANP concentrations were significantly higher in Group I, II, and III (460.0 ± 80.7,
/?<0.05; 1295.9 ± 118.4, /?<0.001 and 1752.2 ±
307.0 pg/ml, p < 0.01, respectively) than in the control
group. The values in Group II and Group IE were
significantly higher (p<0.001 and p<0.0\, respectively) than those in Group I, but the difference between Groups II and III was not significant. Plasma
concentrations of IR-ANP were strongly correlated
with right ventricular weight in infarcted rats (Figure 3:
r = 0.825,p<0.001) and with infarct size (r = 0.816,
p < 0.001).
Table 2 shows the mean values of right and left atrial
IR-ANP concentration and content in each group. The
IR-ANP content of right and left atria in rats with
myocardial infarcts was significantly decreased when
compared with controls (11.55 ±0.60 vs. 13.40 ±
0.62 ng/g, p < 0.05). IR-ANP content in Group III was
significantly less than in controls (9.97 ± 0.69 ng/g,
p<0.01); however, there were no significant differences among controls, Group I, and Group II. The IRANP content of both atrial in infarcted rats was significantly and negatively correlated with right ventricular
weight and also with plasma ANP concentrations
(r= -0.596; p<0.05, r = -0.649, p<0.001, respectively). Right atrial IR-ANP content was not decreased in Group I infarcted rats, but IR-ANP content
in Groups II and III was significantly lower than in the
control group and Group I. No significant difference
was found between Group II and Group III. Right
atrial IR-ANP content was significantly correlated
with right ventricular weight and also with plasma
IR-ANP concentration ( r = - 0 . 7 4 4 , p< 0.001;
r= -0.633, p<0.01, respectively). On the other
hand, there were no significant differences in left atrial
ANP content between control and infarcted groups.
The mean values of right atrial IR-ANP concentrations in Groups II and III were less than those of controls or Group I. Left atrial IR-ANP concentrations in
Group II and Group III were also decreased signifi-
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FIGURE 2. Plasma IR-ANP concentrations in controls and
rats with infarction.
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t-0
RIGHT VENTRICULAR WT.
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FIGURE 3. Relation between plasma IR-ANP concentration
and right ventricular weight (T = 0.825, p<0.001).
Tsunoda et al
259
Atrial Natriuretic Peptide in Heart Failure
TABLE 2. Right (RA) and Left (LA) Atrial IR-ANP Concentration (ng IR-ANP/mgatrial weight) and Content (ng IRANPIg b. wt.)
Myocardial Infarction Groups
Numbers
RA IR-ANP concentration
(ng/mg)
LA IR-ANP concentration
(ng/mg)
RA IR-ANP content (ng/g)
LA IR-ANP content (ng/g)
Control
I
II
HI
Total
39
5
5
6
16
61.1+3.2
54.6±5..3
26.0±4.4*
16.6+1.0*
31.4 ± 4.6t
32.7±2.4
8.73±0.44
4.67 + 0.34
25.5±3..7
8.83±0, .79
4.75 ±0..80
10.1 =t 1.1*
10.0±1.5*
4.40±0.45t
5.57±0.88
14.9±2.2*
5.80±0.65t
5.66±0.61
6.22±0.58t
5.32±0.45
Results are expressed as mean ± SEM.
*p < 0.001, tp < 0.01, control vs. infarction group.
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cantly compared with those of controls or Group I. No
significant difference was observed between controls
and Group I. Figure 4 shows the negative relations
between right and left atrial IR-ANP concentrations
and right ventricular weight (r = - 0 . 8 1 6 , p<0.001;
r = - 0 . 6 8 7 , p < 0 . 0 1 , respectively). In addition, right
and left atrial IR-ANP concentrations were strongly
correlated inversely with plasma IR-ANP concentrations ( r = - 0 . 7 0 8 , p<0.0\; r= - 0 . 6 4 4 , p<0.01,
respectively, Figure 5).
Discussion
The rat coronary artery ligation model of heart failure is particularly suitable for a study of this nature.
This model of myocardial infarction has been shown to
produce a wide range of left ventricular dysfunction in
proportion to infarct size. In previous studies,1718 the
degree of right ventricular hypertrophy was directly
correlated with infarct size, and hemodynamic
changes including left ventricular end-diastolic and
right ventricular systolic pressures. Right ventricular
end-diastolic pressure and right atrial pressure were
also increased, explaining the right ventricular hypertrophy observed in rats with large infarcts. For this
reason, the degree of right ventricular hypertrophy was
employed as an index of severity of heart failure in our
study. Additional support for this approach comes
from the lung and atrial weights, which, with infarct
size, increased in proportion to the degree of right
ventricular hypertrophy in rats with myocardial infarction.
Recently high levels of plasma IR-ANP have been
reported in patients with heart failure, and increasing
severity of heart failure was associated with progressively higher plasma levels of IR-ANP. 1516 A significant correlation between plasma IR-ANP level and
pulmonary capillary wedge pressure has also been reported in humans,20 suggesting that increased atrial
pressure is a stimulus for ANP release. Although we
did not perform hemodynamic studies in the present
experiment, they have been extensively measured and
correlated with right ventricular hypertrophy in previous studies. Our present data show that plasma levels
of IR-ANP are significantly increased in rats with heart
failure compared with those in control animals and
closely correlated with the degree of right ventricular
hypertrophy and infarct size. These findings suggest
that plasma ANP concentration increases in proportion
to the degree of heart failure.
Two previous studies have reported both reduced
content21 and increased content22 of atrial ANP in heart
failure although both laboratories measured atrial ANP
content in BIO 14.6 cardiomyopathic hamsters by bioassay. In our study, right atrial IR-ANP content was
greatly reduced in rats with heart failure and this reduction was negatively correlated with right ventricular
80
80
— 60
o
60-
8
Q. 40
i
40-
20-
_i
20-
I
O-3
10
1-5
RIGHT VENTRICULAR WT.(mq/g)
20
FIGURE 4. Relations between right (*) and left (o) atrial IRANP concentrations and right ventricular weight (r = - 0.816,
p<0.00l; r = -0.687, p<0.0l, respectively).
IOOO
PLASMA IR-ANP
2000
(pg/ml)
3000
FIGURE 5. Relations between right (•) and left (o) atrial IRANP concentrations and plasma IR-ANP concentration fr =
-0.708, p<0.0I; r = -0.644, p<0.01, respectively).
260
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weight. Left atrial IR-ANP content was not reduced
although the reason for these disparate results is not
clear. The reduction in right atrial IR-ANP content was
progressive with increasing severity heart failure. Interestingly, there was a very good correlation between
reduced atrial ANP content and increased plasma ANP
in these animals. This suggests that chronic stimulation leads to increased release of ANP, with elevated
plasma ANP levels and reduced atrial peptide content.
This is in keeping with the known behavior of other
peptide hormones. IR-ANP concentration was much
less in both the right and left atria of rats with heart
failure compared with controls, which may also indicate depletion of atrial ANP content in chronic heart
failure. This result also suggests a significant role for
both atria in the release of ANP in at least this model of
heart failure.
Although the metabolism of circulating ANP in
plasma has not yet been clarified, it is likely that chronic stimulation of ANP release from both atria is responsible for the high levels of plasma IR-ANP found in
heart failure. Atrial distension caused by a variety of
stimuli, including volume loading,14-23 atrial tachycardia, 2 4 " and mitral obstruction,26 has been shown to
stimulate ANP release. Other mechanisms, including
neurohumoral factors such as catecholamines, vasopressin, and angiotensin-II may be involved directly
in ANP release since preliminary studies have revealed
that incubated atria secrete ANP under the influence of
adrenaline and vasopressin.27 Although the direct effect of angiotensin-II on ANP release has not been
confirmed, the possibility remains since angiotensinII, adrenaline, and vasopressin share a common intracellular pathway.28 These observations could partially
explain the mechanism of ANP release from the failing
heart since atrial pressure, circulating catecholamine
concentrations, vasopressin concentrations, and activity of the renin-angiotensin system are often increased
in proportion to the severity of heart failure.
Little is yet known of the pathophysiological significance of the high levels of plasma IR-ANP concentrations in heart failure and their relation to the sodium
and water retention associated with the failing heart. It
is somewhat paradoxical that plasma ANP levels are
elevated in heart failure, as this is a condition associated with salt and water retention. However, it is possible that increased ANP levels represent a homeostatic
response to increased volume and that this lessens the
salt and water retention in heart failure. Possible
mechanisms include not only its diuretic, natriuretic,
and vasodilating action, but also reduction of aldosterone synthesis29-30 and suppression of vasopressin release.31 There is also a possibility of tachyphylaxis,
and alteration of the effects of ANP on its target organs
under pathophysiological conditions.32 Despite this apparent blunting of effect, it has been reported recently
that synthetic ANP stimulates natriuresis without altering renal hemodynamics and causes an increase in
coronary blood flow with a fall in coronary artery
resistance in dogs with acute left ventricular failure.33
This indicates a possible therapeutic role for synthetic
Circulation Research
Vol 59, No 3, September 1986
ANP or ANP analogues in the future treatment of human heart failure.
In conclusion: In rats with chronic heart failure secondary to healed myocardial infarction, chronic stimulation of ANP release is associated with depleted atrial
ANP stores in proportion to the severity of heart failure. The results also suggest that plasma ANP levels
may be used as a reliable index of cardiac decompensation in human heart failure, although the effects of
treatment are as yet unknown. Further study is needed
to elucidate the pathophysiological importance of ANP
in heart failure.
Acknowledgments
This work was supported by a grant from the National Heart
Foundation of Australia. The authors gratefully acknowledge the
assistance of Dr. P. J. Fletcher, Sydney University.
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KEY
WORDS • atrial
natriuretic
peptide
chronic heart failure • myocardial infarction
ventricular dysfunction • rat
Atrial natriuretic peptide in chronic heart failure in the rat: a correlation with ventricular
dysfunction.
K Tsunoda, G P Hodsman, E Sumithran and C I Johnston
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Circ Res. 1986;59:256-261
doi: 10.1161/01.RES.59.3.256
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