Relationship between plasma atrial natriuretic polypeptide concentration and hemodynamic measurements in children with congenital heart diseases

Relationship between plasma atrial natriuretic polypeptide concentration and hemodynamic measurements in children with congenital heart diseases Kiyoshi Kikuchi, MD, K e n y a Nishioka, MD, Tadashi U e d a , MD, Michiko Shiomi, MD, Yoshiaki Takahashi, MD, Akira S u g a w a r a , MD, K a z u w a N a k a o , MD, Hiroo Imura, MD, C h u z o Mori, MD, a n d Haruki M i k a w a , MD From the Department of Pediatrics and Second Department of Internal Medicine, Kyoto University School of Medicine, Radioisotope Research Center, Kyoto University, and Departments of Pediatrics, Mitsubishi Kyoto Hospital, Kyoto, Ohtsu Red Cross Hospital, Ohtsu, and Shimane Medical University, Izumo, Japan The plasma =-atrial natriuretic p o l y p e p t i d e (=-ANP) concentration in the peripheral veins of children with c o n g e n i t a l heart diseases was measured by radioimmunoassay and c o m p a r e d with c a r d i a c catheterization data. Every patient with heart failure had a higher =-ANP concentration (132.1 to 858.7 pg/mL) than the u p p e r limit of the normal range (11.7 to 98.7 pg/mL), whereas more than half of the patients without heart failure had a normal =-ANP c o n c e n t r a t i o n . Although none of the 13 children with atrial septal d e f e c t had heart failure, their mean (+_ SD) plasma =-ANP c o n c e n t r a t i o n (99.4 _+ 40.7 pg/mL) was significantly higher than that in control children (44.6 +__22.3 pg/mL). The plasma =-ANP concentration was significantly correlated with the pulmonary b l o o d flow/ systemic b l o o d flow (Qp/Qs) ratio in the children with atrial septal defect. In the 34 children with ventricular septal d e f e c t the plasma =-ANP c o n c e n t r a t i o n increased in relation to increasing size of the defect. The plasma =-ANP c o n c e n t r a t i o n was significantly correlated with the Qp/Qs ratio, pulmonary artery pressure, and left atrial pressure, estimated from mean pulmonary artery w e d g e pressure, in the children with ventricular septal defect. In the children with tetra!ogy of Fallot, the mean plasma =-ANP concentration was normal, and mean right and left atrial pressures were not increased. The e l e v a t e d =-ANP c o n c e n t r a t i o n in the three patients with heart failure d e c r e a s e d after their conditions imProved with various treatments. Thus the measurement of =-ANP c o n c e n t r a t i o n may be v a l u a b l e in evaluating the presence or a b s e n c e of heart failure and the response to treatment in children with c o n g e n i t a l heart diseases. Distention of the right and left atria might induce the release of =-ANP in patients with atrial and ventricular septal defects, respectively. (J PEDIATR 1987;111:335-42)

Supported by Research Grant 61770657 from the Japanese Ministry of Education. Submitted for publication March 2, 1987; accepted May 19, 1987. Reprint requests: Kiyoshi Kikuchi, MD, Department of Pediatrics, Shimane Medical University, 89-1 Enya-cho, Izumo 693, Japan.

Since the discovery of potent diuretic, natriuretic, and vasorelaxant activities in the extract of rat atria, t multiple forms of natriuretic polypeptides with high and low molecular weights have been isolated from human and rat atria. 2-8Studies using radioimmunoassay have demonstrat335

336

Kikuchi et al.

ANP ASD VSD PDA Qp/Qs R~IA 2-D Echo

Atrial natriuretic polypeptide Atrial septal defect Ventricular septal defect patent ductus arteriosus Pulmonary blood flow/systemic blood flow ratio Radioimmunoassay Two-dimensionalechocardiography

ed that c~-atrial natriuretic polypeptide, a small molecular weight form of these peptides, is present in peripheral blood9-1~ and secreted through the coronary sinus. 1~ Furthermore, intravenous injection of synthetic cr causes diuresis, natriuresis, vasodilation, and inhibition of the aldosterone secretion in humans 12-~5and in experimental animals. ~6-~8These findings indicate that the heart is an endocrine organ as well as a pump organ. The plasma a-ANP concentration is elevated TM ~9.20 and correlates with atrial pressure 21'22in adults with congestive heart failure. However, there are only a few reports about the plasma c~-ANP concentration in children with congenital heart diseases. 23-25 Furthermore, the relationship between the plasma c~-ANP concentration and hemodynamic status in children with congenital heart diseases needs further elucidation. We measured the plasma c~-ANP concentration in the peripheral vein of children with various congenital heart diseases, and the peripheral plasma c~-ANP concentration during diagnostic cardiac catheterization, and compared the results. Moreover, we studied the effect of treatment on elevated a-ANP concentration in children with congenital heart diseases. METHODS Thirty control children and 62 children with congenital heart diseases were studied after informed consent was obtained. The number, age range, and median age of the children are given in Table I. All children enrolled in this study had normal renal function, as assessed by determinations of serum creatinine concentrations. Control children were 14 healthy children and 16 with constitutional delay of puberty, obesity, social and behavioral problems, or who had recovered from a minor operation. Children with heart diseases, bronchopulmonary diseases, and disorders affecting fluid and electrolyte balance were excluded. Among the children with congenital heart diseases, 14 with ventricular septal defect and one with patent ductus arteriosus had heart failure. All patients with heart failure were receiving digoxin and a combination of diuretic agents. Heart failure was diagnosed on the basis of signs and symptoms (tachypnea, intercostal retraction, hepato-

The Journal of Pediatrics September 1987

megaly, and failure to thrive). Seven patients with tetralogy of Fallot were receiving fl-adrenergic blockers. Furthermore, 34 patients with VSD were classified on the basis of findings of electrocardiogram, plain chest x-ray films, and two-dimensional echocardiograms into three groups: Small VSD was defined as that with normal ECG findings and normal chest radiographs; VSD size on 2-D Echo was <5 mm in diameter. Moderate VSD was defined as that with increased pulmonary vascularity and slight cardiac enlargement on chest radiographs, or left ventricular hypertrophy on ECG; VSD size on 2-D Echo was 5 to 10 mm in diameter. Large VSD was defined as that with remarkably increased pulmonary vascularity and considerable cardiac enlargement on chest radiographs, and combined ventricular hypertrophy or right ventricular hypertrophy on ECG; VSD size on 2-D Echo was >_10 mm in diameter. Cardiac catheterization. Twenty-nine children with congenital heart diseases undergoing cardiac catheterization for clinically indicated purposes were studied after informed consent was obtained. A description of the patients is given in Table II. In the patients with atrial septal defect, cardiac catheterization was requested by the surgeon. All four patients with small VSD had prolapse of the aortic valve. Blood samples for measurement of the plasma c~-ANP concentration were taken from the femora[ vein before the injection of contrast medium. Patients were sedated intramuscularly 60 minutes before cardiac catheterization with meperidine HC1 and promethazine HC1. Cardiac catheterization apparently had no effect on the plasma c~-ANP concentration, because the value during cardiac catheterization (mean _+ SD, 63.9 + 20.5 pg/mL) was not significantly different from that obtained on another day (61.2 _+ 19.1 pg/mL) in five children with Kawasaki disease. Blood sampling. Blood samples were taken from the peripheral veins in the supine position and at rest. Blood samples were transferred to chilled siliconized disposable glass tubes containing aprotinin (1000 kallikrein inactivator units/mL) and ethylenediaminetetraacetic acid (1 mg/mL), then immediately placed on ice and promptly centrifuged at 4 ~ C. An aliquot of plasma was immediately frozen at - 2 0 ~ C, and thawed only once at the time of the RIA or extraction. Measurement of plasma c~-ANP concentration. The plasma c~-ANP concentration was measured by RIA as reported previously.11,15,26,27Standard c~-ANP was supplied by H. Matsuo and K. Kangawa (Miyazaki Medical College, Miyazaki, Japan). This RIA recognizes a carboxy-terminal fragment of c~-ANP, and also recognizes other peptides with NH2-terminal extension, such as fl- and "y-ANP. The minimal detectable quantity of c~-ANP was 2

Volume 111 Number 3

a - A N P in congenital heart disease

337

T a b l e I. Peripheral plasma a-atrial natriuretic polypeptide concentration in control children and children with congenital heart diseases

a-ANP concentration (pg/mL) A g e (yr)

Atrial septal defect Ventricular septal defect Patent ductus arteriosus Tetralogy of Fallot Control

Without heart failure

n

Range

Median

M e a n _+ SD

13

1-16

6

99.4 _+ 40.7*

34

~42-15

2

69.2 _+ 36.5~

5

1- 3

2

10 30

y2-12 12d-15

2 4

n

With heart failure

Range

Mean _+ SD

50.0-180.6

--

20

20.5-142.5

350.6 +_ 200.2~

116.3 + 26.5*

4

88.6-151.2

416.0

69.4 +_ 38.8 44.6 _+ 22.3

10

11.6-120.8 11.7-98.7

--

n

Range

14

132.1-858.7

1

*P <0.001 comparedwith control children. tP <0.05 comparedwith control children. :~P <0.001 comparedwith VSD group without heart failure.

T a b l e II. Peripheral plasma a-atrial natriuretic polypeptide concentration and catheterization data in children with congenital heart diseases

A g e (yr) Group

n Range Median

AtriaI septal 9 defect Ventricular septal 11 defect Patent ductus 4 arteriosus Tetralogy of Fallot 5

Mean right atrial pressure* (mm Hg)

Mean left atrial pressure' (mm Hg)

Mean pulmonary artery pressure" (mm Hg)

Qp/Qs ratio

~-ANP concentration (pg/mL)

5-16

8

5 + 2

7 _+ 1

18 _+ 1

3.04 _+ 0.87

98.6 _+ 46.4

1-6

2

4 + 1

10 +_ 3~

33 _+ 16

2.13 _+ 0.59

192.9 _+ 135.1

2-3

2

3 _+ 1

9 _+ 1~

20 _+ 14

1.76 _+ 0.59

182.5 _+ 156.2

2-3

3

3 _+ 2

4 _+ 2

9 +_ 5

--

47.6 _+ 23.9

Values represent mean _+ SD. *Normal range (mean right atrial pressure _-<5mm Hg, mean left atrial pressure =<8 mm Hg, mean pulmonaryartery pressure --<18mm Hg) estimated from 15 children aged 1 to 12 years ,with Kawasaki disease. tEstimated from mean pulmonary artery wedge pressure. pg per tube, and the intra-assay and interassay variations

patients without heart failure. Every patient with heart

were 5.7% and 7.6%, respectively, a - A N P was extracted

failure had a higher concentration (132.1 to 858.7 p g / m L )

from the plasma using a Sep-Pak C18 cartridge (Water

than the upper limit of the normal range. Twenty-eight of

Associates Inc., Milford, Mass.) as previously described.H. 15 Recoveries of 40, 100, 360, and 1000 p g / m L

47 patients without heart failure had a normal a - A N P

a - A N P added to 1 m L plasma were 67%, 65%, 77%, and

concentration. In ASD, VSD, and P D A , the patients without heart failure had a significantly high mean a - A N P

78%, respectively.

concentration, whereas the mean value in the patients with

Statistical analysis. Statistical analysis was performed using paired or unpaired Student t tests. Linear regression analysis was done to determine the correlation between the plasma a - A N P concentration and the cardiac catheterization data. Results are expressed as mean _+ SD. RESULTS

Plasma a-ANP concentration in peripheral blood. The

tetralogy of Fallot was not significantly different from that in the control children (Table I). In

tetralogy of Fallot

there was no significant difference between the mean plasma a - A N P concentration in patients receiving (68.1 _+ 40.1 p g / m L , n -- 7) and not receiving (72.4 _+ 43.9 p g / mL, n = 3) a/3-adrenergic blocker. The mean plasma a - A N P concentration in the children

mean plasma a - A N P concentration in the patients with

with small, moderate, and large VSD were 59.1 _+ 28.9 ( n - - 17), 130.6 ___ 12.2 (n = 5), and 386.2 _+ 194.1

heart failure was significantly higher than that in the

(n = 12) p g / m L , respectively. The plasma concentrations,

338

Kikuchi et al.

The Journal of Pediatrics September 1987

2OO

200

100

100

s 03

tl

z <

0

1

0

2

I

@

9

[

I

0

!

i

0 2

!

|

|

|

4 6 8 10 12 LAP (mmHg)

200

/

E

z <

I

4 6 8 10 12 RAP (mmHg)

r=0.68 (P<.O,051 /

2OO

IX.

I

@

I00

i

'kl ~

9

O

o

1

2

0

9

3

o 9

I

9

4

5

6

Qp/Qs ratio

i

2'o

3'0

mean PAP (mmHg)

Fig, t. Correlation between plasma atrial natriuretic polypeptide (c~-ANP) concentration and cardiac catheterization data in children with atrial septal defect. LAP, RAP, Mean left and right atrial pressures, respectively;PAP, pulmonary artery pressure; Qp/Qs, pulmonary blood flow/systemic blood flow ratio.

of c~-ANP in the children with large and moderate VSD were significantly (P <0.001) high, but there was no significant difference between the mean a-ANP concentration in the children with small VSD and the control children. Relation between plasma a-ANP concentration and cardiac catheterization data. In the children with ASD, the mean right atrial pressure was slightly increased, although the pulmonary blood flow/systemic blood flow (Qp/Qs) ratio was very high; the mean left atrial pressure was not increased (Table II). There was a significant correlation between the plasma ~-ANP concentration and the Qp/Qs ratio, but the a-ANP concentration was not correlated with the other catheterization data such as mean right or left atrial pressure, and systolic, diastolic, and mean pulmonary arterial pressures (Fig 1). The children with VSD or PDA had various degrees of volume load in the left atrium. When the Qp/Qs ratio was high, mean left atrial pressure and mean pulmonary artery pressure were increased in these patients; mean right atrial pressure was not increased (Table II). In 11 children with VSD, the plasma a-ANP concentration was significantly correlated with left atrial pressure, estimated from mean pulmonary artery wedge pressure, Qp/Qs ratio, and systo-

lic, diastolic, and mean pulmonary artery pressures, but there was no correlation between the plasma c~-ANP concentration and mean right atrial pressure (Fig. 2). Essentially similar findings were observed in 15 children with PDA or VSD; the plasma c~-ANP concentration was significantly correlated with mean left atrial pressure (r = 0.76, P <0.005), mean pulmonary artery pressure (r = 0.86, P <0.001), and Qp/Qs ratio (r -" 0.71, P <0.01). In the children with tetralogy of Fallot, the c~-ANP concentration was normal. Mean right and left atrial pressures were not increased (Table II). Effect of treatment on elevated plasma ~-ANP concentration in peripheral blood of patients with heart failure. Patient 1, an infant with a large VSD and pulmonary hypertension, was admitted at 1 month of age because of tachypnea and feeding difficulty. The plasma c~-ANP concentration was 858.7 pg/mL. His condition improved after he received digoxin and diuretics. The plasma c~-ANP concentration had decreased to 265.3 pg/mL at 2 months of age. Patient 2, a child with a large VSD and pulmonary hypertension, had been given digoxin and diuretics. At 1~42 years of age, mean pulmonary artery pressure, mean right atrial pressure, and mean pulmonary artery wedge pres-

o

Volume 111 Number 3

a-.4NP in congenital heart disease

r=0.83 (p~50.005) O

400

400

E 300

300 O

8

r

z

O

200

0

9 |

9

|

3

4

5

6

i

0

1

2

0

./.

o

N

0

1

20O

1 O0

1 O0

0.001)

ou/oo o/

300

0

200

(p.;

o

400 o

2

Qp/Qs ratio

r =0.89

o

400 300

0

.....

r=0.78 (P,;0.005)

3oo z<

|

1'o

0.001)

400

1 O0

15 5 PAWP (mmHg)

0

RAP (mmHg)

r = 0.87 ( P

300

/

200

1 O0 $

0

O

200

100

r=0.68 (p,~0.05) 400

339

20O

D

1 O0 fv

o

f

0

I

I

I

1

30 60 90 systolic PAP (mmHg)

Q

0

9 I

I

I

20 30 40 diastolic PAP (mmHg) 10

*

0

0

I

I

!

*

i

10 20 30 4 0

50 60 mean PAP (mmHg)

Fig. 2. Correlation between plasma atrial natriuretic polypeptide (c~-ANP) concentration and cardiac catheterization data in children with ventricular septal defect, with (o) and without (e) heart failure. RAP, Mean right atrial pressure; PAP, pulmonary artery pressure; PAWP, mean pulmonary artery wedge pressure; Qp/Qs, pulmonary blood flow/systemic blood flow ratio.

sure were 51, 5, and 11 mm Hg, respectively. The Qp/Qs ratio was 2.90, and the plasma a-ANP concentration 386.6 pg/mL. Surgical correction was performed at l~f2years of age. The a-ANP concentration normalized to 63.1 pg/mL 2 months after the operation. Patient 3, a child with a large PDA and pulmonary hypertension, had received digoxin since 7 months of age. At 2V2 years of age, mean pulmonary artery pressure, mean right atrial pressure, and mean pulmonary artery wedge pressure were 42, 5, and 10 mm Hg, respectively. The Qp/Qs ratio was 2.49, and the plasma a-ANP concentration 416.0 pg/mL. Ligation of the PDA was performed at 2)42 years of age; the PDA and aorta were of equal diameters (11.5 mm). The plasma a-ANP concentration normalized to 41.1 pg/mL 13 days after the ligation. DISCUSSION Three different polypeptides--c~-,/3-, and 7-ANP--with potent diuretic, natriuretic, and vasorelaxant activities, have been isolated from human atrial tissue?. ~ Human a-, /3-, and 3'-ANP consist of 28, 56, and 126 amino acids,

respectively. Human /3-ANP comprises an antiparallel dimer of human tx-ANP. Human 3'-ANP carries the human a-ANP sequence at its carboxy-terminal. We have demonstrated that human ANP appears during the very early fetal period, z7 and that c~-ANP is the predominant form in plasma, whereas 3,-ANP is the predominant form in atrial tissue. 1L15,27 c~-ANP is secreted through the coronary sinus to act on target organs, including kidney, adrenal cortex, and the vasculature. 283~ Plasma c~-ANP concentration is elevated in healthy neonates younger than 4 days of age, 24'3t children with congenital heart diseases 23-25or chronic renal failure, 32 and adults with paroxysmal atrial tachycardia, 33 congestive heart failure, ~922or hypertension?4 Our findings indicate that the plasma c~-ANP concentration is dependent on the presence or absence of heart failure in children with congenital heart diseases. These data are compatible with those of Well et al. 24 The same findings have been observed in adults with valvular heart diseases or cononary artery diseases. ]4,~9,2~ Furthermore, the elevated plasma c~-ANP concentration in our three

340

Kikuchi et al.

patients with heart failure decreased after their conditions improved with digoxin and diuretics or with surgical correction. Therefore the measurement of plasma cr concentration in the peripheral blood may provide valuable information in evaluating the presence or absence of heart failure and the responses to treatment in children with congenital heart diseases. Tikkanen et a124 reported that during the infusion of a-ANP, a plasma a - A N P concentration >100 pg/mL induced natriuresis, diuresis, and vasodilation in healthy persons. Therefore the high plasma a-ANP concentration in our patients with heart failure might have physiologic significance. Pharmacokinetic studies have revealed that a - A N P is very short-acting (fast and slow half-lives are 1.7 and 13.3 minutes, respectively) 35'36and that the half-life of a-ANP in adults with heart failure is as short as in healthy persons.36,37Therefore the elevated plasma a-ANP concentration in the patients with heart failure is considered to be related to increased secretion of a-ANP. Evidence has accumulated that there is a functional antagonistic relationship between ANP and the renin-angiotensinzaJdosterone system, ~2,16,18,38-41which generally plays a compensatory role in the pathophysiology of heart failure by elevating peripheral vascular resistance and by inducing the retention of salt and water to maintain blood flow to vital organs. In an advanced stage of heart failure, however, these compensatory changes themselves overburden the already failing heart. Recently, the infusion of ANP has been reported to decrease right atrial and pulmonary artery wedge pressures and increase cardiac output in patients with severe congestive heart failure?7,4~ These findings suggest that ANP may be useful for the treatment of heart failure. The secretory mechanism of ANP from the human heart is not clear. Since the report of Henry et al.42in 1956, many investigators have demonstrated that diuresis and natriuresis are elicited in response to distention of the left atrium, the left and right atrial appendages by inflating a balloon, and in response to the increase in right and left atrial pressures by acute volume expansion in experimental animals?3-4~ Recently, an increase in right atrial pressure by volume loading and in left atrial pressure by mitral valve obstruction have been reported to release ANP from the heart of rats 49'5~and dogs, 51 respectively. In humans, volume expansion,~5 atrial pacing, ~~and paroxysmal atrial tachycardia 33 raise the plasma ANP concentration. These findings suggest that distention of the atrium stimulates ANP secretion from the human heart. We found a significant correlation between the c~-ANP concentration and Qp/Qs ratio in children with ASD. Graham et al. 52 reported that the right atrial maximal volume showed a significant correlation with the Qp/Qs ratio in patients with ASD. Therefore the c~-ANP concen-

The Journal of Pediatrics September 1987

tration may be correlated with right atrial volume in ASD. The children with ASD had a lower plasma c~-ANP concentration for the given values of the Qp/Qs ratio than did the children with VSD, perhaps because the pressures of the right and left atria are not elevated in children with ASD, although the right atrium is volume loaded, or because the right atrium may have a higher threshold than the left atrium to the stimulation of c~-ANP release. In the children with VSD, the plasma c~-ANP concentration increased in relation to the size of the VSD, and there was a significant correlation between the plasma ~-ANP concentration and Qp/Qs ratio. These findings are compatible with those of Matsuoka et al? s A significant correlation between c~-ANP and mean pulmonary artery wedge pressure suggests that the release of a-ANP is induced by distention of the left atrium in patients with VSD. The plasma a-ANP concentration was not elevated in patients with tetralogy of Fallot. This cannot be explained by the effect of/3-adrenergic blockers, because the plasma c~-ANP concentration was not elevated in the three patients who did not take/3-adrenergic blockers. The right and left atrial pressures are not elevated in tetralogy of Fallot, although the right ventricular pressure increases to that of the left ventricle. Heart failure is rarely seen in tetralogy of Fallot during childhood. Therefore it is reasonable to conclude that the plasma a-ANP concentration is not elevated in tetralogy of Fallot, because no known factors affecting c~-ANP secretion, such as increased atrial pressure or atrial expansion, are involved. We conclude that in children with congenital heart diseases with intracardiac communication between the pulmonary and systemic circulations, which results in distention of the atria, plasma concentrations of a-ANP are increased. Further investigation is required to elucidate the secretory mechanism of ANP from the heart, and its physiologic effects.

REFERENCES

1. de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci 1981;28:89. 2. Flynn TG, de Bold ML, de Bold AJ. The amino acid sequence of an atrial peptide with potent diuretic and natriuretic properties. Biochem Biophys Res Commun 1983;117:859. 3. Kangawa K, Matsuo H. Purification and complete amino acid sequence of c~-human atrial natriuretic polypeptide (ahANP). Bioehem Biophys Res Commuu 1984;118:131. 4. Currie MG, Geller DM, Cole BR, et al. Purification and sequence analysis of bioactive atrial peptides (atriopeptins). Science 1984;223:67. 5. Misono KS, Fukumi H, Grammer RT, Inagami T. Rat atrial natriuretic factor: complete amino acid sequence and disulfide linkage essential for biologicalactivity. Biochem Biophys Res Commun 1984;119:524. 6. Seidah NG, Lazure C, Chretien M, et al. Amino acid

Volume 111 Number 3

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

sequence of homologous rat atrial peptides: natriuretic activity of native and synthetic forms. Proc Natl Acad Sci USA 1984;81:2640. Atlas SA, Kleinert HD, Camargo M J, et al. Purification, sequencing and synthesis of natriuretic and vasoactive rat atrial peptide. Nature 1984;309:717. Kangawa K, Fukuda A, Matsuo H. Structural identification of 3- and ",/-human atrial natriuretic polypeptides. Nature 1985;313:397. Tanaka I, Misono KS, Inagami T. Atrial natriuretic factor in rat hypothalamus, atria and plasma: determination by specific radioimmunoassay. Biochem Biophys Res Commun 1984; 124:663. Gutkowska J, Bourassa M, Roy D, et al. Immunoreactive atrial natriuretic factor (IR-ANF) in human plasma. Biochem Biophys Res Commun 1985;128:1350. Sugawara A, Nakao K, Morii N, et al. a-Human atrial natriuretic polypeptide is released from the heart and circulates in the body. Biochem Biophys Res Commun 1985; 129:439. Richards AM, Nicholls MG, Espiner EA, et al. Effects of a-human atrial natriuretic peptide in essential hypertension. Hypertension 1985;7:812. Richards AM, Nicholls MG, Ikram H, Webster MWI, Yandle TG, Espiner EA. Renal, haemodynamic, and hormonal effects of human alpha atrial natriuretic peptide in healthy volunteers. Lancet 1985;1:545. Tikkanen I, Fyhrquist F, Metsarinne K, Leidenius R. Plasma atrial natriuretic peptide in cardiac disease and during infusion in healthy volunteers. Lancet 1985;2:66. Sugawara A, Nakao K, Morii N, et al. Significance of a-human atrial natriuretic polypeptide as a hormone in humans. Hypertension 1986;8:I 151. Burnett JC Jr, Granger JP, Opgenorth TJ. Effects of synthetic atrial natriuretic factor on renal function and renin release. Am J Physiol 1984;247:F863. Yukimura T, lto K, Takenaga T, Yamamoto K, Kangawa K, Matsuo H. Renal effects of a synthetic a-human atrial natriuretic polypeptide (~-hANP) in anesthetized dogs. Eur J Pharmacot 1984;103:363. Maack T, Marion DN, Camargo MJF, et al. Effects of auriculin (atrial natriuretic factor) on blood pressure, renal function, and the renin-aldosterone system in dogs. Am J Med 1984;77:1069. Nakaoka H, Imataka K, Amano M, Fujii J, Ishibashi M, Yamaji T, Plasma levels of atrial natriuretic lector in patients with congestive heart failure. N Engl J Med 1985;313:892. Burnett JC Jr, Kao PC, Hu DC, et al. Atrial natriuretic peptide elevation in congestive heart failure in the human. Science 1986;231 : 1145. Bates ER, Shenker Y, Grekin RJ. The relationship between plasma levels of immunoreactive atrial natriuretic hormone and hemodynamic function in man. Circulation 1986; 73:1155. Raine AGE, Erne P, Burgisser E, et al. Atrial natriuretic peptide and atrial pressure in patients with congestive heart failure. N Engl J Med 1986;315:533. Long RE, Unger T, Ganten D, Well J, Bidlingmaier F, Dohlemann D. c~-Atrial natriuretic peptide concentrations in plasma of children with congenital heart and pulmonary diseases. Br Med J 1985;291:1241. Well J, Bidlingmaier F, Dohlemann C, Kuhnle U, Strom T, Lang RE. Comparison of plasma atrial natriuretic peptide

a - A N P in congenital heart disease

25.

26.

27.

28.

29. 30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

341

levels in healthy children from birth to adolescence and in children with cardiac diseases. Pediatr Res 1986;20:1328. Matsuoka S, Kuranashi Y, Tomimatsu H, et al. Plasma atrial natriuretic peptide levels in patients with ventricular septal defect. J PEDIATR 1987;110:578. Nakao K, Sugawara A, Morii N, et al. Radioimmunoassay for a-human and rat atrial natriuretic polypeptide. Biochem Biophys Res Commun 1984;124:815. Kikuchi K, Nakao K, Hayashi K, et al. Ontogeny of atrial natriuretic polypeptide in human heart. Acta Endocrinol (Copenh) 1987;115:211. Sakamoto M, Nakao K, Kihara M, et al. Existence of atrial natriuretic p01ypeptide in kidney. Biochem Biophys Res Commun 1985;128:1281. Needleman P, Adams SP, Cole BR, et al. Atriopeptins as cardiac hormones. Hypertension 1985;7:469. Lynch DR, Braas KM, Synder SH. Atrial natriuretic factor receptors in rat kidney, adrenal gland, and brain: autoradiographic localization and fluid balance dependent changes. Proc Natl Acad Sci USA 1986;83:3357. Shaffer SG, Geer PG, Goetz KL. Elevated atrial natriuretic factor in neonates with respiratory distress syndrome. J PEDIATR 1986;109:1028. Rascher W, Tulassay T, Lang RE. Atrial natriuretic peptide in plasma of volume-overloaded children with chronic renal failure. Lancet 1985;2:303. Yamaji T, Ishibashi M, Nakaoka H, Imataka K, Amano M, Fujii J. Possible role for atrial natriuretic peptide in polyuria associated with paroxysmal atrial arrhythmias. Lancet 1985; 1:1211. Sugawara A, Nakao K, Sakamoto M, et al. Plasma concentration of atrial natriuretic polypeptide in essential hypertension. Lancet 1985;2:1426. Nakao K, Sugawara A, Morii N, et al. The pharmacokinetics of a-human atrial natriuretic polypeptide in healthy subjects. Eur J Clin Pharmacol 1986;31:101. Yandle TG, Richards AM, Nicholls MG, Cuneo R, Espiner EA, Livesey JH. Metabolic clearance rate and plasma half life of alpha-human atrial natriuretic peptide in man. Life Sci 1986;38:1827. Crozier IG, Nicholls MG, Ikram H, Espiner EA, Gomez H J, Warner NJ. Haemodynamic effects of atrial peptide infusion in heart failure. Lancet 1986;2:1242. Goodfriend TL, Elliott ME, Atlas SA. Actions of synthetic atrial natriuretic factor on bovine adrenal glomerulosa. Life Sci 1984;35:1675. Kudo T, Baird A. Inhibition of aldosterone production in the adrenal glomerulosa by atrial natriuretic factor. Nature 1984;312:756. Riegger AJG, Kromer EP, Kochsiek K. Atrial natriuretic factor in severe congestive heart failure. Dtsch Med Wochenschr 1985;110:1607. Saito Y, Nakao K, Nishimura K, et al. Clinical application of atrial natriuretic polypeptide to patients with congestive heart failure: beneficial effects on left ventricular function. Circulation (in press). Henry JP, Gauer OH, Reeves JL. Evidence of the atrial location of receptors influencing urine flow. Circ Res 1956; 4:85. Ledsome JR, Linden R J, O'Connor WJ. The mechanisms by which distension of the left atrium produces in anaesthetized dogs. J Physiol 1961;159;87. Lydtin H, Hamilton WF. Effect of acute changes in left atrial

342

45.

46. 47.

48.

Kikuchi et al.

The Journal of Pediatrics September 1987

pressure on urine flow in unanesthetized dogs. Am J Physiol 1964;207(3):530. Carswell F, Hainsworth R, Ledsome JR. The effects of left atrial distension upon urine flow from the isolated perfused kidney. Q J Exp Physiol 1970;55:173. Goetz KL, Bond GC, Bloxham DD. Atrial receptors and renal function. Physiol Rev 1975;55:157. Fater DC, Schultz HD, Sunder WD, Mapes JS, Goetz KL. Effects of left atrial stretch in cardiac-denervated and intact conscious dogs. Am J Physiol 1982;242:H1056. Ackermann U, Rudolph JR. Control of right atrial pressure at constant cardiac output suppresses volume natriuresis in anesthetized rats. Can J Physiol Pharmacol 1984;62:798.

49. Dietz JR. Release of natriuretic factor from rat heart-lung preparation by atrial distension. Am J Physiol 1984; 247:R1093. 50. Lang RE, Tholken H, Ganten D, Luft FC, Ruskoaho H, Unger Th. Atrial natriuretic factor: a cir,~ulating hormone stimulated by volume loading. Nature 1985;314:264. 51. Ledsome JR, Wilson N, Courneya CA, Rankin AJ. Release of atrial natriuretic peptide by atrial distension. Can J Physiol Pharmacol 1985;63:739. 52. Graham TP Jr, Atwood GF, Faulkner SL, Nelson JH. Right atrial volume measurements from biplane cineangiocardiography: Methodology, normal values, and alterations with pressure or volume overload. Circulation 1974;49:709.

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