Brain natriuretic peptide versus atrial natriuretic peptide\p=m-\physiological and pathophysiological significance in children andadults: a reviewMuneo Yoshibayashi, Yoshihiko Saito and Kazuwa Nakao

Since the discovery of atrial natriuretic peptide (ANP) inthe cardiac atrium (1, 2), ANP has been implicated inbody fluid homeostasis and blood pressure control as acardiac hormone.

Brain natriuretic peptide (BNP), a second member ofthe natriuretic peptide family, was isolated originallyfrom the mammalian brain and has a remarkablesequence homology to ANP (3\p=n-\5). Following itsdiscovery, it has been elucidated that BNP is synthesizedand secreted primarily by the cardiac ventricle and isalso a cardiac hormone like ANP (6, 7).BNP vs ANP in physiological conditionsIn normal human heart, ANP is mainly synthesized inand secreted from the cardiac atrium, whereas BNP ispredominantly in the cardiac ventricle (7\p=n-\9). In normalhuman adults, the plasma BNP concentration is 1\p=n-\2fmol/ml, which is about one-sixth of the plasma ANPconcentration (7\p=n-\9).

Plasma BNP and ANP concentrations in normalhumans show interesting developmental changes. Wehave measured plasma BNP and ANP concentrations inthe peripheral vein of normal subjects from birth toadult and in the umbilical vein of normal neonates (8-10). Both plasma BNP and ANP concentrations are thehighest at 0 days of age and decrease throughmaturation to be almost constant at 3 months of age(10). Elevation of the plasma concentration in theneonatal period is more remarkable in BNP than inANP. The ratio of plasma concentrations of BNP to ANPis also the highest (about 1.39) at 0 days of age anddecreases through maturation to become the adult level(about 0.17) at 3 months of age (10). It should be notedthat the BNP/ANP ratio in normal 0-day neonates iscomparable to that in patients with severe congestiveheart failure (8, 9). Furthermore, the plasma BNPconcentration of the 0-day neonate is markedly (about21 times) higher than that in the umbilical vein (10).This marked, rapid and preferential increase of BNPimmediately after birth may have a physiological

significance in perinatal circulatory changes fromfetus to neonate. The transition from fetal to neonatalcirculation is accompanied by an increase of pulmonaryblood flow as a result of lung expansion and anelevation of systemic vascular resistance due to theremoval of the very-low-resistance placenta (11). Theseperinatal circulatory changes lead to an increase in leftventricular volume and pressure load (11). Brainnatriuretic peptide is synthesized and secreted mainlyby the cardiac ventricle and its expression in theventricle is induced in ventricular overload andhypertrophy (6). The abrupt increase in left ventricularvolume and pressure load at birth may stimulate BNPsynthesis and secretion in the ventricle and result inelevation of the plasma BNP concentration shortlyafter birth. The elevated plasma BNP concentrationmay act to alleviate the increased left ventricularload after birth and to support the myocardialfunction of the neonate. Different from BNP, theplasma ANP concentration at 0 days of age does notchange significantly from that in the umbilical vein.These observations indicate that BNP and ANPrespond differently to the hemodynamic changes atbirth. A dual natriuretic peptide system of BNP andANP with distinct physiological roles in the perinatalcirculatory control is suggested.

BNP vs ANP in cardiovascular diseases

Congestive heart failureIn patients with dilated cardiomyopathy (DCM) andpatients with old myocardial infarction (OMI), bothplasma BNP and ANP levels are elevated in proportionto the severity of heart failure (8, 9). Plasma BNP andANP concentrations correlate significantly with pulmonary capillary wedge pressure (r = 0.713 andr = 0.844, respectively) and cardiac index (r =

0.533 and r=0.764) (9). In severe cases, theelevation of plasma BNP is more remarkable (100-1000-fold) than ANP (10-100-fold) and the plasma

Department of Pediatrics, Kyoto University School of Medicine, Japan: Second Division , Department of Medicine, Kyoto University School ofMedicine, Japan

BNP surpasses ANP (8, 9). In patients with DCM orOMI, ANP gene expression in the ventricle is augmentedand ANP secretion from the ventricle increases andreaches the atrial level, the ventricle thus becoming asubstantial source ofthe elevated plasma ANP as well asthe atrium (12). Brain natriuretic peptide gene expression in the ventricle and BNP secretion from theventricle are also augmented in these patients but,unlike ANP, BNP is synthesized in and secretedpredominantly from the ventricle (8, 9). In patientswith DCM or OMI, the secretion of BNP and ANP fromthe left ventricle increases in proportion to the severityof left ventricular dysfunction. The amounts of BNP andANP secreted from the left ventricle correlate significantly with the left ventricular ejection fraction(r =

0.735 and r =0.676, respectively) and theleft ventricular end-diastolic volume index (LVEDVI)(r = 0.817 and r = 0.757) (9). In patients with aventricular septal defect, plasma concentrations of BNPand ANP and the ratio of BNP to ANP are all elevated inproportion to LVEDVI (r = 0.58. r = 0.42 and r =0.61, respectively) our unpubl. data). These observations suggest that the secretions of BNP and ANP fromthe left ventricle are regulated mainly by the walltension of the left ventricle in patients with congestiveheart failure.

In patients with mitral stenosis, Yoshimura et al.have shown that the plasma ANP concentration ismarkedly elevated whereas the plasma BNP concentration only increases slightly, suggesting that theincreased atrial tension itself is not a stimulus for BNPsynthesis or secretion (13).

In congestive heart failure, increased BNP and ANPmay play compensatory roles, and in severe heartfailure BNP makes more contribution than ANP to thecompensatory mechanisms.

Hypertrophie cardiomyopathy (HCM)We have demonstrated in pediatrie patients that theplasma BNP concentration is markedly elevated inpatients with HCM compared with that in controlsubjects or in patients with left ventricular hypertrophydue to pressure overload (aortic stenosis or coarctationof the aorta), whereas the plasma ANP concentrationshows only a mild elevation (14). Hasegawa et al. havereported similar observations in adult patients withHCM (15). Using immunohistochemical analysis ofendomyocardial biopsy specimens with specific monoclonal antibodies, they have also demonstrated inpatients with HCM that histological changes such asmyocardial fiber disarray, hypertrophy of myocytes andfibrosis are greater in BNP-positive patients than inBNP-negative patients (15). Thus, the preferentialelevation of plasma BNP concentrations in patientswith HCM may be associated with myocardial hypertrophy or with myocardial abnormalities characteristicof the disease.

Acute myocardial infarction (AMI)Morita et al. have performed serial measurements ofplasma BNP and ANP concentrations in patients withAMI over the time course of 4 weeks (16). They havedemonstrated that the plasma BNP level increasesrapidly and reaches a peak of more than 60-fold thenormal level approximately 20 h after the onset ofsymptoms. The peak plasma BNP level correlatessignificantly (r = -0.476, < 0.01) with the cardiacindex. In contrast, the plasma ANP level shows only amodest change (about a threefold increase, with a peakon day 2-3) and no significant correlation with thecardiac index. They have also demonstrated that somepatients have the second peak of plasma BNP on day 5and these patients show higher creatine kinase-MBisoenzyme levels and a lower left ventricular ejectionfraction. These observations suggest that the regulations of synthesis and secretion of BNP are different fromthose of ANP and that the elevated BNP level may havecompensatory roles for ventricular dysfunction in AMI.

Table 1 summarizes the characteristic changes ofplasma BNP and ANP concentrations in variouscardiovascular diseases and in physiological conditions.

In diseases with chronic ventricular overload, such asDCM, OMI or ventricular septal defect, the plasma BNPand ANP concentrations show parallel elevation. Inthese conditions, BNP as well as ANP may playbeneficial roles for the ventricular myocardium asordinary cardiac hormones. On the other hand, insituations of acute ventricular overload, such as AMI orthe circulatory changes at birth, the plasma BNPconcentration shows a preferential elevation. In theseconditions, BNP may act as an emergent cardiachormone to support the ventricular function.

The plasma renin activity shows a very similarpattern to the plasma ANP and BNP in developmentalchanges from birth to adulthood (17) and in congestiveheart failure (18). ft is known that the distribution ofthe natriuretic peptide system is well overlapped withthat of the renin-angiotensin system (19) and thereare various interactions between angiotensin Ifand natriuretic peptides (18-21). The cardiovascularhomeostasis may be regulated physiologically andpathophysiologically by these two antagonistic systems: the natriuretic peptide system and the renin-angiotensin system.

BNP vs ANP in the clinical effectBrain natriuretic peptide and ANP have similarhemodynamic effects. When administered intravenously in patients with congestive heart failure, bothBNP and ANP decrease pulmonary capillary wedgepressure and systemic vascular resistance and increasethe stroke volume index to a similar extent (13, 22).Thus, both peptides have beneficial effects on leftventricular function in patients with congestive heart

Table l. Plasma brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) concentrations in various cardiovascular diseases andphysiological conditions.3Disease Main pattern of overload BNP ANP BNP/ANP

DCM, OMIDCM, OMI severeVSDMSAS, Co/A, HTHCMAMI acute phaseNormal 0-day

neonateNormal human

(3-month adult)

Ventricle volumeVentricle volume; severe

Ventricle & atrium volumeAtrium

Ventricle pressure() or ventricle pressure() or ventricle volume? (Ventricle volume

& pressure)(-)

TTTT

TT-^orTTorTTTTTIT1-2

fmol/ml

TTTT

TT5-10

fmol/ml

T(1)

T(1)TTT(>1)(>i)

1/611 DCM = dilated cardiomyopathy; OMI = old myocardial infarction; VSD = ventricular septal defect; MS = mitral stenosis; AS = aortic

stenosis; Co/A = coarctation ofthe aorta: HT = hypertension; HCM = hypertrophie cardiomyopathy: AMI = acute myocardial infarction.

failure. The renal and hormonal effects of BNP aredifferent from those of ANP. The BNP infusion markedlyincreases urine volume and urinary sodium excretion inpatients with congestive heart failure (13). In contrastwith BNP, the natriuretic response to ANP infusion isblunted in patients with congestive heart failure (22).Atrial natriuretic peptide has a sympatholytic effect andANP infusion decreases plasma levels of norepinephrine(22), whereas BNP has less effect on the sympatheticnervous system than ANP, and BNP infusion increasesplasma levels of norepinephrine (13).

The real contribution of ANP and BNP to thecardiovascular regulation remains, however, speculative, as no antagonist is available. Further studies arenecessary to elucidate the real roles of the natriureticpeptide system in cardiovascular homeostasis.

References1. 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 1983:117:859-65

2. Kangawa K, Matsuo H. Purification and complete amino acidsequence of -human atrial natriuretic polypeptide. BiochemBiophys Res Commun 1984:118:131-9

3. Sudoh T. Kangawa K, Minammo . Matsuo H. A new natriureticpeptide in porcine brain. Nature 1988:332:78-81

4. Kojima M. Minamino N. Kangawa K. Matsuo H. Cloning andsequence analysis of cDNA encoding a precursor for rat brainnatriuretic peptide. Biochem Biophvs Res Commun 1989:159:1420-6

5. Kambayashi Y, Nakao K. Mukoyama M, Saito Y, Ogawa Y.Shiono S, et al. Isolation and sequence determination of humanbrain natriuretic peptide in human atrium. FEBS Lett 1990:2 59:341-5

6. Ogawa Y. Nakao K. Mukoyama M. Hosoda K. Shirakami G, AraiH. et al. Natriuretic peptides as cardiac hormones in normoten-sive and spontaneously hypertensive rats: the ventricle is a majorsite of synthesis and secretion of brain natriuretic peptide. CircRes 1991:69:491-500

7. Hosoda K. Nakao K, Mukoyama M, Saito Y, Jougasaki M,Shirakami G. et al. Expression of brain natriuretic peptide gene in

human heart: production in the ventricle. Hypertension 1991;17:1152-6

8. Mukoyama M, Nakao , Hosoda , Suga S, Saito Y, Ogawa Y, et

al. Brain natriuretic peptide as a novel cardiac hormone inhumans: evidence for an exquisite dual natriuretic peptidesystem, atrial natriuretic peptide and brain natriuretic peptide. JClin Invest 1991:87:1402-14

9. Yasue H. Yoshimura M. Sumida H, Kikuta , Kugiyama ,Jougasaki M, et al. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-typenatriuretic peptide in normal subjects and patients with heartfailure. Circulation 1994:90:195-203

10. Yoshibayashi M, Kamiya T, Saito Y, Nakao K, Nishioka K. TemmaS, et al. Plasma brain natriuretic peptide concentrations inhealthy children from birth to adolescence: marked and rapidincrease after birth. Eur J Endocrinol 1995:13 3:207-9

11. Heymann MA, Fetal and neonatal circulations. In: Adams FH,Emmanouilides GC, Riemenschneider TA. editors. Moss' heartdisease in infants, children and adolescents. 4th ed. Baltimore:Williams & Wilkins, 1989:24-35

12. Saito Y, Nakao , Arai , Nishimura , Okumura , Obata , etal. Augmented expression of atrial natriuretic polypeptide gene inventricle of failing heart. J Clin Invest 1989:83:298-305

13. Yoshimura M, Yasue H, Okumura K, Ogawa H, Jougasaki M,Mukoyama M. et al. Different secretion of atrial natriureticpeptide and brain natriuretic peptide in patients with congestiveheart failure. Circulation 1993;87:464-9

14. Yoshibayashi M. Kamiya T, Saito Y, Matsuo H. Increased plasmalevels of brain natriuretic peptide in hypertrophie cardiomyopathy. Engl J Med 1993:329:433-4

15. Hasegawa K. Fujiwara H, Doyama K, Miyamae M, Fujiwara T,Suga S, et al. Ventricular expression of brain natriuretic peptide inhypertrophie cardiomyopathy. Circulation 1993;88:372-80

16. Morita E, Yasue H, Yoshimura M, Ogawa H, Jougasaki M,Matsumura T, et al. Increased plasma levels of brain natriureticpeptide in patients with acute myocardial infarction. Circulation1993;88:82-91

17. Brons M, Thayssen P. Plasma renin concentration, activity andsubstrate in normal children. Int J Pediatr Nephrol 1983:4:43-6

18. Dzau VJ. Circulating versus local renin-angiotensin system incardiovascular homeostasis. Circulation 1988:77 Suppl 1:14-13

19. Nakao K, Ogawa Y, Suga S, Imura H. Molecular biology andbiochemistry of the natriuretic peptide system. J Hypertens1992:10:907-12

20. Leckie B. Christie J. Dow JW, Muir T. Production of atrialnatriuretic peptide and cell proliferation in ventricular myocytesgiven angiotensin II in culture. J Hum Hypertens 1994:8:607-8

21. Johnston CI. Hodsman PG. Kohzuki M. Casley DJ. Fabris B.Phillips PA. Interaction between atrial natriuretic peptide and therenin angiotensin aldosterone system. Endogenous antagonists.Am J Med 1989:87:24S-8S

22. Saito Y. Nakao , Nishimura . Sugawara . Okumura . Obata

. et al. Clinical application of atrial natriuretic polypeptide in

patients with congestive heart failure: beneficial effects on leftventricular function. Circulation 1987:76:115-24

Received February 27th. 1996Accepted May 20th. 1996