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journal of Internal Medicine 1994; 235: 507-514 MINISYMPOSIUM: THE NATRIURETIC PEPTIDE HORMONES INTRODUCTION Editorial and historical review Editorial Control of fluid and electrolyte balance and cir- culatory homeostasis involves a complex interplay of regulatory mechanisms including neurohormonal systems. Some of these such as thirst, vasopressin and the sympathetic nervous system have received intensive study over many decades. Others, including prostaglandins and the renin-angiotensin system were accorded limited attention until the relatively recent introduction of sensitive assay systems and the development of selective blocking agents. The importance of newly discovered hormones, for example, medullipin [ l ] and ouabain [2] which are said to alter vascular tone and electrolyte balance, remains to be determined. Discovery of the above systems and many others has extended our knowledge in the fields of bio- chemistry and physiology, and in some instances has advanced considerably the therapeutic approach to clinical disorders such as hypertension and cardiac failure. It is not a new concept that the heart may be an endocrine gland [3]. A milestone in this regard was the demonstration, by de Bold in 1981, that an extract of atrial muscle injected into rats induced a vigorous natriuresis, a fall in arterial pressure and a rise in haematocrit [4]. Subsequent research showed the active compound to be atrial natriuretic peptide (ANP) which has biologic effects also when injected into man. These include natriuresis and diuresis, vasodilatation and suppression of renin and aldo- sterone secretion. ANP was found to be released from the heart in response to atrial stretch, to circulate in plasma with a brief half-life and to be cleared by receptor and enzymatic mechanisms. By the mid-1 980s, editorial reviews expressed interest, but noted that more information was required before ANP could be afforded the status of a physiologically important hormone [5, 61. A sceptical view was expressed in 1986 by Linden & Knapp in Endocrinology [7] and a debate on the role of ANP in fluid homeostasis was published in Hypertension in 1990 [8.9]. The second cardiac natriuretic peptide, brain natriuretic peptide (BNP) entered the arena in 1988. It is largely of ventricular origin being released into the circulation in response to increased pressure or stretch of the ventricles. Its half-life in plasma is considerably longer than that of ANP but like the latter it has natriuretic, diuretic and vasodilator properties, can suppress renin and aldosterone se- cretion and is cleared by enzymatic and receptor mechanisms. Whilst the physiological relevance of ANP and BNP continues to be debated, it is apparent that their levels in plasma provide an index of cardiac dys- function under some circumstances and might prove of prognostic value especially after acute myocardial infarction. Just how useful plasma ANP and BNP levels prove to be in routine clinical practice, however, remains to be seen. In view of their known biological effects, thera- peutic efficacy from administration of ANP or BNP might be anticipated, for example, in cardiac failure and hypertension, and perhaps in certain phases of renal failure. Preliminary results from studies with agents which inhibit enzymatic breakdown of the two peptides is encouraging for the treatment of hypertension and heart failure, but it is still early days. The third natriuretic hormone, C-type natriuretic peptide (CNP) discovered in 1990, appears to be produced mainly in brain and endothelium, and is less likely to play a role as a circulating hormone. Rather, it may act as a paracrine hormone, reducing tone of vascular smooth muscle and inhibiting proliferative responses to vascular injury. Its place in physiology and pathophysiology is much less clear than that of ANP and BNP. The natriuretic peptides have captured the im- agination of researchers, both ‘basic and clinical. In this Minisymposium we have attempted to bring together the important available information on 507

Editorial and historical review

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journal of Internal Medicine 1994; 235: 507-514

M I N I S Y M P O S I U M : T H E N A T R I U R E T I C P E P T I D E HORMONES

I N T R O D U C T I O N

Editorial and historical review

Editorial Control of fluid and electrolyte balance and cir- culatory homeostasis involves a complex interplay of regulatory mechanisms including neurohormonal systems. Some of these such as thirst, vasopressin and the sympathetic nervous system have received intensive study over many decades. Others, including prostaglandins and the renin-angiotensin system were accorded limited attention until the relatively recent introduction of sensitive assay systems and the development of selective blocking agents. The importance of newly discovered hormones, for example, medullipin [ l ] and ouabain [2] which are said to alter vascular tone and electrolyte balance, remains to be determined.

Discovery of the above systems and many others has extended our knowledge in the fields of bio- chemistry and physiology, and in some instances has advanced considerably the therapeutic approach to clinical disorders such as hypertension and cardiac failure.

It is not a new concept that the heart may be an endocrine gland [3]. A milestone in this regard was the demonstration, by de Bold in 1981, that an extract of atrial muscle injected into rats induced a vigorous natriuresis, a fall in arterial pressure and a rise in haematocrit [4]. Subsequent research showed the active compound to be atrial natriuretic peptide (ANP) which has biologic effects also when injected into man. These include natriuresis and diuresis, vasodilatation and suppression of renin and aldo- sterone secretion. ANP was found to be released from the heart in response to atrial stretch, to circulate in plasma with a brief half-life and to be cleared by receptor and enzymatic mechanisms.

By the mid-1 980s, editorial reviews expressed interest, but noted that more information was required before ANP could be afforded the status of a physiologically important hormone [5, 61. A sceptical view was expressed in 1986 by Linden & Knapp in Endocrinology [7] and a debate on the role of ANP in

fluid homeostasis was published in Hypertension in 1990 [8.9].

The second cardiac natriuretic peptide, brain natriuretic peptide (BNP) entered the arena in 1988. It is largely of ventricular origin being released into the circulation in response to increased pressure or stretch of the ventricles. Its half-life in plasma is considerably longer than that of ANP but like the latter it has natriuretic, diuretic and vasodilator properties, can suppress renin and aldosterone se- cretion and is cleared by enzymatic and receptor mechanisms.

Whilst the physiological relevance of ANP and BNP continues to be debated, it is apparent that their levels in plasma provide an index of cardiac dys- function under some circumstances and might prove of prognostic value especially after acute myocardial infarction. Just how useful plasma ANP and BNP levels prove to be in routine clinical practice, however, remains to be seen.

In view of their known biological effects, thera- peutic efficacy from administration of ANP or BNP might be anticipated, for example, in cardiac failure and hypertension, and perhaps in certain phases of renal failure. Preliminary results from studies with agents which inhibit enzymatic breakdown of the two peptides is encouraging for the treatment of hypertension and heart failure, but it is still early days.

The third natriuretic hormone, C-type natriuretic peptide (CNP) discovered in 1990, appears to be produced mainly in brain and endothelium, and is less likely to play a role as a circulating hormone. Rather, it may act as a paracrine hormone, reducing tone of vascular smooth muscle and inhibiting proliferative responses to vascular injury. Its place in physiology and pathophysiology is much less clear than that of ANP and BNP.

The natriuretic peptides have captured the im- agination of researchers, both ‘basic ’ and clinical. In this Minisymposium we have attempted to bring together the important available information on

507

Page 2: Editorial and historical review

508 M. G. NICHOLLS

ANP. BNP and CNP. The emphasis will be on human data, but reference to animal studies is made when necessary. After a brief historical review, biochemical aspects and measurement techniques will be addressed. The subsequent article will discuss physio- logical aspects of the three natriuretic peptides. The two concluding papers provide an overview of the peptides in hypertension and heart failure.

The literature on natriuretic peptides is now vast and only a small percentage of published data can be referred to in this Minisymposium. We hope, never- theless, to have adequately distilled the available information and conveyed some of the excitement attending the discovery and improved understanding of the role of natriuretic peptides.

Historical review

General

Although Starling in 1909 noted that the volume of body fluids must condition the renal excretion of sodium and water [lo], and Peters in 1935 suggested that some change in the distribution of circulatory blood modulated urinary sodium output [ l l ] , Homer Smith in his 19 5 7 review of ‘Salt and water volume receptors’ was not impressed by evidence of intra- thoracic volume receptors. He stated, ‘The thorax may be excluded, possibly in its entirety, by the failure of negative pressure respiration ... to increase sodium excretion’ [12]. Despite the fact that animal

Fig. 1 Sarcoplasmic layer between superficial myotibrils in rat atrial muscle containing specific granules (ag). rough endoplasmic reticulum (rer) and glycogen particles (gl). pm. plasma membrane. Magnification is x 44000. From [20] with permission.

studies in the subsequent decade demonstrated an increase in urine flow with atrial distension at- tributable largely to decreased discharge of renal sympathetic nerves and a reduction in circulating vasopressin levels [13, 141, a review in 1975 by Goetz et al. was cautious in attributing an important role to atrial volume receptors [15]. The 1970s brought evidence that atrial distension could inhibit circulating levels of renin in anaesthetized dogs [16], a response variously attributed to a neurogenic response [17] and a humoral substance [18].

The story of the natriuretic peptides begins with this background of uncertainty as to the importance of the heart as a sensor of central circulatory volume and the relevance of its output signals via the autonomic nervous system, vasopressin and the renin-angiotensin system.

Atrial natriuretic peptide ( A N P )

Kisch in 1956 observed ‘very small bodies’ on electron microscopic examination of guinea-pig atrial myocytes [19]. Jamieson & Palade in 1964 provided a more detailed description of the granules (Fig. 1.) which were found in mammalian (including human) atria but not ventricles [20]. Their concluding sentence was prophetic: ‘In this case, a highly differentiated contractile (atrial) cell appears to pos- sess a second specialized function in its ability to form and store a population of granules presumably secretory in nature ’. Subsequent studies showed that

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MINISYMPOSIUM: INTRODUCTION 509

110

90

8 'O- z 850- m 'E 30 3

10 0

-10

I lniecti0" - -

- - --

I '*jection 110-

90

70

50

30

10 0

E, 1 m

3 C 'C

- - - - - -- Fig. 2 Urinary response to

injection (arrow) of atrial extract (ti = 11). ventricular extract (n = 11) and phosphate buffer ( n = 10) in anaesthetized rats. The heavy lines represent differences between atrial extract and buffer, and the light line between ventricular extract and buffer. For sodium chloride and potassium the units are pmol min-I g-' kidney weight and for urine volume pl min-I g-' kidney weight. From [4] with permission.

-10 L I 1 I I 1 1

60 r

I I 1 I 1 1

0 40 80 120 160

I I 1 I I 1

0 40 80 120 160

Time (min) Time (rnin)

Injection

140

100

Pig. 3 Mean arterial pressure and Haematocrit * haematocrit in anaesthetized rats (W 44 - - - - -;- - - -. -; ------."--==--a

injected intravenously (arrow) I - with atrial extract (heavy lines. n = I I). ventricular extract (light lines, 17 = 11) or buffer (broken lines, n = 10). From [4] with permission.

40

1 I 1 I I I I I 1 I

20 40 60 80 100 120 140 160 180 0 Time (min)

experimentally induced perturbations in sodium and water balance altered atrial granularity [2 1, 221 leading de Bold to suggest 'a relationship between atrial specific granules and the regulation of water- electrolyte balance ...' [22].

In 1981, de Bold et al. injected an extract of rat atrial muscle into anaesthetized rats [4] and observed a rapid, more than 30-fold increase in urinary sodium and chloride excretion, a 10-fold rise in urine volume, and a sustained fall in arterial pressure and increase

in haematocrit (Figs 2 and 3 ) . No such effect was seen following injection of ventricular extract. Sub- sequent fractionation and bioassay of rat atrial homogenates confirmed that bioactivity resided in the atrial granules [23]. The story of the natriuretic peptides had begun.

Within a few years ANP was isolated, its structure determined [24] and the gene (located on the distal short arm of chromosome 1) sequenced [25-281. The circulating carboxy-terminal 28-amino-acid

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510 M. G. NICHOLLS

ANP BNP CNP

H,N -

Fig. 4 Structure of the natriuretic peptide family in man. Identical permission.

component (Fig. 4) was found to have bioactivity when injected or infused into healthy volunteers [29, 301. The natriuretic response was exaggerated in essential hypertension but blunted in heart failure. Whereas early studies utilized massive doses of ANP, subsequent research has demonstrated that infusion rates sufficient to raise circulating levels of the peptide within the physiological and pathophysiological range, have definite biological effects [ 3 1, 3 21.

Methods for the measurement of ANP in plasma were developed in the mid-1980s and led rapidly to the realization that atrial stretch (or strictly atrial transmural pressure rather than pressure within the atrial cavity) was the primary stimulus for release of the peptide [33-361. Concentrations of plasma ANP are in the picomolar range, and are elevated under circumstances where atrial stretch is increased, notably in heart failure. Circulating ANP is cleared rapidly (plasma half-life is approximately 3 min) by both a receptor mechanism (clearance receptors) [3 71 and enzymatic degradation initiated by a ubiquitous neutral endopeptidase (endopeptidase 24.11: NEP) [38]. Inhibition of NEP in man raises endogenous plasma ANP levels, at least temporarily. Most, if not all, of the biologic effects of ANP result from stimulation of cyclic guanosine monophosphate (cGMP)-linked receptors.

Under a variety of circumstances it became evident that ANP antagonized not only renin secretion but also some effects of angiotensin 11, for example, on vascular smooth muscle and the adrenal glomerulosa. Therefore, the renin system and the ANP system were perceived as complementary, the former protecting against volume depletion and low arterial pressure, the latter preventing fluid overload and hypertension [ 3 91.

amino acids are represented by the dark circles. From [59] with

Theory would indicate that ANP might have therapeutic potential, for example, in heart failure and essential hypertension, in view of its demonstrated biologic actions (natriuresis, vaso- dilation, suppression of renin, aldosterone and poss- ible sympathetic activity, and inhibition of growth of vascular smooth muscle). However, it is not feasible to administer the hormone long term as it requires intravenous infusion. Nevertheless, orally active inhibitors of NEP 24.11 are being investigated as possible therapeutic agents in patients with either heart failure or hypertension.

At the time of writing, it appears that ANP is a rapidly responding and physiologically important hormone which serves to protect against fluid overload through a variety of mechanisms (Fig. 5). Its level in plasma provides an index of ventricular dysfunction and may prove useful as a prognostic indicator under some circumstances. Inhibition of its enzymatic breakdown might provide a new thera- peutic approach in heart failure and hypertension.

Brain natriuretic peptide

In 1988, Sudoh et a/. discovered a peptide in porcine brain with similar biological properties and structural homology to ANP [40]. Although it was called brain natriuretic peptide. subsequent studies showed it to be secreted by the heart, predominantly the ventricles [41, 421 but also the atria [42]. In contrast to ANP, which is stored in granules and whose secretion is largely ‘regulated’ (by change in atrial transmural pressure), BNP appears to be released upon secretion (‘constitutive ’), although granules containing both BNP and ANP have been described [43]. In humans the major circulating form of BNP consists of a 32

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MINISYMPOSIUM: INTRODUCTION 511

t Sodium intake

1

1 Atrlal dlstentlon

Fig. 5 Conceptual scheme of ANP. its release in response to atrial stretch and its actions designed to protect against extracellular volume overload. From [60] with permission.

amino acid polypeptide with a central ring structure similar to ANP (Fig. 4). Its concentration in plasma is lower than that of ANP in most circumstances. In contrast to ANP, there is considerable inter-species diversity of amino acid composition. Although rela- tively little information is available regarding stimuli for release of BNP, it appears that increases in ventricular pressure and perhaps volume are of primary importance. Its comparatively long plasma half-life (approximately 22 min) is presumed to reflect a greater volume of distribution [44], reduced affinity for clearance receptors [41] and a slower rate of hydrolysis by endopeptidase 24.11 compared to ANP [45]. Clearance receptors and endopeptidase 24.11 appear to account for removal of BNP from the circulation. The biological effects of BNP injected or infused into man are similar to those of ANP [44] although some studies have utilized the peptide of another species and few doses have been used. Unlike ANP and CNP, no specific BNP receptor has yet been identified but it seems probable that some, if not all. of its actions are mediated by the cGMP-linked natriuretic peptide receptor A (NPR-A) [46 and Yandle, pp. 561-751.

Like ANP, BNP levels in plasma are elevated in cardiac failure [41] and after acute myocardial

* 1 ECF volume and anerial pressure

1

1 1 Alrlai dlstentim

1 Atriel natriumllc pepude

infarction [47]. However, in mitral stenosis BNP levels are increased less obviously than ANP which reflects the dominance of ventricular over atrial production of BNP [48]. In view of its relatively long plasma half-life and its ventricular origins, there is speculation that BNP could provide a more accurate index of ventricular dysfunction than ANP [49].

CNP

In 1990, CNP which has two mature forms, one containing 22 amino acids (Fig. 4) and the other 53, was isolated from porcine brain [SO]. Production occurs in brain (where its concentration far exceeds that of ANP and BNP [51]) and endothelial cells [52], thus there is speculation that it may function as a neurotransmitter and as a paracrine hormone in- ducing relaxation of vascular smooth muscle [53] and inhibiting proliferative responses to vascular injury [54, 551. Its binding affinity for receptors and its stimulatory effect on cGMP production differs from ANP and BNP and is species dependent [46, 561. Circulating levels of CNP are lower than ANP and BNP and, in contrast to the other two peptides, appear not to be raised in cardiac failure [57]. Infusion of the 22 amino acid CNP into healthy

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512 M. G. NICHOLLS

ANP BNP CNP

-25 1 99 126 -26 1 75 108 -23 1 51 103 ....... ......... ....... ........ PmpKI-form rn ....... ......... I I Y

1 1 1 51 &? 103 1 99 126 1 75 108 1

........ t I PrO-fOrm Y A N P t ......... ........ Y I 1

Circularim syslem

1 75 108 c

1 99 126 ......... 1 ......... ........

Y

(L.ANp a W N P 75 108 BNp.32

1 ?

Fig. 6 Proteolytic processing pathways and molecular forms of the three natriuretic peptides in human plasma and central nervous system. From 1511 with permission.

volunteers sufficient to raise plasma levels above those normally seen in man was without effect on urine sodium excretion or blood pressure and had a lesser stimulatory effect on plasma cGMP than comparable doses of ANP or BNP [61]. Therefore, it appears probable that CNP in man is less important as a circulating hormone than as a paracrine or perhaps autocrine hormone, but much more infor- mation is needed.

Overview

In the thirteen years since de Bold described the urinary and haemodynamic responses to the in- jection of atrial muscle extract in rats [4], an enormous literature has accumulated regarding the natriuretic peptides. Information on the processing and structure of ANP. BNP and CNP (Fig. 6) and their receptors has accumulated at a faster pace than has our understanding of their importance in regulating body fluid and haemodynamic status in health and in various circulatory disorders.

Although there is considerable uncertainty and disagreement, it seems probable from current evi- dence than ANP and BNP serve to protect against sodium and fluid overload and hypertension. In this role, and in concert with other natriuretic, diuretic and vasodilator mechanisms, they counterbalance the antinatriuretic, antidiuretic and vasoconstrictor activities of the renin-angiotensin system, aldo-

sterone, the sympathetic system, vasopressin and endothelin. Under usual ' circumstances en- countered in daily living, these contrary systems with their sometimes multiple input signals maintain a delicate balance which ensures relative constancy of body electrolyte and water content, and circulatory homeostasis. However, precise dissection of the physiological role of the natriuretic peptides in man is difficult in the absence of specific inhibitors. Likewise, their importance in the pathophysiology of circulatory disorders remains to be settled.

Discovery of new hormones leads inevitably to a search for syndromes resulting from their auton- omous overproduction or their deficiency. Excessive secretion of ANP or BNP might be expected to result in volume depletion and hypotension, whilst under- production could lead to a mirror-image syndrome of volume expansion and hypertension. Bartter's and Gordon's syndromes were suspected to result from perturbations in natriuretic peptide levels [ 5 81 but the evidence to date is less than convincing,

Apart from their possible physiological role, circulating ANP and BNP levels may provide a useful index of cardiac function and a prognostic indicator following myocardial damage. Finally, agents which inhibit the breakdown of ANP and BNP might prove therapeutically useful in patients with heart failure, hypertension or renal impairment.

The next few years will see consolidation and expansion of our knowledge of the natriuretic

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MINISYMPOSIUM: INTRODUCTION 513

peptides, particularly their importance under physio- logical circumstances and in circulatory disorders. We must wonder, also, how many more natriuretic peptides await discovery.

M. G. NICHOLLS Department of Medicine

The Christchurch School of Medicine Christchurch New Zealand

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1993: 193: 248-53.

252: 120-23.

Received 3 January 1994. accepted 21 January 1994.

Correspondence: Dr M. Gary Nicholls. Department of Medicine. The Christchurch School of Medicine. Christchurch. New Zealand.