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Cardiovascular Research 51 (2001) 495–509 www.elsevier.com / locate / cardiores Review Water and sodium regulation in chronic heart failure: the role of natriuretic peptides and vasopressin a, a,b a Paul R. Kalra *, Stefan D. Anker , Andrew J.S. Coats a Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse Street, London SW3 6 LY, UK b ¨ Centrum for Molecular Medicine, Berlin, Department of Cardiology, Franz-Volhard-Klinik ( Charite´ , Campus Berlin-Buch) at Max Delbruck Germany Received 15 November 2000; accepted 26 March 2001 Keywords: Heart failure; Natriuretic peptide; Vasoconstriction / dilation; Antihypertensive / diuretic agents 1. Introduction Chronic heart failure (CHF) is a complex syndrome characterised by objective evidence of ventricular dysfunction and associated clinical symptoms [1]. Activated neurohormonal mechanisms play an important role in the maintenance of circulatory homeostasis. They can be divided into the vasoconstrictive, sodium retaining and the opposing vasodilatory, natriuretic systems. Vasoconstrictive and sodium retentive actions are provided by the renin– angiotensin–aldosterone system, the sympathetic nervous system, vasopressin, thromboxane and endothelin [2–5]. Initially, in patients with heart failure, these act as important compensatory mechanisms maintaining blood pressure and adequate tissue perfusion. However, prolonged activation of these systems has deleterious effects on haemodynamics and directly on the heart itself. Enhanced vasoconstriction and fluid retention result in adverse loading conditions in the failing ventricle, whilst high levels of angiotensin II directly induce cardiac myocyte necrosis and adversely alter the myocardial matrix structure [6–9]. Angiotensin II also potentiates sympathetic drive by direct stimulation and by impairing its control by the baroreceptors [10]. In view of these adverse effects, it might be anticipated that measurement of plasma levels of neurohormones would be a helpful adjunct during prognostic assessment and even in the tailoring of therapy in CHF. Several studies have demonstrated an impaired prognosis in patients with CHF who have elevated plasma levels of norepinephrine and endothelin-1 [11,12]. Cardiac cachexia *Corresponding author. Tel.: 144-207-351-8127; fax: 144-207-3518733. E-mail address: [email protected] (P.R. Kalra). is a wasting condition that occurs in a significant percentage of patients with CHF, and is associated with a particularly poor prognosis [13]. This group appears to have marked neurohormonal abnormalities, with patients demonstrating elevated levels of norepinephrine and a reduction in plasma sodium concentration [14]. However, drugs that reduce plasma catecholamine levels are not necessarily associated with an improved prognosis, suggesting that the mechanisms involved in blunting the effects of the sympathetic nervous system are much more complex [15]. This may result, at least in part, from the fact that activation of the sympathetic nervous system can be expressed in several different ways and only a small proportion of catecholamines released at the synapse spill over into the circulation. The natriuretic peptide system, nitric oxide and vasodilatory prostaglandins provide counter-regulatory vasodilatation and natriuresis [16–18]. In humans, the natriuretic peptide family consists of at least three structurally related polypeptides. Over the last two decades our understanding of their role in CHF has been greatly enhanced. In patients with CHF, measurement of plasma natriuretic peptide levels is increasingly used to aid diagnosis, assess prognosis and tailor therapy [19–21]. Despite advances in the pharmacological treatment of CHF the prognosis remains poor. Although suppression of the renin–angiotensin–aldosterone and sympathetic nervous systems reduce morbidity and mortality in CHF [22,23], great potential still exists to further manipulate the activated neurohormonal systems. The control of sodium and water regulation is achieved by a series of complex interactions occurring between several different systems. For example, renal sympathetic Time for primary review 28 days. 0008-6363 / 01 / $ – see front matter 2001 Elsevier Science B.V. All rights reserved. PII: S0008-6363( 01 )00297-8 496 P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509 nerves, atrial natriuretic peptide (ANP) and angiotensin II modulate renal juxtaglomerular renin release [24–26]. In addition, vasopressin, norepinephrine and angiotensin II facilitate the release of ANP [27–29]. However, ANP is able to modulate the renal effects of vasopressin [30]. A full review of these important systems is beyond the scope of this article, and therefore we have chosen to focus on the role of the natriuretic peptide system and vasopressin in the pathophysiology of human CHF. Although they function in opposition, there are exciting prospects for their therapeutic manipulation in CHF. As such we will review their respective diuretic and antidiuretic actions, before discussing their role in current and future clinical practice. 2. Mechanisms involved in sodium and water homeostasis in chronic heart failure (Fig. 1) The maintenance of circulatory integrity has, perhaps, the most dominant influence on renal sodium and water excretion [31]. Afferent sensing mechanisms involved in Fig. 1. The role of natriuretic peptides and vasopressin in sodium and water regulation in CHF. Arterial under-filling results in the activation of high-pressure mechanoreceptors and subsequent nonosmotic release of vasopressin. Acting through two different receptors, vasopressin enhances vasoconstriction and decreases water clearance. Increased atrial stretch and ventricular volume overload stimulate the myocardial secretion of ANP and BNP. These circulating peptides enhance natriuresis and diuresis, together with vasodilatation. The exact role of CNP in CHF remains unclear. (GFR, glomerular filtration rate; Na 1 , sodium; NPR, natriuretic peptide receptor). P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509 salt / water homeostasis can be sub-divided into high-pressure and low-pressure mechanoreceptors. High-pressure receptors are located in the left ventricle, carotid sinus, aortic arch and in the renal juxtaglomerular apparatus [32–34]. These receptors respond to decreases in arterial pressure, peripheral vascular resistance or renal perfusion by appearing to stimulate reflexes that result in the activation of the sympathetic and the renin–angiotensin– aldosterone systems and the non-osmotic release of vasopressin. Low-pressure receptors are primarily found within the atria. These react to volume expansion or increased stretch by enhancing the release of atrial and brain natriuretic peptides. In CHF it appears that the highpressure receptors override the low-pressure receptors since sodium and water retention occur despite elevated atrial pressures [35]. However, the mechanisms involved in neurohormonal activation in CHF appear to be much more complicated, as these patients also exhibit blunted baroreflex responses [36]. 3. The natriuretic peptide family In 1981 de Bold and colleagues discovered ANP, identifying the heart as an endocrine organ and stimulating the search for related peptides [37]. Although brain natriuretic peptide (BNP) was first discovered in porcine brain [38], it soon became apparent that it was particularly concentrated within the myocardium [39]. Since then extensive evaluation has led to a greater understanding of the role that these two peptides play in maintaining circulatory homeostasis. C-type natriuretic peptide (CNP) was discovered in 1990 [40] and although less is known regarding its physiological role it appears to have a much wider tissue distribution. 3.1. Structure The three natriuretic peptides share a 17-amino acid ring closed by a disulfide bond between two cysteine residues. ANP is produced as a precursor protein that is cleaved to produce a 98-amino acid N-terminal fragment and the biologically active C-terminal 28-amino acid peptide [41]. The gene coding ANP is also expressed in the kidney, where different processing of the precursor protein results in the formation of a 32-amino acid protein — urodilatin [42]. Similarly, in humans, BNP is produced as a propeptide, with cleavage resulting in the production of the active 32-amino acid peptide (a different molecule to urodilatin) and an N-terminal fragment [43]. Two mature forms of CNP exist [44]. The higher molecular weight CNP-53 predominates in tissues, whereas the 22-amino acid peptide (CNP-22) is found mainly in plasma and cerebrospinal fluid [45,46]. Most of the data on the biological effects of CNP relate to the 22 amino-acid form. 497 3.2. Receptors and metabolism ( Fig. 2 a) The physiological actions of the natriuretic peptides are primarily mediated through interactions with natriuretic peptide receptors (NPR) [47]. Binding of the appropriate natriuretic peptide to the receptor results in the activation of intracellular particulate guanylate cyclase, enabling the formation of cyclic guanosine monophosphate (cGMP), which in turn is thought to mediate the biological effects of the peptides. Three types of NPR (A, B and C) have been identified in human tissues. Unfortunately their nomenclature does not correspond to their interaction with the natriuretic peptides. NPR-A has greater affinity for ANP and BNP, whereas NPR-B is more specific for CNP [48]. The third, NPR-C, lacks the guanylate cyclase domain and is thought to act as a clearance receptor, and is one of two mechanisms by which natriuretic peptides are catabolised [49]. Following binding of a natriuretic peptide to the NPR-C, the resulting receptor–ligand complex undergoes endocytosis and subsequent lysosomal hydrolysis. The second mechanism involves cleavage of the natriuretic peptide molecule by neutral endopeptidase, an enzyme with a wide tissue distribution [50]. Receptors for the natriuretic peptides have been demonstrated within the kidney [51,52]. Recent studies in rats have confirmed NPR-A, -B and -C mRNA expression in all segments of the nephron, although levels varied at different sites [53]. NPR-A mRNA was most abundant in cells of the glomerulus, proximal and distal tubules, whilst NPR-B mRNA was less abundant in all nephron fractions studied. In this study NPR-C had the least expressed mRNA in the glomerulus and tubules. In contrast, Itoh et al. found glomerular mRNA expression for NPR-C was greater than that for NPR-A and –B [54]. In addition, they demonstrated a reversible reduction in the glomerular mRNA for all three receptors in response to dehydration. Immunohistochemistry has demonstrated staining for NPRB on papillary and medullary capillaries, glomeruli and renal arteries in rat kidneys [55]. 3.3. Natriuretic peptide release The prime stimulus for ANP secretion is an increase in atrial stretch, which occurs during intravascular volume expansion [56]. Acute heart failure is a good model for this, where rapid increases in atrial filling pressures result in the elevation of plasma ANP levels [57]. Some controversy still exists with respect to the major site of myocardial BNP synthesis in humans. Although significant BNP immunoreactivity and gene expression have been demonstrated in the ventricular myocardium of subjects with CHF, they have also been found in atrial tissue under normal conditions [58,59]. Luchner et al. evaluated the differential atrial and ventricular expression of myocardial BNP during evolution of heart failure in dogs [60]. Early 498 P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509 Fig. 2. (a) The natriuretic peptide receptor (NPR) is a transmembrane protein with several important domains. Intracellular particulate guanylate cyclase is normally under the inhibition of the kinase homology domain. When an appropriate natriuretic peptide binds to the external domain of the NPR, (ANP or BNP to NPR-A, CNP to NPR-B), this inhibition is released enabling the formation of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). The resulting intracellular elevation of cGMP is thought to mediate the biological effects of the peptides. Following binding of the natriuretic peptide to NPR-C (clearance receptor), the resulting receptor-ligand complex undergoes endocytosis and subsequent lysosomal hydrolysis. (Amended from Levin E.R., Gardner D.G., Samson W.K. Natriuretic peptides. N Engl J Med 1998;339:321–328). (b) In the kidney the vasopressin V2 receptors (V2 -r) are located on the basolateral membrane of collecting duct cells. Binding of vasopressin (VP) to the receptor results in the activation of adenylate cyclase and subsequent generation of intracellular cyclic adenosine monophosphate (cAMP). The net biological effect, a decrease in water clearance, is achieved by ‘shuttling’ of aquaporin-2 water channels from cytoplasmic vesicles to the apical membrane, where they facilitate the movement of water down the osmotic gradient. Aquaporin-2 water channel synthesis is also increased. P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509 left ventricular dysfunction was characterised by a selective increase in levels of atrial BNP and BNP mRNA expression, in association with elevated circulating levels of plasma BNP. On progression to overt heart failure there was a further increase in atrial BNP and BNP mRNA expression, together with a further increase in plasma BNP. At this point ventricular levels of BNP and BNP mRNA were also elevated. A volume-related pattern of release has been proposed for BNP since its plasma levels increase during chronic sodium dietary loading whilst its levels decrease during fluid removal in patients undergoing haemodialysis [61,62]. Furthermore BNP mRNA expression in the right atrium is positively correlated with mean right atrial pressure and ANP mRNA in subjects undergoing cardiac surgery, which has led to the suggestion that atrial pressure may also be an important regulatory mechanism [63]. Much less is known regarding the haemodynamic factors responsible for CNP release. However, in vitro studies have demonstrated marked augmentation of CNP secretion from cultured cells by many important vasoactive mediators. These include cytokines and neurohormones important in the pathogenesis of chronic heart failure, such as tumour necrosis factor, lipopolysaccharide and both ANP and BNP [64,65]. More data are required to determine the in vivo significance of these findings. 3.4. Plasma and urine levels of natriuretic peptides Plasma ANP and BNP concentrations are markedly elevated in CHF and the magnitude of increase correlates to the severity of heart failure [19,66–68]. This has led several investigators to examine the use of plasma natriuretic peptide assays to aid in the diagnosis of CHF [69,70]. In these studies plasma BNP level within the normal range had an exceedingly high negative predictive value. It has therefore been suggested that plasma BNP could be useful as a screening tool — a value in normal range virtually excluding CHF. Further studies have con- 499 firmed the prognostic significance of plasma natriuretic peptides (Table 1). These have included subjects with CHF [71,72], post-myocardial infarction [73] and even a cohort selected purely on the basis of age [74]. In each of these clinical scenarios, BNP was found to be an independent prognostic indicator when assessed by multivariate analysis. Several theories have been postulated as to why BNP appears to be a better predictor of prognosis than ANP in CHF. These have included its ability to more accurately reflect regional wall stress within the ventricle or perhaps result from differences in gene regulation or metabolic clearance for ANP and BNP [73]. Whether this is influenced by the enhanced expression of atrial BNP, as demonstrated by Luchner et al. in early canine heart failure, remains uncertain [60]. Plasma ANP levels have been suggested to be elevated in coronary disease independent of left ventricular enlargement [75], and show a significant fall post successful percutaneous transluminal coronary angioplasty. Postmyocardial infarction plasma BNP levels seem also to relate to infarct artery patency, irrespective of left ventricular ejection fraction, being significantly lower in patients with TIMI 3 flow [76]. Several studies have failed to demonstrate elevation of plasma CNP in CHF above the basal levels found in normal man [77,78]. Interestingly, however, both myocardial and urinary levels of CNP are significantly increased in this condition [77,79]. In the study by Mattingly et al. both CNP-22 and CNP-53 were found in the urine, whereas only CNP-22 has been demonstrated in human plasma [79]. Mean urinary concentrations of CNP were 250 to 750 times the concentrations for ANP and BNP, and were much higher than expected from glomerular filtration alone. The presence of CNP in human kidney has been confirmed in the epithelial cells of all tubular segments [79]. In addition, neutral endopeptidase, the enzyme responsible for natriuretic peptide breakdown, is abundant in the brush border of the proximal renal tubular cell and therefore these findings suggest that the increase seen in Table 1 Relation between plasma natriuretic peptide levels and prognosis as assessed by univariate and multivariate analysis in a variety of studies with different inclusion criteria Study Tsutamoto [71] n Inclusion criteria 85 Follow-up LVEF ,45% 2 years Variables Omland [73] 131 AMI Median 1293 days Tsutamoto [72] 290 Median 812 days Wallen [74] 541 Asymptomatic or minimally symptomatic LV dysfunction Aged 85 years ANP BNP ANP N-ANP BNP ANP BNP 5 years BNP Prognostic significance Univariate (P) Multivariate (P) ,0.0001 ,0.0001 ,0.0001 0.0002 ,0.0001 ,0.0001 ,0.0001 NS ,0.0001 0.45 0.99 ,0.001 0.088 ,0.0001 0.002 n, numbers of subjects; LVEF, left ventricular ejection fraction; AMI, acute myocardial infarction; LV, left ventricle; N-ANP, N-terminal ANP; NS, non-significant. 500 P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509 urinary CNP in CHF is more likely to represent enhanced renal production as opposed to filtration. Definitive proof is, however, still required. Borgeson et al. studied the effects of acute intravascular overload in dogs [80]. This has haemodynamic effects similar to acute heart failure. They found that whilst there was the expected rise in plasma ANP, there was no significant increase in plasma BNP and CNP levels. In contrast there was a marked increase in urinary CNP but not ANP or BNP. It thus appears that there is a differential release of natriuretic peptides from the myocardium and kidney during acute volume overload. 3.5. Biological effects of the natriuretic peptides In humans the majority of data available regarding the biological effects of natriuretic peptides relates to ANP and BNP. These peptides appear to have very similar effects promoting vasodilatation, natriuresis and diuresis, together with inhibition of renin and aldosterone release [37,38,81,82]. 3.5.1. Natriuresis and diuresis The natriuretic and diuretic actions of ANP and BNP appear to be due to several mechanisms. An increase in glomerular filtration rate (GFR) is thought to arise from an increase in pressure within the glomerular capillaries caused by afferent arteriolar vasodilatation and efferent arteriolar vasoconstriction [83]. Filtration may be further enhanced as a result of the increase in the effective area for filtration, occurring as mesangial cells relax in response to natriuretic peptide induced elevations in intracellular cGMP [84]. This is an opposite effect to that caused by angiotensin II, which induces contraction of mesangial cells. In addition, ANP may actually alter the distribution of intrarenal blood flow thereby changing medullary haemodynamics and promoting natriuresis [85]. In normal man, infused ANP results in enhanced electrolyte excretion and diuresis that cannot be accounted for solely by the increase in GFR, suggesting that it may act on renal tubules directly [86]. The major effect seems to be in the collecting duct, where it directly inhibits sodium reabsorption through a cation channel on the apical membrane of the collecting duct cells in the inner medulla [87,88]. The natriuretic and diuretic response to infused ANP is of rapid onset, and therefore it is likely that the early phase of natriuresis and diuresis is a result of direct actions as opposed to being secondary to the inhibition of renin or aldosterone release [89,90]. Additional mechanisms may further contribute to the inhibition of sodium and water transport by natriuretic peptides. ANP antagonizes the actions of vasopressin, thereby inhibiting water transport in the collecting ducts [91]. Angiotensin II usually promotes renal tubular sodium and water transport, an effect again inhibited by ANP [92]. Infused ANP and BNP inhibit the release of renin and aldosterone in normal man [90,93]. The exact mechanisms involved remain uncertain, although ANP has also been shown to directly inhibit renin release from cultured renal juxtaglomerular cells [94]. Inhibition of aldosterone release could potentially occur by several distinct mechanisms, including direct effects of the natriuretic peptides on the adrenal glomerulosa [95] or secondary to renin inhibition [81]. Hunt et al. demonstrated that ANP significantly inhibited angiotensin-II-induced aldosterone secretion, during concomitant infusions of the natriuretic peptides and angiotensin-II in normal man [96]. Although BNP tended to suppress this response to angiotensin-II, it did not reach significance. As mentioned earlier, urodilatin, a 32-amino acid peptide, is produced in the kidney from a precursor protein [42]. Although its in vivo role in humans has yet to be fully clarified, exogenous urodilatin promotes both natriuresis and diuresis at doses lower than those demonstrated with ANP [97]. It is apparent that the natriuretic peptides tend to antagonise the biological effects of the renin–angiotensin– aldosterone system. However, angiotensin II itself and angiotensin-converting enzyme (ACE) inhibitors also influence circulating natriuretic peptide levels. Angiotensin II infused to increase arterial blood pressure and systemic vascular resistance in healthy volunteers increased plasma concentrations of ANP but not BNP or CNP [98]. In contrast, Wiese and colleagues demonstrated an increase in BNP mRNA expression in isolated human atrial and ventricular myocardium in response to angiotensin II [99]. ACE inhibitors have been shown to decrease both circulating ANP and BNP in patients post-myocardial infarction [100,101]. Furthermore, increased vasodilator therapy, in the form of diuretics and ACE inhibitors, can also reduce BNP measurements to the normal range in patients with CHF [102]. However, Vantrimpont et al. failed to demonstrate a reduction in plasma ANP during chronic treatment with ACE inhibitors in subjects with asymptomatic left ventricular dysfunction post-myocardial infarction [103]. Whether the reduction of circulating natriuretic peptides purely reflects the documented beneficial effects of ACE inhibitors on left ventricular remodelling and dilatation or are a consequence of a more direct effect is not fully elucidated. A study in rats has confirmed that losartan, an angiotensin receptor antagonist, can inhibit angiotensin II-stimulated ANP secretion [104]. In addition, combined use of losartan and an endothelin receptor antagonist almost completely blocked volume–load-induced N-terminal ANP release, suggesting a more direct role for endothelin and angiotensin II in volume–load induced ANP secretion. 3.5.2. The role of natriuretic peptides in CHF — data from experimental models and small studies of human CHF The exact extent of natriuretic peptide-induced natriuresis and diuresis in CHF remains somewhat unclear. P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509 3.5.2.1. ANP In healthy dogs infused ANP resulted in marked natriuresis and diuresis, accompanied by a reduction in mean arterial and right atria pressures without a change in heart rate [105]. Renin secretion was suppressed whilst GFR and renal plasma flow increased. In contrast, when ANP was infused in dogs with CHF it merely resulted in a small reduction in mean arterial pressure without affecting other haemodynamic variables or renin concentration. There was no change in natriuresis or diuresis. Intravenously infused ANP was found to have little effect in patients with CHF, whereas in controls it resulted in the expected natriuresis and diuresis [90,106]. Despite this, other favourable effects such as an improvement in haemodynamics and inhibition of neurohormonal activation still occurred. Therefore a degree of renal ANP resistance appears to occur in CHF. Downregulation of natriuretic peptide receptors has been demonstrated on peripheral smooth muscle cells and platelets of patients with CHF [107,108] and in the renal medulla in a rat model of CHF [109], and may occur secondary to the elevated plasma ANP levels seen in CHF. Alternatively it might result from vasoconstrictor-induced NPR downregulation, which has been demonstrated in cultured rat vascular smooth muscle cells with both angiotensin and vasopressin [110]. Whether a similar downregulation of receptors occurs in the human kidney, thereby accounting for this apparent renal resistance to natriuretic peptides in CHF, remains uncertain. Alternative mechanisms may well be involved, including a decrease in the sodium delivery to the collecting tubules, where the major natriuretic effect of the peptides is exerted. Evidence supporting this has come from a rat model of CHF [111], where the administration of an angiotensin II receptor antagonist, which increases sodium delivery to the distal nephron, restores renal responsiveness to exogenous ANP. An interesting recent study by Misono has demonstrated that binding of ANP to its receptor is dependent on local chloride concentration, with a reduction in chloride decreasing binding [112]. This effect could not be overcome by excess ANP. Since chloride concentrations in the renal tubules are tightly coupled with sodium and water transport, Misono proposes that chloride-mediated feedback plays a role in ANPinduced natriuresis in states such as CHF where high circulating levels of ANP are found. Thus, persistent ANPinduced natriuresis would consequently result in a reduction in tubular chloride concentration, which below a certain threshold would result in inhibition of ANP binding to its receptor. Further studies evaluating this hypothesis are required. Other work, however, demonstrated that the renal effects were preserved when exogenous ANP was given as a bolus dose [113]. 3.5.2.2. BNP Whilst early studies of ANP in human CHF have been somewhat disappointing those with BNP have held more promise. Twenty patients with severe CHF were randomized in a double-blind, placebo-controlled 501 trial to receive incremental infusions of human BNP or placebo [114]. Infusion of incremental BNP was associated with favourable haemodynamic and natriuretic effects. More recently Abraham et al. have studied the haemodynamic, neurohormonal and renal effects of infused BNP in patients with decompensated heart failure [115]. They confirmed the beneficial haemodynamic responses, including reductions in both cardiac preload and systemic vascular resistance, which occurred without an associated reflex tachycardia. Although there was a fall in mean arterial pressure there were no significant changes in GFR or renal blood flow. This preservation of renal haemodynamics may relate to the documented renal vasodilating properties of the natriuretic peptides [116]. The natriuretic response was blunted in some of the patients with CHF [115]. Indeed the best predictor of natriuretic response to BNP was distal tubular sodium delivery, as assessed by lithium clearance. This supports the data mentioned above regarding the renal responsiveness to exogenous ANP in rats with CHF [111]. However, the finding that enhanced natriuresis occurs in response to higher concentrations of infused BNP in compensated CHF patients [117], suggests that the action of natriuretic peptides in CHF is more complex. A recent study in a canine model of CHF demonstrated that repeated short-term administration of subcutaneous BNP resulted in an improvement in cardiovascular haemodynamics [118]. If confirmed in humans, this might provide a novel therapeutic method for the chronic administration of BNP in CHF. There are several potential reasons why studies with infused BNP in CHF appear to be encouraging, whilst those with ANP have been a disappointment. Human BNP has a significantly prolonged plasma half-life [119], which may be a reflection of a relative resistance to metabolism by neutral endopeptidase [120]. Differences in study design may have influenced the results of the earlier studies with ANP [114]. Most studies with ANP did not administer the full human ANP peptide chain and it is feasible that the analogues used may have reduced biological effects when compared to the endogenous peptide. Several of the studies used infusions over relatively short time-periods, which may not have been adequate to achieve steady-state plasma levels. Furthermore, most of the patients in the ANP studies were not taking ACE inhibitors. In view of the fact that angiotensin II enhances cGMP degradation, ACE inhibitors or angiotensin receptor blockers may enhance the biological effects of natriuretic peptides [111,121]. 3.5.2.3. CNP The renal actions of CNP have been less extensively investigated and from the few completed studies findings are inconsistent. Hunt et al. infused CNP into healthy volunteers to achieve plasma levels greater than those found in pathological states, but they were unable to demonstrate a natriuretic response, although there was a decrease in plasma aldosterone levels [122]. 502 P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509 However, a further study showed enhanced natriuresis in response to a bolus of CNP [123]. This was associated with significant elevations of both ANP and BNP, perhaps resulting from competition for clearance mechanisms. In comparison to ANP and BNP, CNP has a much shorter plasma half-life at approximately 2.6 min [122]. It remains uncertain how plasma levels of CNP relate to in vivo tissue levels. Of particular interest, CNP is located at high concentration in the vascular endothelium and its receptor, NPR-B, in the adjacent vascular smooth muscle [124]. CNP is therefore in prime position to influence vascular regulation. Indeed in a study by Davidson et al., looking at forearm blood flow, CNP inhibited the vasoconstrictive effect of angiotensin I but not angiotensin II [125]. This suggests that CNP may act as an inhibitor of local vascular ACE, although the exact mechanisms involved are undetermined. 3.5.3. Other biological effects of the natriuretic peptides The natriuretic peptides have many other important actions in addition to their vasodilatory and renal effects. In healthy human subjects, low dose ANP infusion results in enhanced vascular permeability and a subsequent reduction of plasma volume [126]. In vitro studies have also shown that natriuretic peptides inhibit vascular smooth muscle and endothelial cell proliferation [127–129]. In addition, in cultured aortic smooth muscle cells ANP and CNP inhibit plasminogen activator inhibitor-1 mRNA expression in response to various stimuli [130]. This has led some to speculate that the natriuretic peptides may be involved in the response to vascular injury. Evidence in support of this has come from in vivo studies in rabbits, which have shown that an infusion of exogenous CNP can inhibit intimal thickening after injury to the carotid artery [131,132]. A recent study has also shown that the natriuretic peptides, and ANP in particular, are powerful lipolytic agents both in situ in human adipose tissue and in vitro in isolated fat cells [133]. Studies have also confirmed that human adipose tissue expresses NPR messenger RNA [134]. The clinical relevance of this is uncertain and requires further evaluation particularly in the setting of cachexia and heart failure where patients demonstrate significant loss of adipose tissue [135]. Our group has preliminary data showing a significant positive correlation between plasma levels of ANP and BNP to plasma concentrations of tumour necrosis factor, independent of left ventricular dimensions, in patients with CHF [personal communication, M. Rauchhaus]. In addition, cachectic CHF patients had higher BNP levels. A mechanistic relationship for these findings remains unclear and it is feasible that both natriuretic peptides and tumour necrosis factor are merely markers of disease severity. This area deserves more extensive evaluation and as such we are undertaking further studies. Furthermore, how or whether exogenous infused natriuretic peptides influence plasma and myocardial cytokine levels remains to be seen. 4. Vasopressin Vasopressin is synthesised in the hypothalamus as a pre-pro hormone, before being transported along axons to the neuronal terminals in the neurohypophysis, where it is stored in secretory granules. It is subsequently released into the circulation by exocytosis, in response to both osmotic and nonosmotic stimuli [34]. Many patients with CHF have water retention in excess of sodium with resulting hyponatraemia, and this finding is associated with a significantly impaired prognosis [136]. Although increased thirst in CHF can lead to increased water intake, this in itself cannot fully explain the hyponatraemia [137]. Several studies have confirmed an increase in plasma levels of vasopressin in patients with CHF [4,138,139]. It therefore appears that elevated plasma levels of vasopressin occur in patients with CHF despite the associated atrial distension, hyponatraemia and low osmolality, which would usually inhibit its release in normal subjects. This is thought to occur as a result of non-osmotic release of vasopressin. Non-osmotic release of vasopressin results from disturbances in circulatory homeostasis detected by the highpressure mechanoreceptors described earlier [32–34]. Arterial under-filling results in a release in the inhibition of the hypothalamus from neuromodulatory impulses. This results in enhanced vasopressin synthesis and release. 4.1. Vasopressin receptors and water channels ( Fig. 2 b) Vasopressin exerts its biological effects via interactions with specific receptors, of which there are two distinct types, V1 and V2 . Binding of vasopressin to the V1 receptor results in activation of the phosphoinositide pathway and mobilisation of cytosolic calcium [140]. The V1 receptor has two subtypes: V1a is located on a number of cell types including vascular smooth muscle and V1b is present in the anterior pituitary [141,142]. Activation of V1a results in enhanced vasoconstriction and contributes to the maintenance of vascular tone in normal subjects [143]. In dogs with experimental heart failure antagonism of this receptor is associated with a decrease in systemic vascular resistance and an increase in cardiac output [144]. The V2 receptors are primarily located on the basolateral membrane of collecting duct cells in the kidney [140]. Binding of vasopressin to these receptors results in the activation of adenylate cyclase and subsequent generation of intracellular cyclic adenosine monophosphate. The main biological effect of vasopressin in the kidney, a decrease in water clearance, is achieved by the resulting ‘shuttling’ of aquaporin-2 water channels from cytoplasmic vesicles to the apical surface of the collecting duct where they are inserted [145]. At the apical membrane these water channels facilitate water transport across the collecting duct cells in response to the osmotic gradient generated by the counter-current concentrating system. In addition vasopres- P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509 sin actually increases aquaporin-2 water channel synthesis [146]. Vasopressin has other effects in the kidney, including increasing the reabsorption of urea in the final portion of the inner medullary collecting duct thereby maintaining medullary hypertonicity and sodium in the cortical segment [147,148]. 4.1.1. The role of vasopressin in CHF — data from experimental models and small studies of human CHF Recent improvements in the understanding of the functional significance of vasopressin in CHF have been achieved by the development of specific V2 receptor antagonists. In a rat model of heart failure the administration of a V2 antagonist resulted in a reduction of aquaporin2 protein in the collecting duct [149]. Further animal studies have confirmed that antagonism of the V2 receptor results in the anticipated increase in water excretion, with an associated decrease in urinary osmolality [144,149,150]. Studies in humans have produced similar results. Abraham et al. demonstrated that the administration of an oral selective V2 receptor antagonist to patients with CHF significantly increased urine flow and plasma sodium concentration [151]. There was an associated reduction in urine osmolality, therefore confirming an increase in solute-free water clearance. The effect of vasopressin on renal physiology in patients with CHF may be more complicated than initially appreciated. Eisenman et al. have demonstrated that low dose vasopressin can actually restore urine output in patients with the hepatorenal syndrome and in anuric patients with end-stage heart failure [152]. Indeed some studies in animals have shown that after volume expansion, the administration of vasopressin actually results in diuresis [153]. Eisenman et al. speculate that this diuretic effect occurs directly through stimulation of the V1 receptor located in renal epithelial cells and indirectly by enhancing ANP release [152]. 5. Clinical trials involving natriuretic peptides and vasopressin antagonism in CHF 5.1. Natriuretic peptides 5.1.1. Therapy guided by plasma natriuretic peptide levels As mentioned earlier, plasma measurements of ANP and BNP have been used to assist in the diagnosis of CHF and in subsequent prognostic assessment [19,20]. Recent evidence suggests that measurements of BNP may be useful in guiding the tailoring of conventional therapy. Troughton et al. compared conventional drug therapy intensified to reduce plasma amino terminal BNP levels to within normal range against therapy directed by standard clinical assessment, in patients with symptomatic CHF [21]. The investigators hypothesised that titration of therapy guided by plasma BNP levels would prove to be superior, since 503 plasma BNP concentrations are related to ventricular filling pressures and wall stress [154,155]. In addition, previous studies have confirmed that plasma BNP levels fall when left ventricular filling pressure is reduced by vasodilator therapy with ACE inhibitors and diuretics [154,156]. They demonstrated that there were fewer total cardiovascular events (death, hospital admission or heart failure decompensation) in the BNP-guided therapy group than in the clinical group. At 6 months 27% of patients in the BNPguided group had suffered a first cardiovascular event in comparison to 53% in the clinical group (P50.034). However, the use of BNP to titrate therapy was a relatively complicated process and resulted in the BNP group receiving slightly higher doses of ACE inhibitors and diuretics. Of particular note, the use of spironolactone was significantly increased in the BNP-guided group. 5.1.2. Vasopeptidase inhibition In order to potentiate the beneficial circulatory and renal effects of the natriuretic peptide family in CHF, investigators have looked at methods of impairing their breakdown. Initial studies in hypertension and CHF using inhibitors of neutral endopeptidase, the enzyme involved in natriuretic peptide catabolism, revealed limitations due to increased activation of the renin–angiotensin–aldosterone system [157–159]. This led onto the development of vasopeptidase inhibitors, molecules simultaneously inhibiting neutral endopeptidase and ACE. This combines the established benefits of ACE inhibition with the potential benefits of enhancing the natriuretic peptide system. Animal studies with omapatrilat, a recently developed vasopeptidase inhibitor, have shown benefits in CHF models [160]. The efficacy of omapatrilat in human CHF has now been confirmed. McClean et al. demonstrated improvements in functional status, left ventricular performance, together with a reduction in blood pressure after 12 weeks of treatment with the drug [161]. Omapatrilat also resulted in an enhanced natriuresis and a reduction in total blood volume. Despite the decrease in systemic blood pressure and blood volume, renal function was preserved. The recently published IMPRESS study compared the effects of omapatrilat with lisinopril (an ACE inhibitor) with primary end-point being improvement in exercise testing at week 12 [162]. Secondary end-points included death and comorbid events indicative of worsening heart failure. In this study there were no significant differences in principal end-points. However, there were fewer cardiovascular system adverse events (combined data) in the omapatrilat group and although individual cardiovascular end-points related to worsening heart failure did not reach significance, the results favoured omapatrilat in each case. Some concerns have been voiced over the side-effect profile of omapatrilat. The IMPRESS study demonstrated an excess of gastrointestinal side-effects when compared to the lisinopril group [162]. Of more concern has been the rarer, but potentially life-threatening, angioedema. The 504 P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509 0.7% rate found with omapatrilat [163] is in excess of the 0.34% documented with ramipril [164]. The higher rate found with omapatrilat in IMPRESS maybe an untoward side-effect of the drug itself or possibly relate to differences in the population groups studied [165]. This study included significant numbers of black participants, a group known to have a higher rate of angioedema associated with ACE inhibitors compared to Caucasians [166]. Unfortunately there is currently no data available on sub-group analysis from IMPRESS, and as such it remains uncertain as to whether the excess rate of angioedema found with omapatrilat is specific to the drug itself or as a consequence of the populations studied. Further clinical studies, with much larger numbers of patients, are required to establish mortality and morbidity end-points and safety data in order to properly assess the place of omapatrilat in current clinical practice. The relatively small numbers of patients recruited (573) and short length of follow-up (24 weeks) in IMPRESS [155] demonstrate current limitations of clinical studies on vasopeptidase inhibition in CHF, when compared to established studies confirming benefits of ACE inhibitors. For example, the SAVE Trial investigating the benefits of captopril in patients with reduced left ventricular function, recruited 2231 patients followed-up for an average of 42 months [167]. In addition, it remains uncertain how the result of enhancement of natriuretic peptide levels will influence their other biological properties in clinical practice. 5.1.3. Intravenous recombinant human BNP Although intravenous natriuretic peptide administration is not practical in the outpatient management of patients with CHF, it may be beneficial during acute deterioration. Nesiritide, a recombinant human BNP, has recently been studied in two randomised trials involving patients hospitalised with decompensated CHF [168]. The first was a double-blind efficacy study and demonstrated a significant improvement in haemodynamic function and clinical status when compared to placebo. Nesiritide infusion resulted in a dose-related decrease in pulmonary capillary wedge pressure, which was associated with a decrease in systemic vascular resistance and increase in cardiac index. Although there was a decrease in systolic blood pressure there was no associated reflex tachycardia. In the comparative study nesiritide was compared with standard intravenous agents, (including dobutamine and nitrates), which served as controls for clinical efficacy and adverse events. Improvements in clinical status were similar between the groups. This led the authors to suggest that nesiritide may be helpful in the short-term management of decompensated patients with heart failure, particularly since it avoids the tachycardia associated with dobutamine therapy and the tolerance experienced with nitrate infusions. examining the use of vasopressin antagonists in human heart failure. Selective inhibition of the V1 receptor led to immediate improvement in haemodynamic parameters in patients with baseline elevations in plasma vasopressin [169]. This, however, was only a transient response and data on long-term responsiveness and benefits are not available. V2 receptor antagonism in patients with CHF has been performed with an orally active molecule — WAYVPA-985. In a randomised, placebo-controlled study administration of this antagonist resulted in increased solutefree water excretion with resulting elevation of serum sodium concentration [151]. In addition there was a reduction in urinary aquaporin-2 levels, suggesting that the enhanced diuresis may well be secondary to a reduction in aquaporin-2 production and mobilisation. Combined V1 and V2 receptor antagonists offer the potential advantages of reduced vasoconstriction together with enhanced solute-free water excretion. This may be particularly applicable for hyponatraemic patients with CHF, a group with significantly impaired prognosis. Conivaptan (YM087) is an orally active combined V1a / V2 receptor antagonist. An early study has confirmed its efficacy and tolerability in six patients with severe CHF [170]. Administration of the drug resulted in an increase in serum sodium concentration. This was associated with a decrease in urine osmolality and increases in urine output and free-water clearance. Larger studies are required to assess its long-term safety, efficacy and clinical benefit. 6. Conclusions Improvements in the understanding of neurohormonal activation in CHF have confirmed the importance of the balance between the vasoconstricting, sodium-retaining systems and those involved in vasodilatation and natriuresis. These systems interact to maintain circulatory integrity. However, as heart failure progresses enhanced sodium and water retention contributes to the debilitating symptoms experienced by patients and adversely effect myocardial performance. Therapeutic manipulation of neurohormones is now a feasible and exciting prospect in the treatment of CHF. Early clinical data are encouraging for vasopeptidase inhibitors, molecules combining inhibition of ACE and neutral endopeptidase, and intravenous recombinant human BNP. 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