ANP in regulation of arterial pressure and fluid-electrolyte balance: lessons from genetic mouse models

LUIS G. MELO1,2, MARK E. STEINHELPER3, STEPHEN C. PANG4, YAT TSE4 and UWE ACKERMANN1

1 Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8
2 Department of Medicine, Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts 02115
3 Department of Physiology, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas 78284
4 Department of Anatomy and Cell Biology, Queen’s University, Kingston, Ontario, Canada K7L 3N6

ABSTRACT

Melo, Luis G., Mark E. Steinhelper, Stephen C. Pang, Yat Tse, and Uwe Ackermann. ANP in the regulation of arterial pressure and fluid-electrolyte balance: lessons from genetic mouse models. Physiol Genomics 3: 45–58, 2000.—The recent development of genetic mouse models presenting life-long alterations in expression of the genes for atrial natriuretic peptide (ANP) or its receptors (NPR-A, NPR-C) has uncovered a physiological role of this hormone in chronic blood pressure homeostasis. Transgenic mice overexpressing a transthyretin-ANP fusion gene are hypotensive relative to the nontransgenic littermates, whereas mice harboring functional disruptions of the ANP or NPR-A genes are hypertensive compared with their respective wild-type counterparts. The chronic hypotensive action of ANP is determined by vasodilation of the resistance vasculature, which is probably mediated by attenuation of vascular sympathetic tone at one or several prejunctional sites. Under conditions of normal dietary salt consumption, the hypotensive action of ANP is dissociated from the natriuretic activity of the hormone. However, during elevated dietary salt intake, ANP-mediated antagonism of the renin-angiotensin system is essential for maintenance of blood pressure constancy, inasmuch as the ANP gene "knockout" mice (ANP -/-) develop a salt-sensitive component of hypertension in association with failure to adequately downregulate plasma renin activity. These findings imply that genetic deficiencies in ANP or natriuretic receptor activity may be underlying causative factors in the etiology of salt-sensitive variants of hypertensive disease and other sodium-retaining disorders, such as congestive heart failure and cirrhosis.

atrial natriuretic peptide; gene knockout; transgenic; renin-angiotensin system; salt-sensitive hypertension; cardiovascular sympathetic tone

ATRIAL NATRIURETIC PEPTIDE (ANP) is the predominant member of a family of at least three structurally and functionally related peptide hormones that exert a wide array of effects on cardiovascular and renal function (for comprehensive review see Ref. 14). Acute administration of ANP elicits potent and brisk natriuresis and diuresis and reduces arterial blood pressure (ABP) in humans (14, 124) and in a wide variety of other animal species (14, 72). The natriuretic and diuretic effects of the hormone are due, in part, to hemodynamic alterations in glomerular filtration (23) and vasa recta blood flow (70), inhibition of sodium reabsorption in the inner medullary collecting duct (133), and antagonism of the major neural and hormonal salt and fluid conserving mechanisms, such as the sympathetic nervous system (57), renin-angiotensin-aldosterone system (RAS) (66), and antidiuretic hormone (113). The acute hypotensive effect of ANP, on the other hand, is mediated primarily by a decrease in cardiac output, brought about by a reduction in intravascular volume (1, 15, 84, 136), and by inhibition of compensatory autonomic reflex increases in heart rate (137, 143) and vascular resistance (1, 2). The reduction in intravascular volume is dissociated from the renal actions of the hormone, insofar as it is preserved in anephric animals (3, 140), and appears to be due to direct effects on capillary permeability (56) and lymphatic vessel pumping activity (7).

In contrast to the extensive effort invested in characterizing the acute cardiorenal actions of ANP, progress in elucidating a potential role of ANP in chronic regulation of blood pressure and fluid and electrolyte balance had been hampered by the lack of suitable natural models of ANP-induced disease and the unavailability of selective pharmacological receptor antagonists. Early work showed that prolonged (3–7 days) continuous delivery of exogenous ANP into conscious animals, resulting in plasma concentrations of the hormone in the high physiological-to-pathophysiological range as observed, for example, in congestive heart failure (CHF) reduces arterial pressure chronically, without altering absolute renal salt and water excretion (23, 42, 49). These studies, however, are limited by difficulties in maintaining a constant basal plasma level of the hormone and by other technical restrictions. The recent development of genetic mouse models expressing life-long alterations in the activity of ANP (64, 135) and its receptors (92, 97, 114) has provided the opportunity to dissect the role and the mechanisms of this hormone in chronic regulation of cardiovascular and renal homeostasis. Recent work in these murine models suggests that ANP contributes to long-term blood pressure constancy (8, 64, 92, 97, 101, 114, 135) and may play an essential role in mediating cardiovascular and renal adaptations during elevated dietary salt intake (102). In this article, we review the current state of knowledge on the role of ANP in chronic regulation of cardiovascular and renal homeostasis from evidence gathered in the various genetic ANP mouse models and identify potential future topics of investigation that could be studied in these models.

GENETIC MOUSE MODELS OF ANP AND ITS RECEPTORS

Several genetically engineered mouse models presenting single life-long alterations in the expression of the individual components of the ANP system have been developed in the last 10 years. Among these are ANP gene-overexpressing transgenic mice (135) and gene-targeted ("knockout") mice harboring functional disruptions of the genes for ANP (64) or its receptors (92, 97, 114). To our knowledge, the various gene manipulations manifest the cardiovascular and renal functional phenotypes that are predicted on the basis of the known acute effects of the hormone, without triggering any discernible compensatory adjustments by other regulatory systems. These specific genetic alterations, therefore, provide a stable physiological background that is suited for studying chronic effects and mechanisms of ANP action in isolation from other regulatory mechanisms.

Models of Altered ANP Gene Expression
From the standpoint of ANP bioactivity, the ANP-overexpressing transgenic and the ANP gene knockout mouse models may be considered to be functionally opposite with respect to the physiological processes that are influenced by ANP. The circulating level of the hormone in the transgenic mouse lies within the pathophysiological range (Table 1) and, consequently, might be expected to elicit physiological responses similar to those observed in ANP-overproducing disease states, such as CHF (16), with the added benefit that such responses occur without interference from compensatory regulatory mechanisms that are usually activated in disease states. The knockout mouse, on the other hand, should be the functional equivalent of surgical ablation. These two complementary models have been widely used in investigations on the physiological roles of ANP in chronic regulation of blood pressure (8, 64, 92, 97, 101, 114, 135) and renal fluid and electrolyte balance (65, 142).


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Table 1. Phenotypic characteristics of ANP-based genetic mutant mouse models

 
Transthyretin-ANP (TTR-ANP) transgenic mouse.
The generation of ANP-overexpressing transgenic mice is described in detail by Steinhelper et al. (135). In brief, the mouse ANP structural gene consisting of all three exons and ~1.75 kb of the 3' flanking region was isolated from a BALB/cJ genomic library, fused to the transthyretin promoter from the same source, and introduced into the male pronucleus of fertilized embryos of the C3HeB/FeJ background. The incorporation of the transthyretin promoter targets ectopic constitutive expression of the ANP transgene to the liver, resulting in 8- to 10-fold elevation in basal plasma ANP level. The transgenic animals manifest life-long hypotension (25–30 mmHg) relative to their genetically matched nontransgenic (NT) counterparts (Table 1).

ANP gene knockout mouse.
The ANP gene knockout (ANP -/-) mouse model is fully described by John et al. (64). Briefly, a targeting construct containing the neomycin resistance gene was designed to delete 11 base pairs from exon 2 of the mouse pre-proANP by homologous recombination in embryonic stem cells from mouse strain 129. The resulting chimeric mice harboring the mutation were mated to mice of strain C57BL/6J (B6). Matings between the 129 x B6 heterozygotes produced homozygous mutant (-/-), heterozygous (+/-), and wild-type (+/+) mice in approximate Mendelian ratios. Plasma ANP and ANP-specific atrial granules are undetectable in the -/- mice and reduced in the +/- mice compared with the wild-type mice (65). The homozygous mutant mice are hypertensive (20–30 mmHg) compared with the wild-type siblings (Table 1).

Models of Altered ANP Receptor Gene Expression
The development of gene deletion mouse models for the different ANP receptors is the latest addition to the growing list of ANP-based mutant mouse models. These receptor knockout models offer the opportunity to determine the receptor-signal transduction pathways involved in mediating specific physiological effects of the hormone. Two structurally and functionally distinct, high-affinity, membrane-bound ANP receptors have been identified in target tissues, on the basis of their ability to stimulate cGMP (85, 87). The NPR-A (natriuretic peptide receptor-A) is coupled to particulate guanylate cyclase and is thought to mediate most of the biological actions of the peptide (5). The second receptor subtype (NPR-C) is the preponderant ANP binding site in most tissues (5, 87). Although this receptor is involved primarily in the clearance and metabolism of ANP from the circulation (5, 87, 94), some evidence suggests that it may also participate in mediating some of the actions of the hormone via negative modulation of adenylate cyclase (5, 6).

NPR-A receptor gene knockout mouse.
Two NPR-A knockout mouse models have been developed by independent groups (92, 114). The model developed by Lopez et al. (92) uses a neomycin "cassette" to replace a sequence of exon 4 in the NPR-A gene that codes for the extracellular ligand-binding domain in the receptor. The second model, developed by Oliver et al. (114), uses a targeting construct to replace exon 1 through intron 1 with the neomycin resistance gene. The two models present significant and quantitatively similar increases in basal mean arterial pressure compared with their wild-type controls, thereby indicating a fundamental role of the NPR-A receptor in mediating the chronic hypotensive effect of ANP. However, the -/- mice from Oliver et al. (114) develop high mortality rates at ~6 mo of age in association with severe cardiac hypertrophy and sudden death , whereas the -/- mice from Lopez et al. (92) do not show such differences in cardiac morphology and mortality. The underlying cause for the differences in cardiac growth between the two mutant types is not known, but it is unlikely that it could be ascribed to differences in ligand-receptor binding, since both targeting constructs disrupt the sequence encoding the extracellular domain.

A third variant of chronic NPR-A receptor activity employs gene titration to express a variable number of copies of the NPR-A gene in mice, ranging from a single or up to four copies of the gene (115). These animals show dose-dependent increases in basal guanylate cyclase activity and concomitant proportional reductions in basal ABP, thus emphasizing again the central role of this receptor in mediating the chronic cardiovascular effects of ANP. Furthermore, the blood pressure in the mice with one copy of the NPR-A gene is further increased by prolonged feeding on high-salt diet (115), thereby indicating the essential role of this receptor in the cardiovascular and renal adaptations to elevated salt intake. Sensitivity of blood pressure to salt, however, was not observed in the NPR-A null mice of Lopez et al. (92) after 2 wk on 8% NaCl diet. The reason for these conflicting results is not known.

NPR-C receptor gene knockout mouse.
With the recent introduction by Matsukawa et al. (97) of the NPR-C gene deleted mouse, there are now genetic mouse models of all components of the ANP hormonal axis. Similarly to the NPR-A knockout mice, the targeting construct used to produce the NPR-C-deficient mice deletes a sequence of exon 1 of NPR-C that codes for a 215 amino acid sequence of the ligand binding domain. In agreement with the putative role of the NPR-C receptor in metabolic clearance of the peptide (5, 87, 94), the NPR-C null mice show increased half-life of exogenous ANP, whereas the basal plasma levels of endogenous ANP do not differ significantly from the wild-type controls. The null mice show a small but significant (±8 mmHg) reduction in basal blood pressure, which may be partly due to intravascular volume depletion, because these mice go through a period of increased daily urinary output of water relative to the wild-type controls, despite similar levels of daily water consumption. Apart from the differences in cardiovascular and renal phenotypes, the major characteristic of the NPR-C null mice is an increase in basal bone turnover and the incidence of bone deformities (97), which may reveal a novel function of natriuretic peptides in bone metabolism and remodeling.

ROLE OF ANP IN CHRONIC REGULATION OF BLOOD PRESSURE

Chronic Hemodynamic Actions of ANP
The earliest indication that ANP may play a role in chronic regulation of blood pressure originated with the observation that abnormalities in ANP secretion and/or receptor activity are sometimes manifested in hypertensive humans and in some animal models (88, 111). For example, ANP release from isolated hearts of prehypertensive salt-sensitive Dahl rats is reduced relative to the salt-resistant strain (116), and spontaneously hypertensive rats, although presenting higher basal plasma levels of ANP than their normotensive Wistar-Kyoto counterparts, have an attenuated ANP secretory response to potent stimuli such as acute intravascular volume expansion (18, 112). Furthermore, decreased ANP receptor binding and affinity have frequently been reported (for review, see Refs. 5 and 18). In addition, several polymorphisms of the ANP (127) and NPR-A (30) genes have been reported to segregate with high blood pressure, but it is not known whether such polymorphisms result in a reduction in ANP bioactivity. In most of these instances, however, it has not been established whether the hemodynamic alterations are causal or coincidental events in the etiology of hypertension. The former premise appears to be supported by functional studies that were conducted before genetic models became available. For example, chronic immunoneutralization of ANP with a monoclonal antibody not only accelerates the development of hypertension in spontaneously hypertensive rats but also increases the severity of hypertension in these animals (59). Also, pharmacological inhibition of neutral endopeptidase (EC 3.4.24.11), a zinc metalloprotease involved in endogenous ANP metabolism (34), lowers blood pressure in both normotensive and hypertensive humans and animals (for review, see Ref. 131), presumably by increasing the half-life of circulating ANP. The observation that prolonged infusion (3–7 days) of ANP into conscious animals leads to a 15% reduction in mean arterial pressure (21, 42, 45, 49, 121) provides more direct evidence that ANP may exert a tonic effect on blood pressure. However, these findings did not provide unequivocal confirmation for such an effect of ANP, because the studies were not accompanied by control experiments conducted in the presence of an ANP receptor antagonist.

The most definitive evidence for a role of ANP in chronic regulation of blood pressure is derived from studies in the various genetic mouse models of ANP activity (Table 1). As previously described, the ANP-overexpressing transgenic mice (TTR-ANP) are hypotensive by 25–30 mmHg relative to their NT control littermates, in association with the life-long elevation in plasma ANP concentration (135), whereas the ANP gene knockout mice (64) and NPR-A gene knockout mice (92, 114) are hypertensive by 20–30 mmHg compared with the wild-type control mice, in association with the lack of the respective gene products. These functionally opposite models of ANP activity thus provide complimentary evidence that ANP exerts a tonic hypotensive effect, inasmuch as a chronic reduction in endogenous ANP activity is associated with a state of sustained hypertension.

Mechanism of Chronic ANP-Induced Hypotension
Characterization of the mechanism of chronic ANP-induced hypotension continue to be investigated. When ANP is infused over a period of several days, the accompanying hypotension is maintained by a gradual hemodynamic shift towards a fall in peripheral vascular resistance (PVR) from an initial (acute) decrease in cardiac output (21, 42, 45, 49, 121). Charles et al. (21) showed that chronic infusion of ANP in sheep at a rate that barely increases the basal plasma level of the hormone reduces PVR and mean arterial pressure significantly within 24 h of beginning the infusion, without eliciting compensatory changes in heart rate, cardiac function or blood volume. A similar hemodynamic profile has been reported by Barbee et al. (8) for the TTR-ANP mice. Characterization of regional and systemic hemodynamics in these animals indicated that the hypotension (~25% reduction in mean arterial pressure) in these animals is associated with 21% lower PVR and accompanying 27% decrease in total heart weight compared with the NT mice, without any differences in cardiac output, stroke volume, and heart rate between genotypes. The lower PVR in the TTR-ANP mice is associated with 19–35% reductions in regional vascular resistances, with the exception of the coronary and splanchnic vascular beds. Conversely, we reported recently that the hypertension in the ANP -/- mice is accompanied by a disproportionate elevation in basal PVR, in the absence of significant differences in heart rate, cardiac output, stroke volume, or blood volume (101), compared with the wild-type animals. Although the hemodynamic characteristics of the NPR-A null mice have not been described, these animals have elevated basal diastolic blood pressure and left ventricular hypertrophy, which are usually considered to be diagnostic features of chronically elevated PVR (93). Thus these findings confirm that the chronic hypotensive effect of ANP is mediated by predominantly by relaxation of the resistance vasculature.

Nature of Chronic ANP-Induced Vasodilation
The similarities in cardiovascular phenotype between the NPR-A and ANP -/- mice clearly implicate a role for these receptors in mediating the chronic vasodilatory effect of ANP. The question remains, how do these receptors bring about relaxation of the resistance vasculature? Although ANP is generally viewed as a direct vasorelaxing peptide, this effect appears to be restricted to preconstricted segments of large arteries, where at high concentrations, the hormone relaxes vascular smooth muscle by stimulating cGMP accumulation via NPR-A receptor activation (38, 148, 149). On the other hand, resistance vessel smooth muscle, with the possible exception of the renal vascular bed (50), has a scarcity of these receptors (29; for review see Ref. 5) and is relatively insensitive to direct relaxation by ANP (9, 36, 71, 118). These characteristics would preclude a direct role of the NPR-A-cGMP pathway in mediating chronic ANP-induced relaxation of the resistance vasculature and imply that ANP exert its chronic vasodilatory activity indirectly by modulating, presumably via the NPR-A receptor, the activity of other tonic vasoeffector mechanism(s). In this regard, we note that, at least acutely, ANP exerts a generalized sympatholytic effect (2527, 35, 37, 39, 46, 52, 89, 99, 109, 130; for review, see Ref. 81) and modulates the synthetic activity of vascular endothelium (VE), toward enhanced vasodilatory activity (11, 33, 55, 76, 100, 110, 117, 122, 144). The extent to which these effects of ANP may be chronically active is not known. However, some preliminary evidence suggests that ANP can chronically alter the activity of these vasoregulatory pathways. For example, in dogs with severe CHF, both plasma endothelin-1 (ET-1) (144) and norepinephrine (145) concentrations are significantly increased following blockade of NPR-A/NPR-B receptor function with the nonspecific antagonist HS-142-1, suggesting that the underlying elevated ANP level in these animals exerts a tonic inhibitory effect on synthesis and/or release of ET-1 and catecholamines. Furthermore, ANP attenuates the hypertensive effect of chronic norepinephrine infusion (151), suggesting that the hypotensive action of ANP is mediated, at least in part, by interactions with noradrenergic mechanisms of blood pressure regulation. Conceivably, such effects of ANP on sympathetic and endothelial function, if tonically active, could contribute to the chronic vasodilatory action of this hormone in the resistance vasculature, given the major role that these vasoeffector mechanisms play in regulation of vascular tone and blood pressure (17, 141).

We recently employed TTR-ANP and ANP -/- mice and their respective controls to determine whether alterations in basal cardiovascular sympathetic tone and/or endothelial vasoactive factor synthesis and activity may underlie the chronic hypotensive effect of ANP. The premise was that if the sympathoinhibitory action of ANP is tonically active, then the absence of this antagonism in the ANP -/- mice should be associated with an elevation in basal cardiovascular sympathetic tone and hypertension, whereas the chronically elevated plasma ANP activity in the TTR-ANP mice would be accompanied by attenuation of sympathetic tone and hypotension. Likewise, we predicted that if the ANP-endothelium interactions are tonically operative, then the hypotension in TTR-ANP mice should be accompanied by a reduction in ET-1 vasoconstrictor and parallel enhancement of C-type natriuretic peptide (CNP) and NO vasodilatory activities relative to the NT mice, whereas the reverse relationships should be present in the -/- ANP mice relative to their wild-type controls.

The effect of autonomic ganglionic blockade (GB) with hexamethonium on ABP in the TTR-ANP, ANP -/- mice and their respective wild-type controls is shown in Table 2. As expected, GB reduces ABP in all genotypes, thereby confirming the contribution of sympathetic tone to basal hemodynamics. However, the hypotensive response to GB is quantitatively smaller in the TTR-ANP and greater in the ANP -/- than in their respective wild-type controls (103). Interestingly, the hypertension in the ANP -/- mice is paralleled by a significant elevation in basal total plasma catecholamine concentration relative to the ANP +/+ mice, whereas the hypotension in TTR-ANP is accompanied by a tendency toward lower plasma catecholamine levels than in the NT mice (Table 2) (103). Collectively, these findings demonstrate that cardiovascular sympathetic tone varies inversely with the chronic level of endogenous ANP activity, and it is, therefore, inferred that the chronic hypotensive effect of ANP is, at least in part, dependent on attenuation of sympathetic tone to the resistance vasculature. In fact, GB fully abolishes the differences in ABP (Table 2) (101, 103) and PVR (101) between the mutant mice and their respective wild-type controls, indicating that the differences in vascular sympathetic tone per se could account for the genotype-dependent differences in blood pressure. We note that a functional dependency of ANP-mediated vasodilation on inhibition of sympathetic activity has also been reported by others (10, 42, 119, 129), on the basis that the hypotensive effect of exogenously administered ANP is exacerbated by chronically elevated sympathetic tone (42, 119), and is significantly attenuated by GB (10, 129) and by adrenergic receptor blockade (37, 46, 82, 152).


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Table 2. Average ABP and HR during baseline conditions, after autonomic ganglionic blockade and in response to intravenous NE infusion in TTR-ANP, ANP -/- mice, and the respective wild-type control mice

 
The predominance of ANP dependence on attenuation of vascular sympathetic tone for its chronic vasodilatory and hypotensive effects is further strengthened by the finding that neither the synthesizing activity of the VE for ET-1, CNP, and NO nor the cardiovascular responses to these vasoactive endothelial factors are altered by the chronic level of ANP activity (104). The concentrations of ET-1, CNP, and endothelial constitutive nitric oxide synthase (ecNOS) and NOS activity in homogenates of several organs selected to represent the principal regional vascular beds, as well as the responsiveness of ABP and heart rate to endogenous ET-1, CNP, and NO, do not differ significantly between the mutant mice and their respective controls (104), indicating that the chronic vasodilatory effect of ANP is unlikely to be mediated by differences in the activity of these endothelial modulators. This, however, does not preclude a possible involvement of other endothelial factors, such as vasodilatory eicosanoids (58) and carbon monoxide (77). Nevertheless, the lack of a detectable effect of ANP on the synthetic activity of VE and cardiovascular responsiveness to endothelial factors is surprising for the following reasons. First, endothelial cells have an abundance of both NPR-A (5, 85) and NPR-C (5, 86) receptors, and activation of these receptors is consistently found, at least in vitro, to inhibit basal and stimulated ET-1 synthesis (33, 55, 76) and to stimulate CNP (110) and ecNOS activity (100, 122). Second, ANP attenuates vascular reactivity to ET-1 (11, 32, 117) and potentiates basal ecNOS (100) and CNP activity (110) via its inhibitory effect on adenylate cyclase (6, 106, 120) and NRP-C downregulation (13). A possible cause for the absence of differences in endothelial factor synthesis and cardiovascular effects between mutant and wild-type mice could be that endothelial cell responsiveness is attenuated in the TTR-ANP mice by receptor downregulation (69, 79), whereas the lack of ANP may result in endothelial receptor upregulation and a concomitant increase in the basal activity of these receptors in the ANP -/- mice.

The nature of the mechanism underlying the neuromodulatory effects of ANP on sympathetic nerve activity has not been fully elucidated. ANP exerts a pervasive acute sympatholytic effect at all levels of autonomic function (for review, see Ref. 81), and, in principle, any of the identified sympathoinhibitory actions of ANP, if tonically active, could, either singly or in combination, account for the observed ANP genotype-dependent differences in cardiovascular sympathetic tone (101, 103). Preliminary evidence suggests that the chronic sympathoinhibitory activity of ANP is likely to be mediated proximally at one or several prejunctional sites, since neither the absolute pressor or chronotropic responses to peripheral adrenergic receptor stimulation with exogenous norepinephrine nor adrenergic receptor binding (103) differs significantly between the ANP mutant mice and their controls (Table 2). It is conceivable that the absence of a tonic inhibitory effect of ANP on tyrosine hydroxylase activity in postganglionic nerve terminals (39) and in the adrenal medulla (52) could partially account for the elevated plasma catecholamine levels in the ANP -/- mice. It could also be argued that the widespread colocalization of ANP and NPR-A receptors in the autonomic ganglia (5, 26, 27) may function as a tonically active neuromodulatory unit of sympathetic outflow, and, in this regard, we note that Floras (41) has recently shown that, at least in humans, ANP-dependent sympatholysis is mediated preferentially via inhibition of autonomic ganglionic neurotransmission. It is not known whether such a mechanism of sympatholysis is operative in the ANP genetic mouse models, but on the basis of the available evidence, it is likely that a similar mechanism of sympathoinhibition or its absence underlies the differences in PVR between these mutant mouse models.

ROLE OF ANP IN CHRONIC REGULATION OF FLUID AND ELECTROLYTE BALANCE

Long-term constancy of blood pressure is ultimately dependent on maintenance of salt balance and extracellular fluid volume (ECFV) by the kidneys and auxiliary neural and hormonal mechanisms (for review see Ref. 24). In view of the fundamental role played by exchangeable sodium in determining ECFV (24), it would be expected that the renal excretory effects of ANP, if tonically active, could also contribute to the chronic hypotensive effect of the hormone. Such dependency on ANP-mediated renal salt excretion would be evident during elevated dietary salt intake, when the salt-conserving mechanisms are deactivated (24, 31, 51, 83) and the natriuretic action of ANP is maximized (53, 66, 91, 128, 132, 146). However, despite the well-characterized acute effects of ANP on renal salt excretion and ECFV regulation, the issue of whether the renal effects of the hormone are required for chronic salt balance and blood pressure homeostasis has remained controversial, largely because of divergent findings (28, 44, 125, 147). The availability of genetic models expressing life-long alterations in ANP activity has provided the opportunity to undertake a more definitive investigation on the role of this hormone in chronic regulation of salt and fluid balance.

We studied the role of ANP in chronic sodium and fluid balance by placing TTR-ANP, ANP -/-, and control mice on high-salt (HS, 8% NaCl) and low-salt (LS, 0.008% NaCl) diets for 2–4 wk. Our premise was that if ANP exerts a persistent natriuretic effect, then the elevated ANP levels in the TTR-ANP mice should lead to renal salt wasting with a resultant decrease in ECFV and blood pressure, particularly during dietary sodium restriction, when, under conditions of normal ANP metabolism, the circulating levels and renal excretory effects of the hormone are minimal (53). Conversely, absence of ANP activity in the ANP -/- mice would be expected to lead to a reduction in renal salt excretion and consequent expansion of the ECFV and hypertension, particularly in response to elevated salt intake, when maximal ANP activity should be required for renal handling of the sodium load. Alternatively, the chronic hypotensive effect of ANP may be independent of its renal effects, in which case, changes in salt intake should not affect blood pressure. In this case, a persistent natriuretic effect of ANP would need to be counteracted by an increase in salt intake. Obviously, compensatory adjustments in the other salt-regulating mechanisms would be required to ensure salt balance and long-term survival.

Fluid and Electrolyte Balance in TTR-ANP Mice
It follows that, if the premise is correct, that genetically determined levels of plasma ANP are inversely related to extracellular volume, then the LS diet should aggravate the hypotension in the TTR-ANP by reducing ECFV, whereas the high salt intake should tend to normalize ECFV and ABP. However, no differences in cumulative (7 day) dietary intake or urinary excretion of sodium, chloride, and potassium were found between TTR-ANP and NT animals on either diet (142). Water intake and urine volume were elevated in the TTR-ANP mice compared with the NT mice, indicating that tonic increase in ANP activity leads to exaggerated diuresis. More significantly, however, is the fact that fractional excretion of water does not differ between transgenic and wild-type mice (142), indicating comparable ability for fluid balance in both strains. ABP values at the end of the dietary regimen remain significantly lower in the TTR-ANP mice regardless of the level of salt intake (Fig. 1), providing support to the premise that the chronic hypotensive effect of ANP is mediated by direct cardiovascular actions of the hormone, independent of changes in absolute renal sodium excretion. This conclusion, however, does not exclude a contributory role of ANP in fluid and electrolyte homeostasis. The high ANP levels in the TTR-ANP mice are known to remain effective in the kidney because these mice have an exaggerated natriuretic/diuretic response to acute extracellular volume expansion (40, 142). Nevertheless, despite their inability to reduce constitutively elevated ANP levels, the TTR-ANP mice can conserve salt on the LS dietary regimen as efficiently as the NT mice (142), implying that overriding salt-conserving mechanisms must be operating to bring about salt balance in the TTR-ANP mice. The nature of the compensatory adaptations that permit salt balance in these animals is not known. The magnitude of the natriuretic effect of ANP increases almost linearly with perfusion pressure (107), and ANP per se is known to enhance the sensitivity of the pressure natriuresis mechanism (138). Thus one possible mechanism of salt balance in the TTR-ANP mice may be that the reduction in renal perfusion associated with the systemic hypotension opposes the accentuated natriuretic activity of ANP by reducing the sensitivity of the pressure natriuresis mechanism. Alternatively, an ANP-mediated enhancement of the pressure natriuresis mechanism may overcome the counteracting effects of reduced perfusion pressure in the TTR-ANP mice. Either possibility would ensure attainment of salt and fluid balance at a lower perfusion pressure. Also, the possibility that adjustments in the activity of hormonal (i.e., RAS, aldosterone) and neural (sympathetic) salt-regulating mechanisms may contribute to salt and fluid balance in the TTR-ANP should be considered, but the extent to which such adaptations occur in these animals under the dietary conditions described above has not been investigated.



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Fig. 1. Average arterial blood pressure (ABP) in transthyretin-ANP (TTR-ANP) and control (nontransgenic, NT) mice at the end of 2 wk on high-salt (HS), normal salt (NS), or low-salt (LS) diet. Significant differences in ABP were found between TTR-ANP and NT mice in all diets (*P < 0.05) and in either strain between mice fed on HS and LS diets (#P < 0.05). ANP, atrial natriuretic peptide. [Modified from Veress et al. (142).]

 
Fluid and Electrolyte Balance in ANP -/- Mice
Similarly to the TTR-ANP mice, dietary intake and urinary excretion of sodium, chloride, and potassium in the ANP -/- mice do not differ significantly from their wild-type counterparts after 1 wk on HS or LS diets. This finding indicates that despite the absence of ANP activity, the ANP -/- mice are fully capable of maintaining salt balance even on the HS diet (65) and lends further support to the premise that the chronic cardiovascular actions of ANP are largely dissociated from the renal actions of the hormone. However, an HS diet that is maintained beyond the first week exacerbates the hypertension in the ANP -/- mice (64, 102) while having no effect on ABP in the ANP +/+ mice (Fig. 2). Interestingly, a similar phenotype is seen in mice expressing a single copy of the NPR-A gene (115). Conversely, the pressor effect of dietary salt is abolished by ANP gene transfer (30) or by treatment with exogenous ANP peptide (62) in salt-sensitive Dahl and spontaneously hypertensive rats, respectively. Thus a salt-sensitive component of blood pressure develops in response to reduced or absent endogenous ANP activity. This finding suggests that ANP, presumably via interactions with the NPR-A receptor, is essential for the cardiovascular and renal adaptations required for long-term maintenance of blood pressure constancy during elevated dietary salt intake (102). A predisposition to salt sensitivity of blood pressure in ANP-deficient states could, in fact, be predicted on the basis of the normal responses of ANP to high salt intake. For example, plasma ANP concentration usually increases in parallel with salt intake (128, 132, 146) and high dietary salt content potentiates the vasorelaxant effect of ANP in the renal vasculature (4) as well as the natriuretic response to the hormone (53). These are considered to be appropriate adaptations for the renal handling of increased dietary salt.



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Fig. 2. Average ABP in ANP -/- and ANP +/+ mice at the end of a 3–4 wk diet of HS, NS, or LS. Significant differences in ABP were found between ANP -/- and ANP +/+ mice on HS or NS diets (*P < 0.05) and within ANP -/- mice between those fed HS vs. NS (#P < 0.05) or those fed HS vs. LS ({dagger}P < 0.01) diets. [Modified from Melo et al. (102).]

 
How does a decrease in endogenous ANP activity lead to salt-sensitive hypertension? In principle, several single or interacting mechanisms could be involved. For example, it might be thought that lack of ANP-induced natriuretic action in the inner medullary collecting duct could lead to an increase in sodium reabsorption. The consequent expansion of extracellular and intravascular volume might then account for the pressor effect of salt. An alternate explanation for the development of salt-sensitive hypertension in ANP-deficient states may be that there is inadequate downregulation of ANP-modulated salt-conserving mechanisms such as the renin-angiotensin system, aldosterone, and renal sympathetic nerve activity (57, 66, 80). In regard to the first possibility, our data do not support such a mechanism. We have reported that despite their inherently reduced capacity for renal salt excretion (54), ANP -/- mice are fully capable of maintaining salt balance in the absence of any changes in ECFV, even after 4 wk on 8% NaCl diet (105), thus indicating that the absence of ANP-dependent natriuretic activity is adequately compensated by other salt-regulating mechanisms. Regarding the second possibility, we found that whereas the ANP +/+ mice respond to an increase in dietary salt intake with an appropriate reduction in plasma renin activity (PRA), the ANP -/- mice fail to reduce PRA in response to the high salt (Fig. 3) (102). This finding suggests that the sensitization of ABP to salt in the ANP -/- mice is due to inadequate downregulation of PRA. This functional dependency on the underlying elevated basal ANG II activity for sensitization of ABP to salt in ANP -/- mice is further supported by the fact that the salt-induced differences in ABP between mutant and wild-type control mice are fully abolished by chronic inhibition of AT-1 receptor activity with losartan (Table 3) (105). Thus it may be concluded from these findings that ANP-dependent antagonism of RAS activity is essential for the chronic cardiovascular and renal adaptations to elevated dietary salt intake. The nature of the derangement in renin synthesis in the salt-loaded ANP -/- mice is not known, but it does not appear to be caused by a reduction in sodium delivery to the macula densa, because fractional sodium delivery to the inner medullary collecting duct does not differ between ANP -/- and ANP +/+ mice (54).



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Fig. 3. Plasma renin activity (PRA, measured as ng ANG I · ml-1 · h-1) in ANP -/- and ANP +/+ mice fed on HS or LS for 3–4 wk. Significant differences in PRA were found between ANP -/- and ANP +/+ mice fed on HS (*P < 0.05) and within the ANP +/+ group between HS vs. LS diets (#P < 0.05). [Modified from Melo et al. (102).]

 

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Table 3. ABP, HR, and total plasma catecholamine in ANP -/- and ANP +/+ mice fed on HS diet (B% NaCl) for 4 wk and treated daily with losartan or distilled water (control)

 
The question then is, how do ANP -/- animals maintain salt and fluid balance? Tonically elevated basal ANG II levels would be expected to impart a powerful background of antinatriuresis in these animals by reducing the sensitivity of the pressure natriuresis mechanism (47, 78). We hypothesized that a salt-induced increase in renal perfusion pressure would be required to counteract by pressure natriuresis the salt-retaining effects of ANG II (129) and thereby permit long-term salt balance in the ANP -/-. This hypothesis is supported by our recent finding (105) that HS-fed ANP -/- mice, treated chronically with losartan, maintain salt balance despite a marked fall in ABP. If the salt-induced increase in ABP in these mice were not directed at overcoming the reduced sensitivity of the pressure natriuresis mechanism, then the losartan-induced fall in blood pressure would have been expected to cause relative salt retention. Our findings imply also that the mechanism underlying the ANP-mediated increase in the sensitivity of pressure-induced natriuresis may require, at least in part, antagonism of ANG II-dependent sodium reabsorption in the proximal tubule (48, 107). Thus we suggest that the salt-induced increase in blood pressure in ANP -/- mice is essential for salt balance and operates to compensate for the absence of ANP-dependent antagonism of the antinatriuretic action of ANG II.

The remaining question is, how does increased basal ANG II activity cause increased blood pressure sensitivity to dietary salt in the ANP -/- mice? When administered chronically, ANG II, even at subpressor doses, leads to hypertension that is exacerbated by elevated dietary salt intake (78). Although the direct renal and vascular effects of ANG II may contribute to the hypertensive effect of salt (47, 126), there is evidence that the pervasive sympathoexcitatory activity of this peptide may also play a major role in maintaining the pressor effect of salt (123). The HS-fed ANP -/- mice have inappropriately elevated sympathetic tone, compared with the ANP +/+ mice, as indicated by the 10-fold elevation in total plasma catecholamine concentration and by the higher basal heart rates (Table 3) (105). Interestingly, these differences in plasma catecholamine concentration and heart rates are fully abrogated by chronic treatment with losartan, thereby showing the dependency of the elevated sympathetic tone on ANG II activity. This implies that blood pressure sensitization by high dietary salt is, at least partially, due to the tonic potentiation of sympathetic tone by ANG II. It is likely that these two vasoregulatory and salt-conserving mechanisms interact synergistically, each exerting an agonistic effect upon the other (22, 68, 139) that is antagonized by ANP (134).

CONCLUSIONS AND PERSPECTIVES

The recurrent phenotype manifested by all the genetic mouse models expressing chronic deficiencies in ANP or NPR-A receptor activity is characterized by life-long systemic hypertension, whereas chronic increase in ANP activity leads to hypotension in association with changes in PVR. Thus these findings provide conclusive evidence that ANP plays a determining role in long-term regulation of ABP by exerting a tonic vasodilatory effect in the resistance vasculature.

Regarding a role of ANP in chronic regulation of salt and fluid balance, the evidence indicates that ANP-mediated antagonism of RAS activity is essential for the cardiovascular and renal adaptations to elevated dietary salt intake, inasmuch as a salt-sensitive component of hypertension develops during high salt intake in -/- ANP mice, in association with failure to downregulate PRA. Under conditions of normal salt intake, ANP does not appear to be a determining factor in renal regulation of salt excretion but only one of several redundant natriuretic mechanisms, whose activity may not be essential in isolation.

The extent to which these findings may be generalized to the more heterogeneous human population is not fully known. Deficiencies in ANP activity and in target organ responsiveness have been reported to occur in several experimental and natural variants of salt-sensitive hypertension (18, 19, 63, 112) as well as in sodium-retaining disorders such as CHF and cirrhosis (18, 67, 75, 97, 98). The degree to which these deficiencies in ANP activity contribute to the pathology of cardiovascular disease remains controversial. Polymorphisms of the ANP gene have recently been reported to occur with greater frequency in humans with essential hypertension (127), and mutations in the NPR-A gene cosegregate with blood pressure in salt-sensitive Dahl rats (30). Interestingly, prehypertensive salt-sensitive Dahl rats have lower plasma ANP levels than the salt-resistant strain (116) and, when fed on HS diet, display a dysregulation in PRA and sympathetic activity that is strikingly similar to that seen in the ANP -/- mice (12, 43). The presser effect of salt in these rats can be prevented by exogenous ANP gene delivery (90), implying that a deficiency in ANP activity may be a common occurrence in salt-sensitive variants of hypertension. In CHF, there is marked renal hyporesponsiveness to ANP, despite greatly elevated levels of the hormone (16). The hyporesponsiveness to ANP can be corrected by inhibition of ANG II activity (95), suggesting that in this condition the normal ANP-mediated antagonism of RAS is attenuated, and this may account, at least partially, for the elevated sympathetic activity that is characteristic of this disease. In their totality, these findings suggest that a deficit in ANP activity could potentially be an underlying causative factor in the etiology of hypertensive and sodium-retaining disorders such as CHF and cirrhosis

FUTURE DIRECTIONS

The findings summarized in this review open several future topics of investigation, some of which could be adequately addressed by employing the currently available genetic models of ANP and natriuretic receptor activity. The site(s) and mechanism of tonic ANP-mediated sympathoinhibition need to be investigated. As discussed previously in this review, the acute sympatholytic actions of ANP are widespread and manifested at all levels of sympathetic neurotransmission (for review, see Ref. 81). It is likely that the tonic sympatholytic effect of ANP is the overall result of neuromodulatory actions of the peptide at multiple sites in the sympathetic nervous system. Some potential sites and mechanisms of sympathoinhibition include inhibition of central sympathetic outflow from the rostral ventrolateral medulla, inhibition of sympathetic ganglionic neurotransmission, and inhibition of catecholamine synthesis in sympathetic nerve terminals and in the adrenal medulla. The existing ANP and NPR-A and NPR-C knockout models could be employed to identify both the sites along the sympathetic nervous pathway where ANP may inhibit sympathetic neurotransmission, as well as the relative role of each of these receptors in mediating the neuromodulatory actions of ANP.

The role of ANP in chronic regulation of vascular and cardiac growth and remodeling also needs to be defined, particularly in light of evidence that the hormone induces apoptosis and exerts antimitogenic and antihypertrophic effects in a variety of cultured cell types, including vascular smooth muscle cells, endothelial cells, cardiac myocytes, and fibroblasts (20, 60, 61, 108, 150). The extent to which these effects of ANP may occur in vivo is not known. The TTR-ANP mouse shows a 30% reduction in heart-to-body weight ratio (8, 104) and has a blunted right ventricular hypertrophic response to hypoxia-induced pulmonary hypertension (73), whereas the ANP -/- mouse displays an increase in heart-to-body weight ratio of similar magnitude (64, 104) and has an exaggerated right ventricular hypertrophic response to pulmonary hypertension (74). The NPR-A knockout mice developed by Oliver et al. (114) develop severe cardiac hypertrophy in association with extensive fibrosis and have high mortality rates due to sudden death. These findings indirectly suggest an inhibitory effect of ANP on cardiac growth. However, it is impossible to fully dissociate the differences in cardiac size from the underlying hemodynamic alterations in these ANP-related mouse models. Recently Masciotra et al. (96) demonstrated with a cosegregation analysis of crosses of inbred rats derived from a Wistar-Kyoto/spontaneously hypertensive hybrid strain that ventricular ANP content correlates negatively with left ventricular mass, independently of blood pressure. Thus this study provides a genetic link between reduced ventricular ANP levels and left cardiac hypertrophy and suggests a protective role of ANP on cardiac growth, probably via direct antihypertrophic and antiproliferative effects on cardiac myocytes and fibroblasts, respectively. Future developments in conditional ANP transgene expression using tissue-specific promoters to target expression of the genetic alterations to the tissues of interest will undoubtedly allow dissection of local regulatory actions of ANP, including the potential effects of this peptide on regulation of cardiac and vascular growth and remodeling. Until these models are introduced as viable experimental tools, much of the evidence regarding local regulatory effects of ANP in vivo will continue to be inferential in nature.

As the chronic effects of ANP become more clearly defined, effective pharmacological and gene-based therapies may be devised for treatment of conditions in which alterations in ANP activity may play a pathological role. One such example is CHF, in which the conditions of salt retention and volume overload that characterize this syndrome (22) are greatly improved by chronic inhibition of neutral endopeptidase, presumably because of the diminished rate of ANP clearance.

ACKNOWLEDGMENTS

The authors’ work reviewed in this article was supported by grants from the Medical Research Council of Canada, Heart and Stroke Foundation of Ontario, National Institutes of Health, and Ciba-Geigy Canada. L. G. Melo was supported by a research scholarship from the Heart and Stroke Foundation of Canada.

FOOTNOTES

Article published online before print. See web site for date of publication (http://physiolgenomics.physiology.org).

Address for reprint requests and other correspondence: L. G. Melo, Dept. of Medicine, Harvard Medical School and Brigham and Women’s Hospital, 20 Shattuck St., Boston, MA 02115 (E-mail: lmelo{at}rics.bwh.harvard.edu).

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