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Cardiovascular Research 2001 51(4):647-658; doi:10.1016/S0008-6363(01)00256-5
© 2001 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Atrial natriuretic peptides in pathophysiological diseases

David L Vesely*

James A. Haley Veterans’ Hospital – 151, University of South Florida, Cardiac Hormone Center, 13000 Bruce B. Downs Blvd., Tampa, FL 33612, USA

* Tel.: +1-813-972-7624; fax: +1-813-972-7623 vesely.david_l{at}tampa.va.gov

Received 6 October 2000; accepted 15 January 2001

KEYWORDS Blood pressure; Heart failure; Infarction; Natriuretic peptide; Renal function


   1 Introduction
Top
 1 Introduction
2 Pathophysiology of ANPs...
 3 Pathophysiology of ANPs...
 4 Summary
 References
 
Atrial natriuretic peptides (ANPs) consist of a family of peptides which are synthesized and then stored as three different prohormones (i.e., 126 amino acid [a.a.] atrial natriuretic peptide (ANP), 108 a.a. brain natriuretic peptide (BNP), and 126 a.a. C-natriuretic peptide prohormones (CNP) prohormones) [1]. The present review will concentrate on atrial peptides and especially on the natriuretic peptides originating from the ANP prohormone in pathophysiological conditions. There are several excellent recent reviews on the biochemistry and molecular biology of the natriuretic peptides [2,3] and their physiology [4–6] so these aspects will not be reviewed in detail in the present review.


   2 Pathophysiology of ANPs in cardiovascular diseases
Top
 1 Introduction
 2 Pathophysiology of ANPs...
3 Pathophysiology of ANPs...
 4 Summary
 References
 
2.1 Cerebrovascular disease — molecular biology of natriuretic peptides
To understand which of the atrial natriuretic peptides may be associated with cerebrovascular accidents (i.e., strokes) [7,8] and other cardiovascular disease states, it is necessary to briefly review the molecular biology of how the respective atrial natriuretic peptides are synthesized. The gene encoding for the synthesis of atrial natriuretic peptide preprohormone consists of three exons (coding) sequences separated by two intron (intervening) sequences (Fig. 1) [9–12]. Exon 1 encodes the signal peptide which is cleaved from the preprohormone (152 a.a.) in the endoplasmic reticulum to form a prohormone of 126 a.a., which is the storage form of the various atrial peptide hormones within tissues [11–13]. Exon 1 also encodes for the first 16 amino acids of this prohormone [9–12] which after proteolytic processing of the ANP prohormone is also the first 16 a.a. of a peptide hormone named long acting natriuretic peptide (LANP) (Fig. 1). Exon 3 encodes for the terminal tyrosine (i.e., a.a. 126 of the ANP prohormone) in humans and 3 a.a. (Try-Arg-Arg) in rat, mouse, rabbit, and cow [9–13]. Exon 2 encodes for the rest of the prohormone (i.e., a.a. 17–125 in humans) [9–13].


Figure 1
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  		Fig. 1 Structure of atrial natriuretic peptide prohormone (proANF) gene. Reprinted with permission from Ref. [1].

 
In healthy adults, the ANP prohormone's main site of synthesis is the atrial myocyte but it is also synthesized in a variety of other tissues as well [14]. Within this 126 a.a. prohormone are several peptides with blood pressure lowering, natriuretic, diuretic, and/or kaliuretic (i.e., potassium excreting) properties in both animals [15,16] and humans [17,18]. These peptide hormones, numbered by their a.a. sequences beginning at the N-terminal end of the ANP prohormone, consist of the first 30 a.a. of the prohormone (i.e., proANP 1–30; long acting natriuretic peptide), a.a. 31–67; (i.e., proANP 31–67; vessel dilator), a.a. 79–98 (proANP 79–98; kaliuretic peptide) and a.a. 99–126 (ANP) (Fig. 1). The natriuretic effects of long acting natriuretic peptide and vessel dilator have a different mechanism(s) of action from ANP in that they inhibit renal Na+-K+-ATPase secondary to their ability to enhance the synthesis of prostaglandin E2 [19,20] which ANP does not do [19,20].

The ANP prohormone biochemical processing is different within the kidney resulting in an additional 4 a.a. added to the N-terminus of ANP (i.e., proANP 95–126; urodilatin) [21,22]. Urodilatin circulates in very low concentrations (i.e., 9–12 pg/ml) [23]. Infusion of ANP increases the circulating concentration of urodilatin suggesting that some of ANP's effects may be mediated by urodilatin [23]. Infusion of long acting natriuretic peptide, vessel dilator, and kaliuretic peptide, on the other hand, do not affect the circulating concentration of urodilatin in healthy humans [23].

2.2 Cerebrovascular disease — clinical and biochemical correlation
A recent genetic linkage study followed 22,071 male physicians, all of which had no history of stroke, from 1982 to 1999 [7]. DNA extracted from peripheral white blood cells of those individuals who had a subsequent stroke revealed that when compared to those without strokes a molecular variant in exon 1 of the ANP gene was present and associated with a 2-fold (P<0.01) increased risk of stroke [7]. The individuals who had a cerebrovascular accident had significantly (P<0.001) higher systolic and diastolic blood pressures than the persons who did not have a cerebrovascular accident [7]. This molecular variant of the ANP gene was found to be an independent risk factor (in addition to hypertension) for a cerebrovascular accident. This molecular variant was found to be responsible for a valine-to-methionine substitution in the peptide hormone synthesized by exon 1, i.e., long acting natriuretic peptide (LANP) (Fig. 1) [7]. (Exon one does not encode for ANP). In these 16 amino acids there is only one valine, which is at position 7 of long acting natriuretic peptide [1]. Residue #7 (i.e., amino acid #7 of the ANP prohormone) is highly conserved among different species [9]. In this human study of cerebrovascular accidents there was not any defect in the structure or expression of the brain natriuretic peptide gene [7]. Thus this large prospective, case-controlled study revealed that carrier status for a mutation in the gene encoding for long acting natriuretic peptide is associated with a significant increased (2-fold) risk of stroke [7]. Long acting natriuretic peptide (LANP) has potent vasodilatory properties in both animals [16] and humans [17]. Antisera to LANP (i.e., to block the biologic activity of this peptide hormone) results in a significant increase in mean arterial pressure from 112±12 to 131±9 mm Hg in normotensive animals and exacerbates hypertension in spontaneously hypertensive rats (SHR) from 140±10 to 159±9 mm Hg [24]. This antisera data indicates an important physiological role for long acting natriuretic peptide in the regulation of arterial pressure [24]. If exon 1 is making a form of LANP that lacks biologic activity, with a resultant loss of this important blood pressure lowering peptide hormone's biologic effects, then this defect could cause a stroke mediated by this physiologic regulator of blood pressure. It is important to note, however, that the mutated form of LANP that is made by exon 1 has not as yet been directly tested to determine if it has lost its blood pressure lowering ability.

Through genotype/phenotype cosegregation analysis of F2 intercross, from the crossbreeding of stroke-prone and stroke-resistant spontaneously hypertensive rats (SHRs) it was found that a different point mutation in the ANP gene confers a stroke delaying effect [8]. This point mutation, which is different from the above mutation found in humans, results in a serine replacing glycine at amino acid 74 of the ANP prohormone of the stroke-prone rats [8]. If a serine replacing glycine in position 74 of the ANP prohormone is important to help prevent strokes, it is of interest that a serine is normally present in position 74 in mice, rabbits, and dogs [1] which may confer some protection from strokes in these species. There were no mutations in the BNP gene and no differences in BNP gene expression between stroke-prone and stroke-resistant animals [5]. Thus, these studies in stroke-prone animals suggest that the gene synthesizing the ANP prohormone may be protective against cerebrovascular accidents and this data is consistent with the human data mutations in one or more portions of this gene can lead to an increased incidence of cerebrovascular accidents.

Further evidence of the importance of the ANP prohormone gene knockout in mice, all develop salt-sensitive hypertension within 1 week leading to stroke [25]. The BNP gene does not upregulate to prevent hypertension and/or stroke when there is ANP gene knockout [25]. Downregulation of the ANP gene within the brain in the stroke-prone SHRs has further been found to co-segregate with the occurrence of early strokes in their F2 descendents [26].

2.3 Hypertension
Hypertension is an independent risk factor in addition to mutation in the ANP gene [7] for a cerebrovascular accident. The original hypothesis for hypertension was that there was a defect in the production of the blood pressure lowering atrial natriuretic peptides [27,28]. Experimental evidence revealed that rather than being decreased these blood pressure lowering peptides are elevated in the circulation in an apparent attempt to overcome the elevated blood pressure [27–30]. ANP increases in essential hypertension [27,28] and in persons with pheochromocytomas [30]. The hypertension associated with pheochromocytomas is characterized by increased circulating concentrations of the vessel dilator and long acting natriuretic peptide (LANP) as well as ANP [31]. Each of these blood pressure lowering hormones increase further with surgical manipulation-induced increases in blood pressure, and these peptides then return to normal after surgical removal of the pheochromocytomas and lowering of blood pressure [30,31]. The hypertension of obesity also is associated with increased circulating concentrations of ANP [29] LANP [32] and vessel dilator [32] which decrease into the normal range with weight-reduction induced decrease of the high blood pressure.

In a normal pregnancy, atrial natriuretic peptides increase in each trimester with the plasma volume expansion which accompanies a normal pregnancy [33]. ANP, vessel dilator and LANP increase dramatically with the hypertension of pre-eclampsia compared to their circulating concentrations in healthy pregnant women [34]. The increased circulating levels of these vasodilatory peptides in hypertension suggests a receptor or postreceptor defect(s) in vasculature is the pathophysiological cause of their increase in hypertension [31]. These peptides increase in the circulation in an apparent attempt to "override" the defect [1]. This is similar to the negative feedback system of essentially all hormones where a defect in the receptor (or post receptor defect) in the target organ causes an increase in the hormone which stimulates the respective receptor [1]. Each of the atrial natriuretic peptides discussed above do have a negative feedback system regulating their own and the other natriuretic peptides release [18].

If one knocks out the ANP gene which synthesizes the four atrial natriuretic peptides in Fig. 1, within 1 week the animals develop salt-sensitive hypertension [25] while, on the other hand, transgenic mice overexpressing the ANP gene, develop hypotension [35]. In addition to directly vasodilating vasculature, kaliuretic peptide and ANP inhibit the release of the potent vasocontrictive peptide endothelin which is produced by the vascular endothelium [36]. The ANP gene and the peptide hormones synthesized by it, thus, appear very important in blood pressure control in both health and in pathological diseases.

2.4 Congestive heart failure
In persons with congestive heart failure there is no defect in the production of these peptides from the ANP prohormone but rather each are increased within the circulation in the attempt by the heart to overcome the abnormal sodium and water retention by releasing more of these peptides which cause sodium and water excretion [37,38]. As part of the pathophysiology of congestive heart failure (CHF), for example, vessel dilator and LANP increase in direct proportion to the severity of CHF as classified by the symptomatic New York Heart Association (NYHA) [37,38]. When compared against nine other potential markers (including ANP, brain natriuretic peptide, N-terminus BNP prohormone, etc.) vessel dilator (Fig. 1) was the only marker with 100% sensitivity and 100% specificity in differentiating persons with mild (Class I NYHA) CHF from healthy individuals) [38]. The plasma concentrations of ANP, BNP and N-terminal proBNP, on the other hand, are not different from those of healthy persons until heart failure becomes more severe [38]. In the Survival And Ventricular Enlargement (SAVE) trial, similar findings were found in that N-terminal proANP, but not ANP or other neurohormones, was an independent predictor of the development of CHF and of cardiovascular mortality [39]. Lerman et al. also confirmed ANP plasma levels do not increase until CHF is advanced and they further demonstrated that an N-terminal proANP assay could detect persons with early asymptomatic Class I CHF [40]. The peptides from the N-terminus of the ANP prohormone appear to be one of the best markers of which CHF patients will survive and their response to treatment [41–43].

With respect to pathophysiology, the cause of the increase of these atrial peptides in the circulation of persons with CHF appears at least in part due to an increase in ANP prohormone gene expression (with an increased synthesis of these peptides) within the ventricle but not the atria of the heart [44–46]. The ANP clearance receptor pathway is not linked to the avid sodium retention and/or to the renal ANP resistance observed in CHF [47].

As part of the adaptive response to the pathophysiology of congestive heart failure, atrial natriuretic peptides increase in circulation [37–40]. This knowledge has suggested that several of the atrial natriuretic peptides may be useful in the treatment of congestive heart failure [48,49]. The rationale for treatment of the pathophysiology of CHF with atrial peptides (which are already increased in the circulation) is based upon other hormonal systems where if one gives pharmacological rather than physiological concentrations of a hormone one often can overcome a defect in the target organ with respect to a particular hormone. In congestive heart failure, the pathophysiology with respect to atrial natriuretic peptides appears to be in the target organ(s) (i.e., kidney has a diminished response to some of the atrial peptides) rather than the heart not producing enough of the respective hormones [1]. As outlined above the heart actually produces more of these peptide hormones (i.e., the heart does not have a defect in the production of these hormones) in persons with CHF compared to healthy individuals [37–40]. When ANP was investigated for possible treatment of the pathophysiology of CHF, it was found to have a markedly attenuated natriuretic response [50–52]. High dose administration of ANP produces little or no diuresis or natriuresis in humans with CHF [52]. Preliminary studies suggested that brain natriuretic peptide (BNP) in CHF individuals could cause a small increase in urine volume (90±38 vs. 67±27 ml/h) [53]. Further evaluation indicated that there is no significant natriuresis [54] or diuresis [55,56] with BNP infusion in persons with CHF. In CHF animals, BNP has had no significant natriuretic or diuretic effects [57]. BNP can cause significant hypotension, however, in CHF subjects [54,56] with an incidence of 27% reported with 0.06 µg/kg/min dose [56].

One of the other cardiac peptide hormones, i.e., vessel dilator, on the other hand, when given intravenously for 60 min to NYHA Class III CHF subjects increases urine flow 2–13-fold, which is still increased 3 h after its infusion is stopped [48]. Vessel dilator enhances sodium excretion three to 4-fold in CHF subjects (Fig. 2) and the fractional excretion of sodium (FENa) 6-fold, which are still significantly (P<0.01) elevated 3 h after vessel dilator's infusion [48]. Vessel dilator simultaneously decreases systemic vascular resistance 24%, pulmonary vascular resistance 25%, pulmonary capillary wedge pressure 33% and central venous pressure 27% while simultaneously increasing cardiac output 34%, cardiac index 35%, and stroke volume index 24% in individuals with CHF (Fig. 3) [48]. There were no side effects with infusion of vessel dilator in CHF subjects [48]. The natriuretic and diuretic effects of vessel dilator to help reverse the pathophysiology of CHF are as potent (i.e., not decreased) in persons with CHF as those observed in healthy persons [48]. The ability of vessel dilator to retain its beneficial effects in persons with CHF while the effects of ANP and BNP become blunted appears to be due to the ability of vessel dilator to enhance prostaglandin E2 synthesis in the kidney, which, in turn, inhibits renal Na+-K+-ATPase, resulting in a natriuresis [19,20]. ANP does not enhance the synthesis of prostaglandin E2 or inhibit renal Na+-K+-ATPase [19,20].


Figure 2
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  		Fig. 2 Vessel dilator enhances sodium excretion in persons with CHF. *Time points at which sodium excretion was significantly (P<0.05) increased compared with baseline sodium excretion in the same subjects when evaluated by repeated measures of ANOVA. Reprinted with permission from Ref. [49].

 

Figure 3
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  		Fig. 3 Systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), pulmonary capillary wedge pressure (PWP), and central venous pressure (CVP) decrease secondary to vessel dilator (P<0.05). No significant changes were found in heart rate (HR) or pulmonary artery pressure (PAP). Cardiac output (CO), cardiac index (CI), and stroke volume index (SVI) increased (P<0.05) when evaluated by repeated measures ANOVA. Reprinted with permission from Ref. [49].

 
Long acting natriuretic peptide (LANP) maximally increases urine flow and natriuresis only twofold in persons with CHF [49] compared to 4–5-fold increase in urine flow and 3–8-fold increase in natriuresis in healthy individuals [17]. Thus, long acting natriuretic peptide's effects in CHF individuals are blunted compared to its effects in healthy individuals [17,49].

In pathophysiologic states such as CHF, kaliuretic peptide's synthesis is increased in the heart [13,14,44–46] with increased release into the circulation [38]. Because of the increased synthesis of kaliuretic peptide with its diuretic properties is an attempt to overcome the fluid retention of CHF, kaliuretic peptide has been investigated for its ability to improve the pathophysiology of CHF [58]. Kaliuretic peptide causes a 4-fold diuresis in persons with CHF, which is double the diuresis it causes in healthy individuals [58]. Kaliuretic peptide enhances sodium excretion 3-fold in persons with CHF [58]. This enhancement of sodium excretion by kaliuretic peptide is unique to persons with CHF since kaliuretic peptide does not cause a natriuresis in healthy individuals [17]. Kaliuretic peptide and ANP also enhance potassium excretion in persons with CHF [58]. ANP has been shown to inhibit the opening of the potassium channel in human kidney epithelial cells [59] which may be part of its mechanism in persons with CHF.

Treatment of end-stage CHF with cardiac transplantation when successful normalizes the circulating concentrations of atrial natriuretic peptides to those of healthy adults within 5–12 days post-transplant [41]. In those CHF individuals whose atrial peptides do not normalize within 12 days post-transplant, decompensated heart failure is still present and there is a worse prognosis for these CHF subjects [41].

2.5 Acute myocardial infarction
With infarction of myocardium, atrial natriuretic peptides are released from the myocyte into the circulation [60,61]. With acute myocardial infarction the circulating concentrations of vessel dilator, ANP, and long acting natriuretic peptide are usually elevated by the time the patient arrives at the hospital (Fig. 4) [60,61]. Maximal increase of these peptides in the circulation is on day 3–4 post infarction (Fig. 4) [60,61]. These peptides remain elevated for 7–10 days as further necrosis of cardiac muscle occurs. Utilization of thrombolytic therapy, i.e., tissue plasminogen activator (TPA), at the time of infarction prevents the release of these peptides from the heart into the circulation [61]. Patients who only have myocardial ischemia without infarction do not have an increased release of these peptides [61]. In subjects who do not develop congestive heart failure or cardiac arrhythmias, the circulating concentrations of long acting natriuretic peptide, vessel dilator, and ANP return to the circulating concentrations of healthy adults by 12 days post infarction (Fig. 4) [60,61]. Each of these peptides appear to correlate with infarct size when this was directly measured in an animal model of acute myocardial infarction [62]. Only vessel dilator of these peptides, however, appears capable of predicting which animals would survive the acute myocardial infarction and which would not survive [62]. With respect to prognosis, measurement of the N-terminus of the ANP prohormone has been suggested to be an independent predictor of long-term prognosis in humans when measured 3–16 days after infarction [39].


Figure 4
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  		Fig. 4 Time course of the whole N-terminus (proANF 1–98, {bigtriangleup}), ANP ({blacksquare}), vessel dilator (i.e., proANF 31–67, {circ}), and serum creatine phosphokinase (CPK, bullet) of 17 patients followed for 14 days following acute myocardial infarction. Units for CPK on the right ordinate. The units for proANF 1–98 and vessel dilator are on the far left ordinate while the units for ANP, i.e., ANF are on the near left ordinate. The normal range for vessel dilator and ANF are defined as the upper horizontal line and the normal range for CPK defined by the lower horizontal line. Reprinted with permission from Ref. [61].

 
Thus, if one has normal circulating atrial peptides (i.e., no evidence of CHF or arrhythmia being present) 14 days post myocardial infarction one's prognosis is better. From the retrospective Thrombolysis in Myocardial Infarction (TIMI) trial, there is even a suggestion that measuring the plasma levels of the N-terminus of the ANP prohormone within 12 h of an acute myocardial infarction can predict one year mortality [63].

2.6 Supraventricular and ventricular arrhythmias
Long acting natriuretic peptide, vessel dilator, and ANP increase in the circulation of persons with supraventricular [64,65] or ventricular tachycardias [64,66]. Polyuria with paroxysmal atrial arrhythmias or paroxysmal supraventricular tachycardias was first described more than 70 years ago by Wenekebach and Winterberg [67]. Polyuria is now known to occur with atrial fibrillation, atrial flutter, and ventricular tachycardias when the heart rate is greater than 120 beats per min [68]. Pacing studies have revealed that when the heart rate reaches 125 beats per min each of the atrial peptides are released [69], which correlates directly with the onset of polyuria. When these abnormal cardiac rhythms are cardioverted, the elevated circulating concentrations of vessel dilator, long acting natriuretic peptide and ANP return to the levels of healthy individuals [69] and the polyuria ceases. Thus, this pathophysiologic polyuria associated with heart rates of greater than 120 beats/min appears directly related to the ANPs with their potent diuretic properties [64,66].


   3 Pathophysiology of ANPs in non-cardiovascular diseases
Top
 1 Introduction
 2 Pathophysiology of ANPs...
 3 Pathophysiology of ANPs...
4 Summary
 References
 
3.1 Production and function of atrial natriuretic peptides in the kidney
The kidney is one of the prime target organs (along with vasculature) of the physiologic effects of atrial natriuretic peptides (ANPs, 1). Immunohistochemical studies have localized ANP, vessel dilator and long acting natriuretic peptide to the sub-brush border of the pars convuluta and pars recta of the proximal tubules of animal [70] and human [71] kidneys. Immunofluorescent studies reveal that each of these peptides has a strong inclination for the perinuclear region in both the proximal and distal tubules [70,71]. Immunohistochemical studies localize urodilatin, a four amino acid extension of ANP formed by a different post-translational processing of the ANP prohormone in the kidney compared to the heart, to the distal tubule with no evidence of urodilatin in the proximal tubule [71]. Demonstration that both the N-terminus and C-terminus of the ANP prohormone are present in the kidney suggests that the whole prohormone is synthesized in the kidney [70,71]. (The amount of the ANP prohormone present in the kidney is only about 1/190th of that produced in the atria of the heart [71]). ANP messenger-RNA studies have confirmed that the ANP prohormone is synthesized in the kidney [72]. These studies taken together suggest that since urodilatin is found mainly in the distal nephron [71] and is part of the ANP prohormone, synthesis of the ANP prohormone may take place in the distal nephron [70,71,73].

Atrial natriuretic peptides inhibit sodium reabsorption in the kidney but the mechanism of action of ANP (i.e., via cyclic GMP) is different from that of vessel dilator, LANP, and kaliuretic peptide which inhibit Na+-K+-ATPase secondary to their ability to enhance the synthesis of prostaglandin E2 [19,20] which ANP does not do [19,20]. In addition, kaliuretic peptide, long acting natriuretic peptide and ANP inhibit aldosterone secretion [74] while vessel dilator decreases renin secretion by 66% [75]. Thus, these atrial peptides have direct and indirect effects in the kidney. Each of these mechanisms are altered in the pathophysiology of renal diseases discussed below.

3.2 Renal failure
The disease state associated with the highest circulating concentrations of atrial natriuretic peptides is renal failure [76–78]. One would suspect that atrial natriuretic peptides are higher in renal failure versus Class IV CHF because of the added pathophysiology of decreased degradation of these peptides with the decreased functioning renal parenchyma [76,77]. The circulating concentrations of ANPs in chronic renal failure appear to reflect volume status and have been suggested as possible indicators of when to perform dialysis in persons with chronic renal failure [77–80] but Franz et al. [78] data suggest that ANPs are not useful to predict when hemodialysis is necessary.

3.3 Treatment of acute renal failure with atrial natriuretic peptides
Several of the atrial peptides have been investigated as possible treatments of acute renal failure (ARF). Atrial natriuretic peptide had encouraging results in early studies of ARF in animals [81,82]. However, the administration of 0.2 µg of ANP·kg body wt–1·min–1 for 24 h to humans with ARF revealed that ANP did not cause significant improvement and did not reduce the need for dialysis or reduce mortality [83]. ANP was associated with decreased survival in the nonoliguric ARF subjects, which was 75% of the subjects [83]. The usefulness of ANP for treatment is hampered by its short half-life of 2.5 min [1,84] and by its very short duration of action [16–18]. Of 504 ARF patients treated with ANP, 46% developed hypotension [83], which would further limit its usefulness in ARF [83].

Vessel dilator (0.3 µg·kg–1·min–1 via intraperitoneal pump) decreases blood urea nitrogen (BUN) and serum creatinine from 162±4 mg/dl and 8.17±0.5 mg/dl to 53±17 and 0.98±0.12 mg/dl in acute renal failure animals where ARF was established for 2 days (after vascular clamping) before vessel dilator was given [85]. At day six of ARF, mortality decreased to 14% with vessel dilator from 88% without vessel dilator [85]. The ARF animals that did not receive vessel dilator had moderate (i.e., 25–75% of all tubules involved) to severe (i.e., >75% of all tubules necrotic) acute tubular necrosis by day 8 after their ischemic event (Fig. 5B). As shown in Fig. 5, the tubules of these animals were almost completely destroyed. The destruction of the tubules included both the proximal and distal tubules with the proximal tubules being more severely affected (Fig. 5B). The glomerulus of the ARF animals was spared compared with tubules with glomerulus appearing to be normal (Fig. 5A and B).


Figure 5
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  		Fig. 5 Renal histology of healthy Sprague–Dawley rat with intact proximal tubular brush border (A, arrowhead) and acute renal failure (ARF) rat at day 8 with marked tubular necrosis (B, open triangle) and without intact brush border (over 75% of tubules are necrotic). Glomerulus (x) appears to be normal. ARF rat treated with vessel dilator from day 2 to 5 of ARF with kidney examined after day 8 of ARF reveals brush border to be present in proximal tubule (C, arrowhead). None of the tubules are necrotic in this ARF animal treated with vessel dilator. Glomerulus (x) is intact. (Magnification of hematoxylin and eosin in A+C=x426; in B=x320.) Reprinted with permission from Ref. [85].

 
The addition of vessel dilator after renal failure had been present for 2 days resulted in a marked improvement in the renal histology with scores ranging from 0 (i.e., no tubular necrosis) to 1+ (i.e., <5% of the tubules involved) [85]. When the kidneys were examined at day 8 of renal failure, the brush borders of the proximal tubules of the ARF animals treated with vessel dilator were present (Fig. 5C), which was similar to the proximal tubules of healthy animals (Fig. 5A). The presence of brush borders in the vessel dilator-treated animals (Fig. 5C) was distinctly different from the ARF animals not treated with vessel dilator where the brush borders of the tubules had been destroyed (Fig. 5B). The glomeruli of vessel dilator-treated ARF animals also appeared normal (Fig. 5C). It should be pointed out that the animals treated with vessel dilator did have severe renal failure before vessel dilator was begun on the second day of renal failure [85]. It is important to note that the animals treated with vessel dilator who had a significant increase in survival had non-oliguric renal failure [85]. As noted above, non-oliguric renal failure subjects treated with ANP had a decreased survival and it was the non-oliguric renal failure subjects who did not respond to ANP [83].

Other atrial natriuretic peptides investigated to treat ARF have each resulted in severe hypotension and bradycardia [83,86]. For example, ANP resulted in 46% of renal failure patients becoming hypotensive [83]. Urodilatin has been suggested as a possible treatment of renal failure [86] and this peptide has also been associated with severe hypotension and bradycardia when given as a potential treatment of congestive heart failure [87]. Vessel dilator, LANP, and kaliuretic peptide, on the other hand, have never caused a hypotensive episode when given to either healthy animals or humans [16–18] or when given to humans with sodium and water retention [48,49].

Successful transplantation of functioning kidneys decreases the markedly elevated circulating levels of atrial natriuretic peptides in persons with ARF [88,89]. Non-functioning renal allografts continue to have elevated circulating concentrations of atrial natriuretic peptides [88]. Post renal transplant, it takes 7 days for ANP and 10 days for vessel dilator to return to normal [89]. This suggests that the allograft kidney does not fully function immediately with respect to clearing these peptides. The half-life of ANP in healthy persons is only 3 1/2 min [1,84]. If the transplanted kidneys began to function immediately, one would have expected the circulating concentration of ANP to have decreased to the normal range within 24 h (i.e., 360 half-lives). Vessel dilator has a longer half-life than ANP [84] which may explain why it takes 3 more days for this peptide hormone to normalize in the circulation after successful renal transplantation. If one gives ANP (via infusion) at the time of renal transplant this does not appear to have any beneficial effect on the outcome of the renal allograft [90].

3.4 Cirrhosis with ascities
Decompensated Laennec's cirrhosis frequently is complicated pathophysiologically by progressive impairment of renal sodium handling, leading to the formation of ascites and peripheral edema [91]. Although central blood volume is often reduced in cirrhotics [91], suggesting that atrial natriuretic peptides release might be diminished secondary to decreased atrial distension (a major stimulus for ANPs release), the circulating levels of atrial natriuretic peptides are not suppressed but rather are normal or increased compared to healthy volunteers [92–97]. Infusion of ANP decreases ascites in persons with chronic liver disease [98], but diminished renal responsiveness to ANP [99] appears to contribute to their sodium retention. Central hypervolemia induced by head-out water-immersion provokes a prompt and sustained increase of both the N-terminus and C-terminus of the ANP prohormone in cirrhotic subjects indicating that there is no defect in the release of these peptides in cirrhotic persons [95,96].

The amount of sodium in a cirrhotic person's diet appears to markedly influence the pathophysiology and the basal circulating concentrations of atrial natriuretic peptides [95,96]. With a high-sodium diet (100 mmol/day) atrial natriuretic peptides’ circulating concentrations are significantly higher in the same individuals than when they were on a low-sodium diet (10 mmol/day) [95,96]. In cirrhosis with ascites, the ANP prohormone gene upregulates with a 4-fold increased expression within the ventricle of the heart which accounts at least in part for the increased circulating pathophysiologic concentrations of atrial natriuretic peptides in cirrhotics [100].

3.5 Hyperthyroidism
Hyperthyroidism's pathophysiology is characterized by having enhanced natriuresis [101,102] and vasodilation [103,104]. This increased natriuresis and vasodilation are associated with increased circulating concentrations of ANP [105,106], long acting natriuretic peptide [103], and vessel dilator [106]. After successful treatment of hyperthyroidism, and reversal of the above pathophysiology, the circulating concentrations of ANP, vessel dilator and long acting natriuretic peptide return to the normal range of healthy volunteers [106], strongly suggesting that they mediate this pathophysiology. The biochemical mechanism causing the increase in the ANPs in hyperthyroidism appears to be a direct effect of thyroid hormone (thyroxine, T4) enhancing the ANP gene's function resulting in an increased synthesis of the ANP prohormone [107,108]. The majority of this increase in ANP mRNA secondary to T4 is in the ventricle rather than in the atria [107,108]. The release of the ANPs in hyperthyroidism appears related to the heart rate [106].

3.6 Hypothyroidism
The pathophysiology of hypothyroidism includes impaired water excretion [109] and vasoconstriction with increased peripheral vascular resistance [110]. Hypothyroidism is the best characterized disease state associated with decreased circulating concentrations of ANP [105,106,111], vessel dilator [103] and long acting natriuretic peptide [106]. The decrease in these diuretic peptides results in decreased (i.e., impaired) water excretion [106]. Thyroxine administration to hypothyroid rats increases ANP mRNA [107,108]. Thyroxine increases the circulating concentration of ANP, vessel dilator and long acting natriuretic peptide in hypothyroid humans [106]. With doses as low as 50 µg of the thyroxine per day for 4 weeks, atrial natriuretic peptides are increased in the circulation of hypothyroid humans and the impaired water excretion of hypothyroidism is ameliorated [106]. Thus, this is another disease state in which the renal pathophysiology (i.e., impaired water excretion) mediated by ANPs can be corrected by proper treatment of the specific disease.


   4 Summary
Top
 1 Introduction
 2 Pathophysiology of ANPs...
 3 Pathophysiology of ANPs...
 4 Summary
References
 
A molecular variant in exon 1 of atrial natriuretic peptide prohormone gene is associated with a 2-fold increased risk of stroke. The gene product of exon 1, i.e., long acting natriuretic peptide [LANP] is a physiological regulator of blood pressure based upon antisera to LANP causing a significant increase in blood pressure in both normotensive and in spontaneously hypertensive animals. These data taken together suggest that the single amino acid change in LANP may contribute to cerebrovascular accidents. In salt and water retaining states such as congestive heart failure and cirrhosis with ascites, atrial natriuretic peptides increase proportionally in the circulation to the severity of the sodium and water retention. Their increase is in an apparent attempt to overcome the sodium and water retention. One of the atrial natriuretic peptides, i.e., vessel dilator, enhances urine flow 2–13-fold and sodium excretion 4-fold while decreasing systemic vascular resistance 24% and increasing cardiac output 34% in CHF individuals. Vessel dilator markedly improves acute tubular necrosis even when given 2 days after an acute renal ischemia and reduces mortality from 88 to 14% in an animal model of acute renal failure.

Time for primary review 32 days.


   Acknowledgements
 
This work was supported by a Merit Award from the United States Department of Veterans Affairs, a Grant-in-Aid from the American Heart Association, Florida Affiliate, and NIH Grant HL44868.


   References
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 1 Introduction
 2 Pathophysiology of ANPs...
 3 Pathophysiology of ANPs...
 4 Summary
 References
 

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