Natriuretic peptides and acute renal failure

David L. Vesely

Departments of Medicine, Physiology, and Biophysics, University of South Florida Cardiac Hormone Center, and James A. Haley Veterans Medical Center, Tampa, Florida 33612


    ABSTRACT
 TOP
 ABSTRACT
 ANPs
 IMMUNOCYTOCHEMICAL LOCALIZATION...
 INFLUENCE OF ARF ON...
 PROTECTIVE AND THERAPEUTIC...
 SUMMARY AND FUTURE DIRECTIONS
 REFERENCES
 
Atrial natriuretic peptides (ANPs) are a family of peptide hormones, e.g., ANP, long-acting natriuretic peptide, vessel dilator, and kaliuretic peptide synthesized by the ANP gene. Brain natriuretic peptide (BNP) and C-type natriuretic peptide are also members of this family but are synthesized by separate genes. Within the kidney, the ANP prohormone's posttranslational processing is different from that of other tissues, resulting in an additional four amino acids added to the NH2 terminus of ANP (e.g., urodilatin). Each of these natriuretic and diuretic peptides increases within the circulation with acute renal failure (ARF). Renal transplantation but not hemodialysis returns their circulating concentrations to those of healthy individuals. BNP and adrenomedullin, a 52-amino acid natriuretic peptide, have beneficial effects on glomerular hypertrophy and glomerular injury but do not improve tubular injury (i.e., acute tubular necrosis). Vessel dilator ameliorates acute tubular necrosis with regeneration of the brush borders of proximal tubules. Vessel dilator decreases mortality in ARF from 88 to 14% at day 6 of ARF, even when given 2 days after renal failure has been established.

adrenomedullin; atrial natriuretic peptide prohormone; acute tubular necrosis; transplantation; hemodialysis


ACUTE RENAL FAILURE (ARF) develops in 2–5% of all patients sent to tertiary-care hospitals (125). In 60% of patients, the underlying cause is a renal insult [i.e., acute tubular necrosis (ATN)] (39, 125). In the mid-1940s, when dialysis was introduced, the mortality from severe ARF was ~50% (39). This poor prognosis has not improved, and mortality now remains in the 40–80% range in oliguiric ARF patients (4, 9, 22, 38, 39, 90, 125). The occurrence of ARF in the hospital increases the relative risk of dying by 6.2-fold and the length of hospitalization by 10 days (77). Thus ARF not only occurs with a high frequency but is also associated with high morbidity and mortality.

The present review will concentrate on the atrial natriuretic peptides (ANPs), adrenomedullin (ADM), and urodilatin, their pathophysiological changes with ARF, and their potential for the treatment of ARF. There are several excellent reviews on the biochemistry and molecular biology (28, 32, 56, 69, 73, 83, 106) and the physiology (7, 10, 36, 43, 54, 84, 86, 105, 119) of these natriuretic peptides so these aspects will not be reviewed in detail in the present review.


    ANPs
 TOP
 ABSTRACT
 ANPs
 IMMUNOCYTOCHEMICAL LOCALIZATION...
 INFLUENCE OF ARF ON...
 PROTECTIVE AND THERAPEUTIC...
 SUMMARY AND FUTURE DIRECTIONS
 REFERENCES
 
ANPs consist of a family of peptides that are synthesized by three different genes (28, 32, 56, 73, 83) and then stored as three different prohormones [i.e., 126-amino acid (aa) ANP, 108-aa brain natriuretic peptide (BNP), and 126-aa C-type natriuretic peptide (CNP) prohormones] (56, 104). 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, including the kidney (31, 116). The sites of synthesis of the ANPs in the approximate order in which they contribute to the synthesis are listed in Table 1.


View this table:
[in this window]
[in a new window]
 
Table 1. Site(s) of synthesis, molecular weight, and hemodynamic and natriuretic properties of natriuretic peptides

 

Peptide Hormones Originating From the ANP Prohormone

Within the 126-aa ANP prohormone are four peptide hormones (Fig. 1), with blood pressure-lowering, natriuretic, diuretic, and/or kaliuretic (i.e., potassium-excreting) properties in both animals (8, 25, 26, 35, 37, 61, 113, 118, 127) and humans (109112). These peptide hormones, numbered by their aa sequences beginning at the NH2-terminal end of the ANP prohormone, consist of the first 30 aa of the prohormone [i.e., proANP-(1—30); long-acting natriuretic peptide (LANP)], aa 31–67 [i.e., proANP-(31—67); vessel dilator], aa 79–98 [proANP-(79—98); kaliuretic peptide], and aa 99–126 (ANP) (Fig. 1). Each of these four peptide hormones circulates in healthy humans, with LANP and vessel dilator concentrations in plasma being 15- to 20-fold higher than ANP and 100-fold higher than BNP (24, 29, 30, 41, 114, 123). More than one peptide hormone originating from the same prohormone is common with respect to the synthesis of hormones (104). ACTH, for example, is derived from a prohormone that contains four known peptide hormones (104). The BNP and CNP genes, on the other hand, appear to each synthesize only one peptide hormone within their respective prohormones, i.e., BNP and CNP (7, 28, 32, 54, 55, 73). The natriuretic effects of LANP, kaliuretic peptide, and vessel dilator have different mechanism(s) of action from ANP, in that they inhibit renal Na+-K+-ATPase secondarily to their ability to enhance the synthesis of prostaglandin E2, which ANP does not do (18, 35). The effects of ANP, BNP, and CNP in the kidney are thought to be mediated by cGMP (10, 36, 84, 104).



View larger version (25K):
[in this window]
[in a new window]
 
Fig. 1. Structure of the atrial natriuretic peptide prohormone (proANP) gene. Four peptide hormones [e.g., atrial natriuretic peptide (ANP), long-acting natriuretic peptide (LANP), vessel dilator, and kaliuretic peptide] are synthesized by this gene. Each of these peptide hormones has biological effects, e.g., natriuresis and diuresis, mediated via the kidney (8, 25, 26, 35, 37, 61, 113, 118, 127). LANH, long-acting natriuretic hormone (a different nomenclature for LANP); a.a., amino acids. Reprinted by permission (Pearson Education, Inc., 1992) (104).

 

ANP has been found to be a potent in vivo and in vitro inhibitor of aldosterone secretion via a direct effect on the adrenal (5, 14, 17, 23, 33, 51, 59) and indirectly through inhibition of renin release from the kidney (14, 53, 59, 103). Kaliuretic peptide and long-acting natriuretic peptide are also potent inhibitors of the circulating concentrations of aldosterone in healthy humans (108). Kaliuretic peptide and LANP effects on decreasing plasma aldosterone levels last for at least 3 h after their infusions have stopped, whereas ANP no longer has any effect on plasma aldosterone concentrations within 30 min of cessation of its infusion (108). Vessel dilator does not appear to have direct effects on aldosterone synthesis but is a potent inhibitor (66%) of plasma renin activity (117). The site of synthesis, molecular weight, and hemodynamic effects of each of the natriuretic peptides in humans is summarized in Table 1. ANP, LANP, and vessel dilator cause a significant diuresis and natriuresis in healthy humans (112). Kaliuretic peptide does not cause a significant natriuresis in healthy humans, but when infused in humans with congestive heart failure it causes a significant natriuresis (70).

Urodilatin. ANP prohormone posttranslational processing is different within the kidney from that which occurs in the heart, resulting in an additional four amino acids added to the NH2 terminus of ANP [i.e., proANP-(95—126); urodilatin] (56, 69, 93) (Fig. 2). The rest of the amino acids in urodilatin are identical and in the same sequence as those in ANP (Fig. 2). Urodilatin and ANP have identical ring structures formed with cysteine-to-cysteine bonding (Fig. 2). Urodilatin is not formed in the heart or in other tissues except the kidney. This peptide hormone is synthesized by the same gene that synthesizes ANP, but in the kidney, as opposed to all other tissues that have been investigated, the ANP prohormone is processed differently, resulting in the formation of urodilatin rather than ANP (56, 69, 93). Urodilatin circulates in very low concentrations (i.e., 9–12 pg/ml) (115). Infusion of ANP increases the circulating concentration of urodilatin, suggesting that some of ANP's effects may be mediated by urodilatin (115). Infusion of LANP, vessel dilator, and kaliuretic peptide, on the other hand, do not affect the circulating concentration of urodilatin in healthy humans (115).



View larger version (40K):
[in this window]
[in a new window]
 
Fig. 2. Amino acid sequences of the natriuretic peptides. Each of the sequences are the human sequences except for Dendroaspis natriuretic peptide (DNP), whose sequence is only known in the snake. The brackets illustrate the location of cystine bridges that help to form a ring structure in a number of these peptides. BNP, brain natriuretic peptide; CNP, C-type natriuretic peptide.

 

BNP and CNP

BNP. BNP has similar diuretic and natriuretic effects and a short half-life as ANP (98). BNP's half-life is 100-fold shorter than the half-lives of vessel dilator and LANP (1, 54, 98, 99, 104). BNP has remarkable sequence homology to ANP, with only four amino acids being different in the 17-aa ring structure common to both peptides (Fig. 2) (54, 55, 73, 83, 84, 98). Although BNP was named (98) for where it was first isolated (i.e., porcine brain), the main source of its synthesis and secretion is the heart (Table 1) (36, 54, 56, 84, 101). As with ANP, the highest levels of BNP are found in the atria of the heart (36, 101). BNP levels in the atria, however, are <1% of ANP levels (101). The immunoreactive level of BNP within the ventricles is only 1% of BNP's concentration within the atria (101). BNP, however, has been termed a "ventricular" peptide based on ventricular BNP mRNA levels being similar to those in the atria, and the ventricles are much larger than the atria (69).

The 108-aa BNP prohormone is processed within the heart to yield a biologically functioning BNP consisting of aa 77–108 of the BNP prohormone and the NH2 terminus of the BNP prohormone (aa 1–76 of prohormone), both of which circulate (54). The circulating concentration of BNP is <20% that of ANP (36). The sequence homology of BNP differs appreciably across species (both in size and amino acid sequence) (28, 54, 68, 73, 101). BNP's marked sequence variability explains, in part, the variations in its biological activity in different species. The peptide hormones from the ANP prohormone, on the other hand, have remarkable homology across different species (28, 32, 73, 104). Mice overexpressing the BNP gene, where the circulating concentration of BNP is 10- to 100-fold higher than in healthy mice, have less glomerular hypertrophy and mesangial expansion with intraglomerular cells than healthy mice 16 wk after both received renal ablation (45). This mouse model of subtotal renal ablation, however, also has significantly increased ANP concentrations (74, 102, 128), which may also have contributed to the effects attributed to BNP in the BNP gene-overexpressing mice (45).

CNP. CNP has remarkable similarity to ANP in its amino acid sequence but lacks the COOH-terminal tail of ANP (Fig. 2) (6, 7, 99). CNP is present within the human kidney (62, 100) and has been found to have little effect on renal vasoconstriction (126). Although CNP has been reported to have natriuretic effects in some animals, when infused in humans at physiological concentrations and in concentrations that reached 4- to 10-fold above those observed in disease states, CNP did not affect renal function (6). Thus in healthy humans CNP had no effect on renal hemodynamics, systemic hemodynamics, intrarenal sodium handling, sodium excretion, or plasma levels of renin and aldosterone (6). In another study of infusion of CNP in healthy humans, CNP increased 60-fold in plasma and there were no significant hemodynamic or natriuretic effects (40). The authors of this study concluded that it is unlikely that CNP has any endocrine role in circulatory physiology (40). There is one study in humans where infusion of CNP to increase CNP plasma levels 550-fold caused a 1.5-fold increase in urinary volume and sodium excretion (42). With this very high plasma concentration of CNP, both ANP and BNP also increased 2.4-fold (42), which may have been the cause of the natriuresis and diuresis observed. Each of these studies suggests that CNP does not contribute physiologically to any natriuresis or diuresis in humans (6, 40, 42).

ADM

ADM, a 52-aa peptide originally isolated from an extract of a pheochromocytoma (48), also has biological properties nearly identical to those of the ANPs (Table 1) (43, 48, 86). Infusion of ADM lowers blood pressure and produces a diuresis and natriuresis (43, 48, 86). ANP but not LANP, vessel dilator, or kaliuretic hormone increases the circulating concentration of ADM three- to fourfold, suggesting that some of the reported effects of ANP may be mediated via ADM (107). However, the natriuresis and diuresis secondary to ANP in the above investigation were much larger than has ever been observed with ADM (107), suggesting that ADM does not mediate all of the natriuretic and diuretic effects of ANP. ADM is not produced in the atrium of the heart and therefore is not one of the ANPs per se as these peptides were so named because they are synthesized in the atrium of the heart (Table 1). ADM is a larger peptide than any of the ANPs, with its main site of synthesis being in the adrenal, but isolated renal cells also have the ability to synthesize ADM secondarily to stimulation by vasopressin via V2 receptors (Table 1) (88). Because vasopressin [antidiuretic hormone (ADH)] inhibits a diuresis, these findings are opposed to findings that ADM causes a diuresis (43, 48, 86).

Dendroaspis Natriuretic Peptide

Dendroaspis natriuretic peptide (DNP) is the newest of the natriuretic peptides. This peptide was isolated from the venom of the green mamba, Dendroaspis angusticeps (94). The venom also contains several polypeptide toxins that block cholinergenic receptors to cause paralysis (94). DNP-like peptide has been reported to be present in human plasma and in heart atria (91). In plasma, DNP's concentration is very low, i.e., 6 pg/ml, which is one-half of 1% of the circulating ANPs (91). This peptide has a 17-aa disulfide ring structure similar to ANP, BNP, and CNP (Fig. 2) and causes a natriuresis and diuresis in dogs (58). Infusion of DNP does not cause any significant change in the circulating levels of ANP, BNP, or CNP (58).

Richards et al. (81) have questioned whether DNP actually exists in humans and mammals because it has not been characterized by HPLC linked to immunoassay, followed by purification and analysis to establish the human amino acid sequence as has been done with the above natriuretic peptides. The gene for DNP has not been cloned in the snake or in any mammal as has been done for each of the other natriuretic peptides (81). Richards et al. suggest that DNP may be "snake BNP" because BNP varies markedly in amino acid sequence among species (and the BNP sequence in this snake is unknown). The peptides from the ANP prohormone are markedly conserved among species (36, 104), and one would not suspect that DNP is one of these peptides as their amino acid sequences are markedly different from DNP. Further experimentation with the above studies suggested by Richards et al. (81) should give us more insight with respect to this interesting peptide.


    IMMUNOCYTOCHEMICAL LOCALIZATION AT ANPs IN THE KIDNEY
 TOP
 ABSTRACT
 ANPs
 IMMUNOCYTOCHEMICAL LOCALIZATION...
 INFLUENCE OF ARF ON...
 PROTECTIVE AND THERAPEUTIC...
 SUMMARY AND FUTURE DIRECTIONS
 REFERENCES
 
The kidney is a prime target organ (along with vasculature) of the physiological effects of ANPs (10, 56, 104). Immunohistochemical studies have localized ANP, vessel dilator, and LANP to the sub-brush border of the pars convuluta and pars recta of the proximal tubules of animal (79) and human (85) kidneys (Fig. 3). Immunofluorescent studies reveal that each of these peptides has a strong inclination for the perinuclear region in both the proximal and distal tubules (79, 85). Immunohistochemical studies localize urodilatin to the distal tubule, with no evidence of urodilatin in the proximal tubule (85). ANP mRNA studies have confirmed that ANP prohormone is synthesized in the kidney (34, 76, 97, 102). The amount of ANP prohormone present in the kidney, however, is only one one-ninetieth of that produced in the atria of the heart (104). These studies taken together suggest that because urodilatin (93) is found mainly in the distal nephron (82, 85) and because it is part of the ANP prohormone (104), synthesis of the ANP prohormone may take place in the distal nephron (82, 85). The ANP prohormone gene is present and can be expressed in the kidney (34, 76, 97, 102). The gene is upregulated within the kidney in early renal failure in diabetic animals (34) and in the remnant kidney of rats with 5/6 reduced renal mass (102).



View larger version (111K):
[in this window]
[in a new window]
 
Fig. 3. Vessel dilator immunoperoxidase staining in the rat kidney reveals strong staining of the sub-brush border of proximal convoluted tubules (arrowheads in A and B), including a proximal tubule (A) originating directly from the top left portion of the glomerulus. The interstitial artery (C) had strong proANP-(31—67) staining of the elastica with moderate staining of endothelial cells (arrow) and media (*). The distal tubules and collecting ducts (arrows in A and B) had weak staining with no demonstrable staining in some of the collecting duct cells. Magnification: x940. Reprinted by permission (Blackwell Publishing, Ltd., 1992) (79).

 


    INFLUENCE OF ARF ON THE CIRCULATING CONCENTRATION OF ANPs
 TOP
 ABSTRACT
 ANPs
 IMMUNOCYTOCHEMICAL LOCALIZATION...
 INFLUENCE OF ARF ON...
 PROTECTIVE AND THERAPEUTIC...
 SUMMARY AND FUTURE DIRECTIONS
 REFERENCES
 
Each of the ANPs from the ANP prohormone (30, 41, 50, 70, 114, 123, 124), BNP (13, 16, 21, 54, 55), and CNP (7, 40, 42) increases in the circulation in salt- and water-retaining states such as congestive heart failure and renal failure compared with their concentrations in healthy individuals. Thus in salt- and water-retaining states there is no decrease in production of these natriuretic and diuretic peptides, but rather there is increased production (mainly from the ventricle of the heart) (32, 76) in an apparent attempt to overcome the salt and water retention via their natriuretic and diuretic properties (123). The disease state associated with the highest circulating concentrations of ANPs is renal failure (29, 30, 89, 122, 124). One would suspect that ANPs are higher in renal failure vs. class IV congestive heart failure patients because of the added pathophysiology of decreased degradation of these peptides with the decreased functioning of renal parenchyma (124). However, Franz et al. (30) have shown that there is an increased excretion of ANPs in renal failure and that the increase in vessel dilator excretion occurs even before serum creatinine levels begin to rise. The circulating concentrations of ANPs in chronic renal failure (CRF) appear to reflect volume status (50, 66, 80, 124). Despite increased circulating ANPs in sodium-retaining disease states, the kidney retains sodium and is hyporesponsive to ANP, LANP, and BNP (11, 54, 77, 109). The mechanism for the attenuated renal response to these natriuretic peptides is multifactoral and includes renal hypoperfusion and activation of the renin-angiotensin-aldosterone and sympathetic nervous systems (10, 36, 65).

Hemodialysis

ANPs. These peptides have been suggested as possible indicators of when to perform dialysis in persons with CRF (50, 66, 80, 89, 124). However, other data suggest that ANPs are not useful in predicting when hemodialysis is necessary (29). Hemodialysis lowers the circulating concentration of ANP by 34–42%, with the amount of decrease appearing to be related to the volume status of the patients (50, 121, 124). Hemodialysis does not decrease the circulating concentrations of vessel dilator and LANP (124). Part of the reason for the difference in the effects of hemodialysis on ANPs is that <1.5% of vessel dilator and LANP crosses the dialysis membrane compared with 15–25% of ANP crossing hemodialysis membranes (124). Hemodialysis using cellulose-triacete dialyzers reduces plasma levels of these peptides in ARF more than hemodialysis therapy with polysulfone dialyzers (29).

BNP. Hemodialysis has been reported to both lower (55) and have no effect on circulating BNP levels (49). Before dialysis in persons with CRF, plasma BNP levels have no relationship to serum creatinine or mean blood pressure (55). In those CRF patients in whom plasma BNP levels decrease with dialysis, this decrease correlates with the degree of postural blood pressure drop, but there is no correlation with the fall in serum creatinine (55). In none of the studies of BNP and dialysis (13, 21, 49, 55) has BNP ever returned to its circulating concentration in healthy individuals. With volume repletion after hemodialysis, there is an exaggerated release of ANP, but changes in BNP are small and without any correlation with either atrial or ventricular volume (21).

Renal Transplantation

Successful transplantation of functioning kidneys decreases the markedly elevated circulating levels of ANPs in persons with ARF to those in healthy individuals (75, 78). Nonfunctioning renal allografts continue to have elevated circulating concentrations of ANPs (78). Postrenal transplantion, it takes 7 days for ANP and 10 days for vessel dilator to return to normal (75). 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 2.5–3.5 min (1, 104). 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 20-fold longer half-life compared with that of ANP (1, 104), 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 transplantion, this does not appear to have any beneficial effect on the outcome of the renal allograft (87).


    PROTECTIVE AND THERAPEUTIC EFFECTS OF ANPs IN ARF
 TOP
 ABSTRACT
 ANPs
 IMMUNOCYTOCHEMICAL LOCALIZATION...
 INFLUENCE OF ARF ON...
 PROTECTIVE AND THERAPEUTIC...
 SUMMARY AND FUTURE DIRECTIONS
 REFERENCES
 
ANP and Urodilatin

Several of the atrial peptides have been investigated as possible treatment(s) of ARF. ANP had encouraging results in early studies of ARF in animals (20, 57). The infusion of ANP (20, 57, 60, 66, 68, 71, 74, 77, 90, 95) or urodilatin (63, 92, 96) in rat models of ischemic ARF attenuated renal tissue damage and preserved glomerular filtration rate (GFR). Nakamoto et al. (68) and Shaw et al. (95) were able to shorten the course of renal artery cross-clamping-induced ARF in rats with ANP. Conger et al. (20) found a marked improvement in GFR in a rat renal artery clamp model when ANP-III (0.2 µg·kg1·min1) was given intravenously immediately after clamp release in combination with dopamine sufficient to maintain mean arterial pressure above 100 mmHg. In the rat, ANP had no effect on GFR when given intravenously (56) but did have an effect on GFR when given directly into the renal artery for 4 h (95). The inability of ANP to increase GFR when given intravenously could be restored if dopamine were given simultaneously (20). In the dog, the improvement in renal perfusion only lasted for a short period after a 180-min infusion of ANP (71). When ANP was given by intra-arotic bolus on days 1 and 2 after the above-mentioned infusion, there was not any significant improvement in renal perfusion on those days (71). Thus in animals the improvement in renal failure with ANP was only of short duration and depended on whether ANP was given intravenously or directly into the artery (20, 56, 71).

The administration of 0.2 µg of ANP·kg body wt1·min1 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 (3). ANP infusions were associated with decreased survival in the nonoliguric ARF subjects, who represented 75% of the subjects (3). The usefulness of ANP for treatment is hampered by its short half-life of 2.5 min (1, 104) and by its very short duration of action (20, 57, 59, 61, 77, 112). Of 504 ARF patients treated with ANP, 46% developed hypotension, which would further limit its usefulness in ARF (3). Use of several of the ANPs investigated to treat ARF has each resulted in severe hypotension and bradycardia (3, 47). In addition to ANP resulting in 46% of renal failure patients becoming hypotensive (3), urodilatin has also been associated with severe hypotension and bradycardia, when given as a potential treatment of congestive heart failure (47). ANP is now considered more harmful than helpful with respect to the treatment of ARF (11). ANP has also been investigated in humans with CRF to determine whether it could prevent radiocontrast-induced nephropathy, one cause of hospital-acquired ARF (52). When ANP was given before and during a radiocontrast study in 247 patients, no beneficial effect was found (52). Urodilatin has been suggested as a possible treatment of renal failure (63, 92, 96), but in double-blind trials in ARF patients urodilatin was found to have no beneficial effect (63).

Vessel Dilator

Vessel dilator appears to be one of the ANPs with promising therapeutic potential in the treatment of ARF. Vessel dilator (0.3 µg·kg1·min1 via ip pump) decreases blood urea nitrogen and serum creatinine from 162 ± 4 and 8.17 ± 0.5 mg/dl, respectively, to 53 ± 17 and 0.98 ± 0.12 mg/dl in ARF animals in which ARF was established for 2 days (after vascular clamping) before vessel dilator was given (19). At day 6 of ARF, mortality decreased to 14% with vessel dilator from 88% without vessel dilator (19). 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) ATN by day 8 after the ischemic event (Fig. 4B). As shown in Fig. 4B, the tubules of the 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. 4B). The glomerulus of the ARF animals was spared compared with the renal tubules, with the glomerulus appearing to be normal in the ARF animals (Fig. 4, A and B).



View larger version (102K):
[in this window]
[in a new window]
 
Fig. 4. Renal histology of a normal Sprague-Dawley rat (A) with intact proximal tubular brush border (arrowhead). B: acute renal failure (ARF) rat at day 8 with marked tubular necrosis (open triangle) and without intact brush border present (>75% of tubules are necrotic). The glomerulus (x) appears to be normal. C: ARF rat treated with vessel dilator from days 2–5 of ARF with kidney examined after day 8 of ARF reveals brush border to be present in proximal tubule (arrowhead). No tubules are necrotic in this ARF animal treated with vessel dilator. The glomerulus (x) is intact. Magnification of hematoxylin and eosin: x426 (A and C) and x320 (B). Reprinted from Ref. 19.

 

The addition of vessel dilator after renal failure had been present for 2 days resulted in a marked improvement in renal histology, with scores ranging from 0 (i.e., no tubular necrosis) to 1+ (i.e., <5% of the tubules involved) (19). When the kidneys were examined at day 8 of renal failure, the brush borders of the proximal tubules in the ARF animals treated with vessel dilator were present (Fig. 4C), which was similar with respect to the proximal tubules in healthy animals (Fig. 4A). In the ARF animals not treated with vessel dilator, the brush borders of the tubules were destroyed (Fig. 4B). The glomeruli of vessel dilator-treated ARF animals also appeared normal (Fig. 4C). 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 (19). It is also important to note that the animals treated with vessel dilator that had a significant increase in survival had nonoliguric renal failure (19). As noted above, nonoliguric renal failure subjects treated with ANP had a decreased survival rate, and it was nonoliguric renal failure subjects who did not respond to ANP (3). Vessel dilator, LANP, and kaliuretic peptide, as opposed to ANP, BNP, and urodilatin, have never caused a hypotensive episode when given to either healthy animals or humans (61, 111, 112) or when given to humans with sodium and water retention (70, 109, 110).

The ability of vessel dilator to reverse ischemic ARF is consistent with the important concept, based on experiments at the cellular level and in humans with ATN, that the pathophysiology of ischemic ARF is due to a sublethal and reversible injury to renal tubular cells (9, 64). This reversible injury is now thought to contribute more predominately to renal tubular dysfunction than permanent tubular cell necrosis (9, 64). Pathological similarities between humans and rats with ischemic ATN are that the injury is to the proximal brush border, with a predilection for the most severe injury to occur in the proximal straight (S3 segments) tubules (64). As outlined above, it was the proximal tubule brush borders that were mainly regenerated by vessel dilator even when given 2 days after ischemic ATN (19). Part of the improvement by using vessel dilator may be due to its ability to cause intrarenal vasodilation because it is a strong vasodilator (113). The reason vessel dilator has greater benefical effects than ANP, BNP, CNP, and urodilatin in ARF appears due, at least in part, to its ability to cause the endogenous synthesis of renoprotective PGE2, which ANP, BNP, CNP, and urodilatin do not have (18, 35).

Prostaglandins have renoprotective effects in ARF (2, 46, 121). An indication that PGE2 is renoprotective (by maintaining glomerular hemodynamics) is the observation that cyclooxygenase inhibitors in congestive heart failure and volume depletion states augment the reduction in renal blood flow and GFR (27, 120). With respect to the mechanism of the protective effects of prostaglandins in ARF, after ischemic injury there is a dramatic decrease in perfusion in the outer medulla (44), a region of renal tissue that normally operates "on the verge of ischemia" (12). Prostaglandins have a favorable effect on blood flow distribution to this region (67). In addition, prostaglandins have distinct cytoprotective effects and improve microvascular permeability in ischemic ARF (15, 46). Prostaglandins are not stored in the kidney but rather have to be synthesized acutely secondarily to a stimulating agent such as vessel dilator (18, 35) for prostaglandins to have a positive beneficial effect in renal failure.

ADM

There is evidence that ADM is renoprotective in Dahl salt-sensitive rats in that when they were perfused for 7 days, their glomerular injury score was 54% less (P < 0.05) than in untreated Dahl salt-sensitive rats (72). The ADM-treated salt-sensitive rats, however, had considerably more (P < 0.01) glomerular sclerosis and anteriolar sclerosis and atrophic tubules after treatment than the control Dahl salt-resistant rats (72).

CNP

CNP increases in the circulation in ARF (42), but its effects in ARF are unknown. As above, CNP has no natriuretic effects in healthy humans (6, 40, 42).

DNP

DNP has been evaluated in persons with end-stage renal disease on dialysis and was found not to correlate (P = 0.62) with the echocardiographic left ventricular mass index, whereas ANP and BNP did correlate with the left ventricular mass index of these end-stage renal patients (16). DNP has not been investigated with respect to its possible therapeutic effects in renal failure.


    SUMMARY AND FUTURE DIRECTIONS
 TOP
 ABSTRACT
 ANPs
 IMMUNOCYTOCHEMICAL LOCALIZATION...
 INFLUENCE OF ARF ON...
 PROTECTIVE AND THERAPEUTIC...
 SUMMARY AND FUTURE DIRECTIONS
 REFERENCES
 
ANPs are both synthesized (34, 76, 102), and have some of their most potent biological effects, e.g., natriuresis and diuresis, within the kidney (8, 25, 26, 35, 37, 61, 118, 127). Vessel dilator, via its ability to ameliorate ARF and enhance tubule regeneration in ATN (19), may prove useful in the future in the treatment of ARF. BNP and ADM, with their effects in glomerular hypertrophy (45) and glomerular injury (72), respectively, may be useful in the treatment of renal glomerular diseases. Because BNP, ANP, and ADM do not appear to help tubular diseases such as ATN, the major cause of ARF (39, 125), their therapeutic potential in ATN appears limited. Future studies with these peptide hormones in humans with ARF and/or glomerular diseases are necessary to determine whether the findings in animal models of ARF are applicable to the treatment of humans with ARF.


    DISCLOSURES
 
This work was supported in part by grants from the National Institutes of Health, a Merit Award from the U.S. Department of Veteran Affairs, and a Grant-in-Aid from the American Heart Association, Florida-Puerto Rico Affiliate.


    ACKNOWLEDGMENTS
 
The author thanks Charlene Pennington for secretarial assistance and the numerous coinvestigators without whom all of the investigations reported herein could not have been completed.


    FOOTNOTES
 

Address for reprint requests and other correspondence: D. L. Vesely, USF Cardiac Hormone Ctr., 13000 Bruce B. Downs Blvd., Tampa, FL 33612 (E-mail: david.vesely{at}med.va.gov).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


    REFERENCES
 TOP
 ABSTRACT
 ANPs
 IMMUNOCYTOCHEMICAL LOCALIZATION...
 INFLUENCE OF ARF ON...
 PROTECTIVE AND THERAPEUTIC...
 SUMMARY AND FUTURE DIRECTIONS
 REFERENCES
 

  1. Ackerman BH, Overton RM, McCormick MT, Schocken DD, and Vesely DL. Disposition of vessel dilator and long-acting natriuretic peptide in healthy humans after a one-hour infusion. J Pharmacol Exp Therap 282: 603–608, 1997.[Abstract/Free Full Text]
  2. Agmon Y, Peleg H, Greenfeld Z, Rosen S, and Brezis M. Nitric oxide and prostanoids protect the renal outer medulla from radiocontrast toxicity in the rat. J Clin Invest 94: 1069–1075.
  3. Allgren RL, Marbury TC, Rahman SN, Weisberg LS, Fenves AZ, Lafayette RA, Sweet RM, Genter FC, Kurnik BRC, Conger JD, and Sayegh MH. Anaritide in acute tubular necrosis. N Engl J Med 336: 828–834, 1997.[Abstract/Free Full Text]
  4. Anderson RJ and Schrier RW. Acute renal failure. In: Diseases of the Kidney and Urinary Tract (7th ed.), edited by Schrier RW. Philadelphia, PA: Lippincott Williams & Wilkins, 2001, p. 1093–1136.
  5. Atarashi K, Mulrow PJ, Franco-Saenz R, Snajdar R, and Rapp J. Inhibition of aldosterone production by an atrial extract. Science 224: 992–994, 1984.[ISI][Medline]
  6. Barletta G, Lazzeri C, Vecchiarino S, Del Bene R, Messeri G, Dello Sbarba A, Mannelli M, and LaVilla G. Low-dose C-type natriuretic peptide does not affect cardiac and renal function in humans. Hypertension 31: 802–808, 1988.[Medline]
  7. Barr CS, Rhodes P, and Struthers AD. C-type natriuretic peptide. Peptides 17: 1243–1251, 1996.[ISI][Medline]
  8. Benjamin BA and Peterson TV. Effects of proANF-(31–67) on sodium excretion in conscious monkeys. Am J Physiol Regul Integr Comp Physiol 269: R1351–R1355, 1995.[Abstract/Free Full Text]
  9. Brady HR, Brenner BM, Clarkson MR, and Lieberthal W. Acute renal failure. In: Brenner & Rector's The Kidney (6th ed.), edited by Brenner BM. Philadelphia, PA: Saunders, 2000, p. 1201–1262.
  10. Brenner BM, Ballermann BJ, Gunning ME, and Zeidel ML. Diverse biological actions of atrial natriuretic peptide. Physiol Rev 70: 665–699, 1990.[Free Full Text]
  11. Brenner RM and Chertow GM. The rise and fall of atrial natriuretic peptide for acute renal failure. Curr Opin Nephrol Hypertens 6: 474–476, 1997.[ISI][Medline]
  12. Brezis M, Rosen S, Silva P, and Epstein FH. Renal ischemia: a new perspective. Kidney Int 26: 375–383, 1984.[ISI][Medline]
  13. Buckley MG, Sethi D, Markandu ND, Sagnella GA, Sincer DR, and MacGregor GA. Plasma concentrations and comparisons of brain natriuretic peptide and atrial natriuretic peptide in normal subjects, cardiac transplant recipients and patients with dialysis-independent or dialysis-dependent chronic renal failure. Clin Sci (Colch) 83: 437–444, 1992.[ISI][Medline]
  14. Burnett JC Jr, Granger JP, and Opgenorth TJ. Effects of synthetic atrial natriuretic factor on renal function and renin release. Am J Physiol Renal Fluid Electrolyte Physiol 247: F863–F866, 1984.[Abstract/Free Full Text]
  15. Casey KF, Machiedo GW, Lyons MJ, Slotman GJ, and Novak RT. Alteration of postischemic renal pathology by prostaglandin infusion. J Surg Res 29: 1–10, 1980.[ISI][Medline]
  16. Cataliotti A, Malatino LS, Jougasaki M, Zoccali C, Castellino P, Giacone G, Bellanuova I, Tripepi R, Seminara G, Parlongo S, Stancanelli B, Bonanno G, Fatuzzo P, Rapisarda F, Belluardo P, Signorelli SS, Heublein DM, Lainchbury JG, Leskinen HK, Bailey KR, Redfield MM, and Burnett JC Jr. Circulating natriuretic peptide concentrations in patients with end-state renal disease: role of brain natriuretic peptide as a biomarker for ventricular remodeling. Mayo Clin Proc 76: 1111–1119, 2001.[ISI][Medline]
  17. Chartier L, Schiffrin E, and Thibault G. Effect of atrial natriuretic factor (ANF)-related peptides on aldosterone secretion by adrenal glomerulosa cells: critical role of the intramolecular disulphide bond. Biochem Biophys Res Commun 122: 171–174, 1984.[ISI][Medline]
  18. Chiou S and Vesely DL. Kaliuretic peptide: the most potent inhibitor of Na+-K+-ATPase of the atrial natriuretic peptides. Endocrinology 136: 2033–2039, 1995.[Abstract]
  19. Clark LC, Farghaly H, Saba SR, and Vesely DL. Amelioration with vessel dilator of acute tubular necrosis and renal failure established for 2 days. Am J Physiol Heart Circ Physiol 278: H1555–H1564, 2000.[Abstract/Free Full Text]
  20. Conger JD, Falk SA, Yuan BH, and Schrier RW. Atrial natriuretic peptide and dopamine in a rat model of ischemic acute renal failure. Kidney Int 35: 1126–1132, 1989.[ISI][Medline]
  21. Corboy JC, Walker RJ, Simmonds MB, Wilkins GT, Richards AM, and Espiner EA. Plasma natriuretic peptides and cardiac volume during acute changes in intravascular volume in haemodialysis patients. Clin Sci (Colch) 87: 679–684, 1994.[ISI][Medline]
  22. Davidman M, Olson P, Kohen J, Leither T, and Kjellstrand C. Iatrogenic renal disease. Arch Intern Med 151: 1809–1812, 1991.[Abstract]
  23. De Lean A, Gutkowska J, McNicoll N, Schiller PW, Cantin M, and Genest J. Characterization of specific receptors for atrial natriuretic factor in bovine adrenal zona glomerulosa. Life Sci 35: 2311–2318, 1984.[ISI][Medline]
  24. De Palo EF, Woloszczuk W, Meneghetti M, DePalo CB, Nielsen HB, and Secher NH. Circulating immunoreactive proANP (1–30) and proANP (31–67) in sedentary subjects and athletes. Clin Chem 46: 843–847, 2000.[Abstract/Free Full Text]
  25. Dietz JR, Scott DY, Landon CS, and Nazian SJ. Evidence supporting a physiological role for pro ANP (1–30) in the regulation of renal excretion. Am J Physiol Regul Integr Comp Physiol 280: R1510–R1517, 2001.[Abstract/Free Full Text]
  26. Dietz JR, Vesely DL, Gower WR Jr, and Nazian SJ. Secretion and renal effects of ANF prohormone peptides. Clin Exp Pharmacol Physiol 22: 115–120, 1995.[ISI][Medline]
  27. Fink MP, Mac Vittie TJ, and Casey LC. Effects of nonsteroidal anti-inflammatory drugs on renal function in septic dogs. J Surg Res 36: 516–525, 1984.[ISI][Medline]
  28. Flynn TG. Past and current perspectives on the natriuretic peptides. Proc Soc Exp Biol Med 213: 98–104, 1996.[Medline]
  29. Franz M, Woloszczuk W, and Horl WH. N-terminal fragments of the proatrial natriuretic peptide in patients before and after hemodialysis treatment. Kidney Int 58: 374–378, 2000.[ISI][Medline]
  30. Franz M, Woloszczuk W, and Horl WH. Plasma concentration and urinary excretion of N-terminal proatrial natriuretic peptides in patients with kidney diseases. Kidney Int 59: 1928–1934, 2001.[ISI][Medline]
  31. Gardner DG, Deschepper CT, Ganong WF, Hane S, Fiddes J, Baxter JD, and Lewicki J. Extra-atrial expression of the gene for atrial natriuretic factor. Proc Natl Acad Sci USA 83: 6697–6701, 1986.[Abstract]
  32. Gardner DG, Kovacic-Milivojevic BK, and Garmai M. Molecular biology of the natriuretic peptides. In: Atrial Natriuretic Peptides, edited by Vesely DL. Trivandrum, India: Research Signpost, 1997, p. 15–38.
  33. Goodfriend TL, Elliott ME, and Atlas SA. Actions of synthetic atrial natriuretic factor on bovine adrenal glomerulosa. Life Sci 35: 1675–1682, 1984.[ISI][Medline]
  34. Gower WR Jr, San Miguel GI, Carter GM, Hassan I, Farese RV, and Vesely DL. Enhanced atrial natriuretic prohormone gene expression in cardiac and extracardiac tissues of type II diabetic Goto-Kakizaki rat. Mol Cell Biochem. In press.
  35. Gunning ME, Brady HR, Otuechere G, Brenner BM, and Zeidel ML. Atrial natriuretic peptide (31–67) inhibits Na+ transport in rabbit inner medullary collecting duct cells: role of prostaglandin E2. J Clin Invest 89: 1411–1417, 1992.[ISI][Medline]
  36. Gunning ME and Brenner BM. Natriuretic peptides and the kidney: current concepts. Kidney Int 42, Supp 38: S127–S133, 1992.
  37. Habibullah AA, Villarreal D, Freeman RH, Dietz JR, Vesely DL, and Simmons JC. Atrial natriuretic peptide fragments in dogs with experimental heart failure. Clin Exp Pharmacol Physiol 22: 130–135, 1995.[ISI][Medline]
  38. Hock R and Anderson RJ. Prevention of drug-induced nephrotoxicity in the intensive care unit. J Crit Care 10: 33–43, 1995.[ISI][Medline]
  39. Hou SH, Bushinsky DA, Wish JB, Cohen JJ, and Harrington JT. Hospital acquired renal insufficiency: a prospective study. Am J Med 74: 243–248, 1983.[ISI][Medline]
  40. Hunt PJ, Richards AM, Espiner EA, Nicholls MG, and Yandle TG. Bioactivity and metabolism of C-type natriuretic peptide in normal man. J Clin Endocrinol Metab 78: 1428–1435, 1994.[Abstract]
  41. Hunter EFM, Kelly PA, Prowse C, Woods FJ, and Lowry PJ. Analysis of peptides derived from pro atrial natriuretic peptide that circulate in man and increase in heart disease. Scan J Clin Lab Invest 58: 205–216, 1998.[ISI][Medline]
  42. Igaki T, Itoh H, Suga S, Hama N, Ogawa Y, Komatsu Y, Mukoyama M, Sugawara A, Yoshimasa T, Tanaka I, and Nakao K. C-type natriuretic peptide in chronic renal failure and its action in humans. Kidney Int 49, Suppl 55: S144–S147, 1996.
  43. Jougasaki M and Burnett JC Jr. Adrenomedullin: potential in physiology and pathophysiology. Life Sci 66: 855–872, 2000.[ISI][Medline]
  44. Karlberg L, Norlen BJ, Ojteg G, and Wolgast M. Impaired medullary circulation in postischemic acute renal failure. Acta Physiol Scan 118: 11–17, 1983.[ISI][Medline]
  45. Kasahara M, Mukoyama M, Sugawara A, Makino H, Suganami T, Ogawa Y, Nakagawa M, Yahata K, Goto M, Ishibashi R, Tamura N, Tanaka I, and Nakao K. Ameliorated glomerular injury in mice over expressing brain natriuretic peptide with renal ablation. J Am Soc Nephrol 11: 1691–1701, 2000.[Abstract/Free Full Text]
  46. Kaufman RP Jr, Anner H, Kobzik L, Valeri CR, Shepro D, and Hechtman HB. Vasodilator prostaglandins (PG) prevent renal damage after ischemia. Ann Surg 205: 195–198, 1987.[ISI][Medline]
  47. Kentsch M, Drummer C, Gerzer R, and Muller-Esch G. Severe hypotension and bradycardia after continuous intravenous infusion of urodilatin (ANP 95–126) in a patient with congestive heart failure. Eur J Clin Invest 25: 281–283, 1995.[ISI][Medline]
  48. Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, and Eto T. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun 192: 553–560, 1993.[ISI][Medline]
  49. Kohse KP, Feifel K, and Mayer-Wehrstein R. Differential regulation of brain and atrial natriuretic peptides in hemodialysis patients. Clin Nephrol 40: 83–90, 1993.[ISI][Medline]
  50. Kojima S, Inoue I, Hirata Y, Kimura G, Saito F, Kawano Y, Satani M, Ito K, and Omae T. Plasma concentrations of immunoreactive-atrial natriuretic polypeptide in patients on hemodialysis. Nephron 46: 45–48, 1987.[ISI][Medline]
  51. Kudo T and Baird A. Inhibition of aldosterone production in the adrenal glomerulosa by atrial natriuretic factor. Nature 312: 756–757, 1984.[ISI][Medline]
  52. Kurnik BR, Allgren RL, Genter FC, Solomon RJ, Bates ER, and Weisberg LS. Prospective study of atrial natriuretic peptide for the prevention of radiocontrast-induced nephropathy. Am J Kidney Dis 31: 674–680, 1998.[ISI][Medline]
  53. Kurtz A, Della Bruna R, Pfeilschifter J, Taugner R, and Bauer C. Atrial natriuretic peptide inhibits renin release from juxtaglomerular cells by cGMP-mediated process. Proc Natl Acad Sci USA 83: 4769–4773, 1986.[Abstract]
  54. Lainchbury J, Richards AM, and Nicholls MG. Brain natriuretic peptide in heart failure. In: Atrial Natriuretic Peptides, edited by Vesely DL. Trivandrum, India: Research Signpost, 1997, p. 151–158.
  55. Lang CC, Choy AM, Henderson IS, Coutie WJ, and Struthers AD. Effect of haemodialysis on plasma levels of brain natriuretic peptide in patients with chronic renal failure. Clin Sci (Colch) 82: 127–131, 1992.[ISI][Medline]
  56. Levin ER, Gardner DG, and Samson WK. Natriuretic peptides. N Engl J Med 339: 321–328, 1998.[Free Full Text]
  57. Lieberthal W, Sheridan AM, and Valeri CR. Protective effect of atrial natriuretic factor and mannitol following renal ischemia. Am J Physiol Renal Fluid Electrolyte Physiol 258: F1266–F1272, 1990.[Abstract/Free Full Text]
  58. Lisy O, Jougasaki M, Heublein DM, Schirger JA, Chen HH, Wennberg PW, and Burnett JC. Renal actions of synthetic dendroaspis natriuretic peptide. Kidney Int 56: 502–508, 1999.[ISI][Medline]
  59. Maack T, Marion DN, Camargo MJ, Kleinert HD, Laragh JH, Vaughan ED Jr, and Atlas SA. Effects of auriculin (atrial natriuretic factor) on blood pressure, renal function, and the renin-aldosterone system in dogs. Am J Med 77: 1069–1075, 1984.[ISI][Medline]
  60. Marin-Grez M, Fleming JT, and Steinhausen M. Atrial natriuretic petpide causes pre-glomerular vasodilatation and post-glomerular vasoconstriction in rat kidney. Nature 324: 473–476, 1986.[ISI][Medline]
  61. Martin DR, Pevahouse JB, Trigg DJ, Vesely DL, and Buerkert JE. Three peptides from the ANF prohormone NH2-terminus are natriuretic and/or kaliuretic. Am J Physiol Renal Fluid Electrolyte Physiol 258: F1401–F1408, 1990.[Abstract/Free Full Text]
  62. Mattingly MT, Brandt RR, Heublein DM, Wei CM, Nir A, and Burnett JC Jr. Presence of C-type natriuretic peptide in human kidney and urine. Kidney Int 46: 744–747, 1994.[ISI][Medline]
  63. Meyer M, Pfarr E, Schirmer G, Uberbacher HJ, Schope K, Bohm E, Fluge T, Mentz P, Scigalla P, and Forssmann WG. Therapeutic use of the natriuretic peptide ularitide in acute renal failure. Ren Fail 21: 85–100, 1999.[ISI][Medline]
  64. Molitoris BA, Meyer C, Dahl R, and Geerdes A. Mechanism of ischemia-enhanced aminoglycoside binding and uptake by proximal tubule cells. Am J Physiol Renal Fluid Electrolyte Physiol 264: F907–F916, 1993.[Abstract/Free Full Text]
  65. Morgan DA, Peuler JD, Koepke JP, Mark AL, and DiBona GF. Renal sympathetic nerves attenuate the natriuretic effects of atrial peptide. J Lab Clin Med 114: 538–544, 1989.[ISI][Medline]
  66. Morrissey EC, Wilner KD, Barager RR, Ward DM, and Ziegler MG. Atrial natriuretic factor in renal failure and posthemodialytic postural hypotension. Am J Kidney Dis 12: 510–515, 1988.[ISI][Medline]
  67. Moskowitz PS, Korobkin M, and Rambo ON. Diuresis and improved renal hemodynamics produced by prostaglandin E1 in the dog with norepinephrine-induced acute renal failure. Invest Radiol 10: 284–299, 1975.[ISI][Medline]
  68. Nakamoto M, Shapiro JI, Shanley PF, Chan L, and Schrier RW. In vitro and in vivo protective effect of atriopeptin III on ischemic acute renal failure. J Clin Invest 80: 698–705, 1987.[ISI][Medline]
  69. Nakao K, Ogawa Y, Suga S, and Imura H. Molecular biology and biochemistry of the natriuretic peptide system. I. Natriuretic peptides. J Hypertens 10: 907–912, 1992.[ISI][Medline]
  70. Nasser A, Dietz JR, Siddique M, Patel H, Khan N, Antwi EK, San Miguel GI, McCormick MT, Schocken DD, and Vesely DL. Effects of kaliuretic peptide on sodium and water excretion in persons with congestive heart failure. Am J Cardiol 88: 23–29, 2001.[ISI][Medline]
  71. Neumayer HH, Blossei N, Seherr-Thohs U, and Wagner K. Amelioration of postischaemic acute renal failure in conscious dogs by human atrial natriuretic peptide. Nephrol Dial Transplant 5: 32–38, 1990.[Abstract]
  72. Nishikimi T, Mori Y, Kobayashi N, Tadokoro K, Wang X, Akimoto K, Yoshihara F, Kangawa K, and Matsuoka H. Renoprotective effect of chronic adrenomedullin infusion in Dahl salt-sensitive rats. Hypertension 39: 1077–1082, 2002.[Abstract/Free Full Text]
  73. Ogawa Y, Itoh H, and Nakao K. Molecular biology and biochemistry of natriuretic peptide family. Clin Exp Pharmacol Physiol 22: 49–53, 1995.[ISI][Medline]
  74. Ortola FV, Ballermann BJ, and Brenner BM. Endogenous ANP augments fractional excretion of Pi, Ca, and Na in rats with reduced renal mass. Am J Physiol Renal Fluid Electrolyte Physiol 255: F1091–F1097, 1988.[Abstract/Free Full Text]
  75. Pevahouse JB, Flanigan WJ, Winters CJ, and Vesely DL. Normalization of elevated circulating N-terminal and C-terminal atrial natriuretic factor prohormone concentrations by renal transplantations. Transplantation 53: 1375–1377, 1992.[ISI][Medline]
  76. Poulos JE, Gower WR Jr, Sullebarger JT, Fontanet HL, and Vesely DL. Congestive heart failure: Increased cardiac and extracardiac atrial natriuretic peptide gene expression. Cardiovasc Res 32: 909–919, 1996.[ISI][Medline]
  77. Rahman SN, Kim GE, Mathew AS, Goldberg CA, Allgren R, Schrier RW, and Conger JD. Effects of atrial natriuretic peptide in clinical acute renal failure. Kidney Int 45: 1731–1738, 1994.[ISI][Medline]
  78. Raine AE, Anderson JV, Bloom SR, and Morris PJ. Plasma atrial natriuretic factor and graft function in renal transplant recipients. Transplantation 48: 796–800, 1989.[ISI][Medline]
  79. Ramirez G, Saba SR, Dietz JR, and Vesely DL. Immunocytochemical localization of proANF1–30, proANF 31–67, and atrial natriuretic factor in the kidney. Kidney Int 41: 334–341, 1992.[ISI][Medline]
  80. Rascher W, Tulassay T, and Lang RE. Atrial natriuretic peptide in plasma of volume-overloaded children with chronic renal failure. Lancet 2: 303–305, 1985.[ISI][Medline]
  81. Richards AM, Lainchbury JG, Nicholls MG, Cameron AV, and Yandle TG. Dendroaspis natriuretic peptide: endogenous or dubious? Lancet 359: 5–6, 2002.[ISI][Medline]
  82. Ritter D, Chao J, Needleman P, Tetens E, and Greenwald JE. Localization, synthetic regulation, and biology of renal atriopeptin-like prohormone. Am J Physiol Renal Fluid Electrolyte Physiol 263: F503–F509, 1992.[Abstract/Free Full Text]
  83. Rosenzweig A and Seidman CE. Atrial natriuretic factor and related peptide hormones. Annu Rev Biochem 60: 229–255, 1991.[ISI][Medline]
  84. Ruskoaho H. Atrial natriuretic peptide: synthesis, release, and metabolism. Pharmacol Rev 44: 479–602, 1992.[ISI][Medline]
  85. Saba SR, Ramirez G, and Vesely DL. Immunocytochemical localization of ProANF 1–30, ProANF 31–67, atrial natriuretic factor and urodilatin in the human kidney. Am J Nephrol 13: 85–93, 1993.[ISI][Medline]
  86. Samson WK. Adrenomedullin and the control of fluid and electrolyte homeostasis. Annu Rev Physiol 61: 363–389, 1999.[ISI][Medline]
  87. Sands JM, Neylan JF, Olson RA, O'Brien DP, Whelchel JD, and Mitch WE. Atrial natriuretic factor does not improve the outcome of cadaveric renal transplantation. J Am Soc Nephrol 1: 1081–1086, 1991.[Abstract]
  88. Sato K, Imai T, Iwashina M, Marumo F, and Hirata Y. Secretion of adrenomedullin by renal tubular cell lines. Nephron 78: 9–14, 1998.[ISI][Medline]
  89. Saxenhofer H, Gnadinger MP, Weidmann P, Shaw S, Schohn D, Hess C, Uehlinger DE, and Jahn H. Plasma levels and dialysance of atrial natriuretic peptide in terminal renal failure. Kidney Int 32: 554–561, 1987.[ISI][Medline]
  90. Schafferhans K, Heidbreder E, Grimm D, and Heidland A. Norepinephrine-induced acute renal failure: beneficial effects of atrial natriuretic factor. Nephron 44: 240–244, 1986.[ISI][Medline]
  91. Schirger JA, Heublein DM, Chen HH, Lisy O, Jougasaki M, Wennberg PW, and Burnett JC Jr. Presence of Dendroaspis natriuretic peptide-like immunoreactivity in human plasma and its increase during human heart failure. Mayo Clin Proc 74: 126–130, 1999.[ISI][Medline]
  92. Schramm L, Heidbreder E, Schaar J, Lopau K, Zimmermann J, Gotz R, Ling H, and Heidland A. Toxic acute renal failure in the rat: effects of diltiazem and urodilatin on renal function. Nephron 68: 454–461, 1994.[ISI][Medline]
  93. Schulz-Knappe P, Forssmann K, Herbst F, Hock D, Pipkorn R, and Forssmann WG. Isolation and structural analysis of 'urodilatin,' a new peptide of the cardiodilatin-(ANP)-family, extracted from human urine. Klin Wochenschr 66: 752–759, 1988.[ISI][Medline]
  94. Schweitz H, Vigne P, Moinier D, Frelin C, and Lazdunski M. A new member of the natriuretic peptide family is present in the venom of the green mamba (Dendroaspis angusticeps). J Biol Chem 267: 13928–13932, 1992.[Abstract/Free Full Text]
  95. Shaw SG, Weidmann P, Hodler J, Zimmermann A, and Paternostro A. Atrial natriuretic peptide protects against ischemic renal failure in the rat. J Clin Invest 80: 1232–1237, 1987.[ISI][Medline]
  96. Shaw SG, Weidmann P, and Zimmermann A. Urodilatin, not nitroprusside, combined with dopamine reverses ischemic acute renal failure. Kidney Int 42: 1153–1159, 1992.[ISI][Medline]
  97. Shin SJ, Lee YJ, Tan MS, Hsieh TJ, and Tsai JH. Increased atrial natriuretic peptide mRNA expression in the kidney of diabetic rats. Kidney Int 51: 1100–1105, 1997.[ISI][Medline]
  98. Sudoh T, Kangawa K, Minamino W, and Matsuo H. A new natriuretic peptide in porcine brain. Nature 332: 78–81, 1988.[ISI][Medline]
  99. Sudoh T, Minamino N, Kangawa K, and Matsuo H. C-type natriuretic peptide (CNP): a new member of the natriuretic peptide family identified in porcine brain. Biochem Biophys Res Commun 168: 863–870, 1990.[ISI][Medline]
  100. Suzuki E, Hirata Y, Hayakawa H, Omata M, Kojima M, Kangawa K, Minamino N, and Matsuo H. Evidence for C-type natriuretic peptide production in the rat kidney. Biochem Biophys Res Commun 192: 532–538, 1993.[ISI][Medline]
  101. Tateyama H, Hino J, Minamino N, Kangawa K, Ogihara T, and Matsuo H. Characterization of immunoreactive brain natriuretic peptide in human cardiac atrium. Biochem Biophys Res Commun 166: 1080–1087, 1990.[ISI][Medline]
  102. Totsune K, Mackenzie HS, Totsune H, Troy JL, Lytton J, and Brenner BM. Upregulation of atrial natriuretic peptide gene expression in remnant kidney of rats with reduced renal mass. J Am Soc Nephrol 9: 1613–1617, 1998.[Abstract]
  103. Vari RC, Freeman RH, Davis JO, Villarreal D, and Verburg KM. Effect of synthetic atrial natriuretic factor on aldosterone secretion in the rat. Am J Physiol Regul Integr Comp Physiol 251: R48–R52, 1986.[Abstract/Free Full Text]
  104. Vesely DL. Atrial Natriuretic Hormones. Englewood Cliffs, NJ: Prentice Hall, 1992, p. 1–256.
  105. Vesely DL. Atrial natriuretic peptides in pathophysiological diseases. Cardiovasc Res 51: 647–658, 2001.[ISI][Medline]
  106. Vesely DL. Atrial natriuretic peptide prohormone gene expression: Hormones and diseases that upregulate its expression. IUBMB Life 53: 153–159, 2002.[ISI][Medline]
  107. Vesely DL, Blankenship M, Douglass MA, McCormick MT, Rodriguez-Paz G, and Schocken DD. Atrial natriuretic peptide increases adrenomedullin in the circulation of healthy humans. Life Sci 59: 243–254, 1996.[ISI][Medline]
  108. Vesely DL, Chiou S, Douglass MA, McCormick MT, Rodriguez-Paz G, and Schocken DD. Kaliuretic peptide and long acting natriuretic peptide as well as atrial natriuretic factor inhibit aldosterone secretion. J Endocrinol 146: 373–380, 1995.[Abstract]
  109. Vesely DL, Dietz JR, Parks JR, Antwi EA, Overton RM, McCormick MT, Cintron G, and Schocken DD. Comparison of vessel dilator and long acting natriuretic peptide in the treatment of congestive heart failure. Am Heart J 138: 625–632, 1999.[ISI][Medline]
  110. Vesely DL, Dietz JR, Parks JR, Baig M, McCormick MT, Cintron G, and Schocken DD. Vessel dilator enhances sodium and water excretion and has beneficial hemodynamic effects in persons with congestive heart failure. Circulation 98: 323–329, 1998.[Abstract/Free Full Text]
  111. Vesely DL, Douglass MA, Dietz JR, Giordano AT, McCormick MT, Rodriguez-Paz G, and Schocken DD. Negative feedback of atrial natriuretic peptides. J Clin Endocrinol Metab 78: 1128–1134, 1994.[Abstract]
  112. Vesely DL, Douglass MA, Dietz JR, Gower WR Jr, McCormick MT, Rodriguez-Paz G, and Schocken DD. Three peptides from the atrial natriuretic factor prohormone amino terminus lower blood pressure and produce diuresis, natriuresis, and/or kaliuresis in humans. Circulation 90: 1129–1140, 1994.[Abstract]
  113. Vesely DL, Norris JS, Walters JM, Jespersen RR, and Baeyens DA. Atrial natriuretic prohormone peptides 1–30, 31–67 and 79–98 vasodilate the aorta. Biochem Biophys Res Commun 148: 1540–1548, 1987.[ISI][Medline]
  114. Vesely DL, Norsk P, Winters CJ, Rico DM, Sallman AL, and Epstein M. Increased release of the N-terminal and C-terminal portions of the prohormone of atrial natriuretic factor during immersion-induced central hypervolemia in normal humans. Proc Soc Exp Biol Med 192: 230–235, 1989.[Abstract]
  115. Vesely DL, Overton RM, Blankenship M, McCormick MT, and Schocken DD. Atrial natriuretic peptide increases urodilatin in the circulation. Am J Nephrol 18: 204–213, 1998.[ISI][Medline]
  116. Vesely DL, Palmer PA, and Giordano AT. Atrial natriuretic factor prohormone peptides are present in a variety of tissues. Peptides 13: 165–170, 1992.[ISI][Medline]
  117. Villarreal D, Freeman RH, Taraben A, and Reams GP. Modulation of renin secretion by atrial natriuretic factor prohormone fragment 31–67. Am J Med Sci 318: 330–335, 1999.[ISI][Medline]
  118. Villarreal D, Reams GP, Taraben A, and Freeman RH. Hemodynamic and renal effects of proANF 31–67 in hypertensive rats. Proc Soc Exp Biol Med 221: 166–170, 1999.[Abstract]
  119. Vuolteenaho O, Leskinen H, Magga J, Taskinen P, Mantymaa P, Leppaluoto J, and Ruskoaho H. Regulation of atrial natriuretic peptide synthesis and secretion. Atrial Natriuretic Peptides, edited by Vesely DL. Trivandrum, India: Research Signpost, 1997, p. 39–52.
  120. Walshe JJ and Venuto RC. Acute oliguric renal failure induced by indomethacin: possible mechanism. Ann Intern Med 91: 47–49, 1979.[ISI][Medline]
  121. Werb R, Clark WF, Lindsay RM, Jones EO, Turnbull DI, and Linton AL. Protective effect of prostaglandin [PGE2] in glycerol-induced acute renal failure in rats. Clin Sci Mol Med 55: 505–507, 1978.[ISI][Medline]
  122. Wilkins MR, Wood JA, Adu D, Lote CJ, Kendall MJ, and Michael J. Change in plasma immunoreactive atrial natriuretic peptide during sequential ultrafiltration and haemodialysis. Clin Sci (Colch) 71: 157–160, 1986.[ISI][Medline]
  123. Winters CJ, Sallman AL, Baker BJ, Meadows J, Rico DM, and Vesely DL. The N-terminus and a 4000 molecular weight peptide from the mid portion of the N-terminus of the atrial natriuretic factor prohormone each circulate in humans and increase in congestive heart failure. Circulation 80: 438–449, 1989.[Abstract]
  124. Winters CJ and Vesely DL. Change in plasma immunoreactive N-terminus, C-terminus, and 4000 dalton mid portion of atrial natriuretic factor prohormone with hemodialysis. Nephron 58: 17–22, 1991.[ISI][Medline]
  125. Woolf AS, Mansell MA, Hoffbrand BI, Cohen SL, and Moult PJ. The effect of low dose intravenous 99–126 atrial natriuretic factor infusion in patients with chronic renal failure. Postgrad Med J 65: 362–366, 1989.[Abstract]
  126. Yoshida K, Yamagata T, Tomura Y, Suzuki-Kusaba M, Yoshida M, Hisa H, and Satoh S. Effects of c-type natriuretic peptide on vasoconstriction in dogs. Eur J Pharmacol 338: 131–134, 1997.[ISI][Medline]
  127. Zeidel ML. Regulation of collecting duct Na+ reabsorption by ANP 31–67. Clin Exp Pharmacol Physiol 22: 121–124, 1995.[ISI][Medline]
  128. Zhang PL, Mackenzie HS, Troy KL, and Brenner BM. Effects of natriuretic peptide receptor inhibition on remnant kidney function in rats. Kidney Int 46: 414–420, 1994.[ISI][Medline]