Natriuretic peptides and acute renal failure - 《American Journal of Physiology》美国生理学杂志干细胞之家



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发表于 2009-4-21 13:41 |只看该作者 |倒序浏览 |打印

作者：David L. Vesely作者单位：Departments of Medicine, Physiology, and Biophysics, University of SouthFlorida Cardiac Hormone Center, and James A. Haley Veterans Medical Center,Tampa, Florida 33612 5 j% m, \1 ^0 {; ?- C


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      【摘要】3 P# @2 W9 k  @
   Atrial natriuretic peptides (ANPs) are a family of peptide hormones, e.g.,ANP, long-acting natriuretic peptide, vessel dilator, and kaliuretic peptidesynthesized by the ANP gene. Brain natriuretic peptide (BNP) and C-typenatriuretic peptide are also members of this family but are synthesized byseparate genes. Within the kidney, the ANP prohormone's posttranslationalprocessing is different from that of other tissues, resulting in an additional four amino acids added to the NH 2 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 nothemodialysis returns their circulating concentrations to those of healthyindividuals. BNP and adrenomedullin, a 52-amino acid natriuretic peptide, havebeneficial effects on glomerular hypertrophy and glomerular injury but do not improve tubular injury (i.e., acute tubular necrosis). Vessel dilatorameliorates acute tubular necrosis with regeneration of the brush borders ofproximal 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 beenestablished. # |; w; N& u* ~: Q! m4 U
      【关键词】 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, whendialysis was introduced, the mortality from severe ARF was 50%( 39 ). This poor prognosis hasnot improved, and mortality now remains in the 40-80% range in oliguiricARF patients ( 4, 9, 22, 38, 39, 90, 125 ). The occurrence of ARFin the hospital increases the relative risk of dying by 6.2-fold and thelength of hospitalization by 10 days( 77 ). Thus ARF not only occurs with a high frequency but is also associated with high morbidity andmortality.

The present review will concentrate on the atrial natriuretic peptides(ANPs), adrenomedullin (ADM), and urodilatin, their pathophysiological changeswith ARF, and their potential for the treatment of ARF. There are severalexcellent 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 natriureticpeptides so these aspects will not be reviewed in detail in the presentreview.9 d8 x$ W3 H9 [( T( ?7 d

ANPs& r6 T7 B% X1 X1 S$ `$ L
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ANPs consist of a family of peptides that are synthesized by threedifferent genes ( 28, 32, 56, 73, 83 ) and then stored as threedifferent prohormones [i.e., 126-amino acid (aa) ANP, 108-aa brain natriureticpeptide (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 alsosynthesized in a variety of other tissues, including the kidney( 31, 116 ). The sites of synthesisof the ANPs in the approximate order in which they contribute to the synthesis are listed in Table 1.6 i: K* l( ^2 ^' I: v
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Table 1. Site(s) of synthesis, molecular weight, and hemodynamic and natriureticproperties of natriuretic peptides4 v, m5 c& J+ d# B( Y9 ^
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Peptide Hormones Originating From the ANP Prohormone
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Within the 126-aa ANP prohormone are four peptide hormones ( Fig. 1 ), with bloodpressure-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( 109 - 112 ).These peptide hormones, numbered by their aa sequences beginning at theNH 2 -terminal end of the ANP prohormone, consist of the first 30 aaof the prohormone [i.e., proANP-(1-30); long-acting natriuretic peptide (LANP)], aa 31-67 [i.e., proANP-(31-67); vessel dilator], aa79-98 [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 vesseldilator concentrations in plasma being 15- to 20-fold higher than ANP and100-fold higher than BNP ( 24, 29, 30, 41, 114, 123 ). More than one peptidehormone originating from the same prohormone is common with respect to thesynthesis of hormones ( 104 ).ACTH, for example, is derived from a prohormone that contains four knownpeptide hormones ( 104 ). TheBNP and CNP genes, on the other hand, appear to each synthesize only onepeptide 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) ofaction from ANP, in that they inhibit renal Na -K -ATPase secondarily to their ability to enhancethe synthesis of prostaglandin E 2, 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 ).

Fig. 1. Structure of the atrial natriuretic peptide prohormone (proANP) gene. Fourpeptide hormones [e.g., atrial natriuretic peptide (ANP), long-actingnatriuretic peptide (LANP), vessel dilator, and kaliuretic peptide] aresynthesized by this gene. Each of these peptide hormones has biologicaleffects, e.g., natriuresis and diuresis, mediated via the kidney( 8, 25, 26, 35, 37, 61, 113, 118, 127 ). LANH, long-actingnatriuretic hormone (a different nomenclature for LANP); a.a., amino acids.Reprinted by permission (Pearson Education, Inc., 1992)( 104 ).1 m, e/ t. e7 E, \2 a5 ~

ANP has been found to be a potent in vivo and in vitro inhibitor ofaldosterone secretion via a direct effect on the adrenal ( 5, 14, 17, 23, 33, 51, 59 ) and indirectly throughinhibition of renin release from the kidney( 14, 53, 59, 103 ). Kaliuretic peptide andlong-acting natriuretic peptide are also potent inhibitors of the circulatingconcentrations of aldosterone in healthy humans( 108 ). Kaliuretic peptide andLANP effects on decreasing plasma aldosterone levels last for at least 3 hafter their infusions have stopped, whereas ANP no longer has any effect onplasma 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 potentinhibitor (66%) of plasma renin activity( 117 ). The site of synthesis,molecular weight, and hemodynamic effects of each of the natriuretic peptidesin humans is summarized in Table1. ANP, LANP, and vessel dilator cause a significant diuresis andnatriuresis in healthy humans( 112 ). Kaliuretic peptidedoes not cause a significant natriuresis in healthy humans, but when infusedin humans with congestive heart failure it causes a significant natriuresis( 70 ).0 ?1 C( m! u% a/ O$ p

Urodilatin. ANP prohormone posttranslational processing is different within the kidney from that which occurs in the heart, resulting inan additional four amino acids added to the NH 2 terminus of ANP[i.e., proANP-(95-126); urodilatin] ( 56, 69, 93 )( Fig. 2 ). The rest of the aminoacids in urodilatin are identical and in the same sequence as those in ANP( Fig. 2 ). Urodilatin and ANPhave 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 peptidehormone is synthesized by the same gene that synthesizes ANP, but in thekidney, as opposed to all other tissues that have been investigated, the ANPprohormone is processed differently, resulting in the formation of urodilatinrather than ANP ( 56, 69, 93 ). Urodilatin circulates invery low concentrations (i.e., 9-12 pg/ml)( 115 ). Infusion of ANPincreases the circulating concentration of urodilatin, suggesting that some ofANP's effects may be mediated by urodilatin( 115 ). Infusion of LANP,vessel dilator, and kaliuretic peptide, on the other hand, do not affect thecirculating concentration of urodilatin in healthy humans( 115 ).  |3 z% `5 I+ y3 i5 Q
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Fig. 2. Amino acid sequences of the natriuretic peptides. Each of the sequences arethe human sequences except for Dendroaspis natriuretic peptide (DNP),whose sequence is only known in the snake. The brackets illustrate thelocation of cystine bridges that help to form a ring structure in a number ofthese peptides. BNP, brain natriuretic peptide; CNP, C-type natriureticpeptide.& u/ Z; |  [% F0 p" G- u* Z
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BNP and CNP
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BNP. BNP has similar diuretic and natriuretic effects and a shorthalf-life as ANP ( 98 ). BNP'shalf-life is 100-fold shorter than the half-lives of vessel dilator and LANP( 1, 54, 98, 99, 104 ). BNP has remarkablesequence homology to ANP, with only four amino acids being different in the17-aa ring structure common to both peptides( Fig. 2 )( 54, 55, 73, 83, 84, 98 ). Although BNP was named( 98 ) for where it was firstisolated (i.e., porcine brain), the main source of its synthesis and secretionis the heart ( Table 1 )( 36, 54, 56, 84, 101 ). As with ANP, thehighest levels of BNP are found in the atria of the heart( 36, 101 ). BNP levels in theatria, however, are 101 ). The immunoreactivelevel of BNP within the ventricles is only 1% of BNP's concentration withinthe atria ( 101 ). BNP,however, has been termed a "ventricular" peptide based onventricular BNP mRNA levels being similar to those in the atria, and theventricles are much larger than the atria( 69 ).' v0 {, l; K; I9 S
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The 108-aa BNP prohormone is processed within the heart to yield abiologically functioning BNP consisting of aa 77-108 of the BNPprohormone and the NH 2 terminus of the BNP prohormone (aa1-76 of prohormone), both of which circulate( 54 ). The circulatingconcentration of BNP is ( 36 ). The sequence homology ofBNP differs appreciably across species (both in size and amino acid sequence)( 28, 54, 68, 73, 101 ). BNP's marked sequencevariability explains, in part, the variations in its biological activity indifferent species. The peptide hormones from the ANP prohormone, on the other hand, have remarkable homology across different species( 28, 32, 73, 104 ). Mice overexpressing theBNP gene, where the circulating concentration of BNP is 10- to 100-fold higher than in healthy mice, have less glomerular hypertrophy and mesangial expansionwith intraglomerular cells than healthy mice 16 wk after both received renalablation ( 45 ). This mousemodel of subtotal renal ablation, however, also has significantly increasedANP concentrations ( 74, 102, 128 ), which may also havecontributed to the effects attributed to BNP in the BNP gene-overexpressingmice ( 45 ).
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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 thehuman kidney ( 62, 100 ) and has been found tohave little effect on renal vasoconstriction ( 126 ). Although CNP has beenreported to have natriuretic effects in some animals, when infused in humansat physiological concentrations and in concentrations that reached 4- to10-fold above those observed in disease states, CNP did not affect renalfunction ( 6 ). Thus in healthyhumans CNP had no effect on renal hemodynamics, systemic hemodynamics,intrarenal sodium handling, sodium excretion, or plasma levels of renin andaldosterone ( 6 ). In another study of infusion of CNP in healthy humans, CNP increased 60-fold in plasmaand there were no significant hemodynamic or natriuretic effects( 40 ). The authors of thisstudy concluded that it is unlikely that CNP has any endocrine role incirculatory physiology ( 40 ).There is one study in humans where infusion of CNP to increase CNP plasmalevels 550-fold caused a 1.5-fold increase in urinary volume and sodiumexcretion ( 42 ). With this veryhigh plasma concentration of CNP, both ANP and BNP also increased 2.4-fold( 42 ), which may have been thecause of the natriuresis and diuresis observed. Each of these studies suggeststhat CNP does not contribute physiologically to any natriuresis or diuresis inhumans ( 6, 40, 42 ).
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ADM, a 52-aa peptide originally isolated from an extract of apheochromocytoma ( 48 ), alsohas biological properties nearly identical to those of the ANPs( Table 1 )( 43, 48, 86 ). Infusion of ADM lowersblood pressure and produces a diuresis and natriuresis ( 43, 48, 86 ). ANP but not LANP, vesseldilator, or kaliuretic hormone increases the circulating concentration of ADMthree- to fourfold, suggesting that some of the reported effects of ANP may bemediated via ADM ( 107 ).However, the natriuresis and diuresis secondary to ANP in the aboveinvestigation were much larger than has ever been observed with ADM( 107 ), suggesting that ADMdoes not mediate all of the natriuretic and diuretic effects of ANP. ADM isnot produced in the atrium of the heart and therefore is not one of the ANPsper se as these peptides were so named because they are synthesized in theatrium of the heart ( Table 1 ).ADM is a larger peptide than any of the ANPs, with its main site of synthesisbeing in the adrenal, but isolated renal cells also have the ability tosynthesize ADM secondarily to stimulation by vasopressin via V 2 receptors ( Table 1 )( 88 ). Because vasopressin[antidiuretic hormone (ADH)] inhibits a diuresis, these findings are opposedto findings that ADM causes a diuresis( 43, 48, 86 ).5 r4 @+ K1 U5 P

Dendroaspis Natriuretic Peptide* X& ^3 x' A. t0 G7 D( q
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Dendroaspis natriuretic peptide (DNP) is the newest of the natriuretic peptides. This peptide was isolated from the venom of the greenmamba, Dendroaspis angusticeps ( 94 ). The venom also containsseveral polypeptide toxins that block cholinergenic receptors to causeparalysis ( 94 ). DNP-likepeptide has been reported to be present in human plasma and in heart atria( 91 ). In plasma, DNP'sconcentration is very low, i.e., 6 pg/ml, which is one-half of 1% of thecirculating ANPs ( 91 ). This peptide has a 17-aa disulfide ring structure similar to ANP, BNP, and CNP( Fig. 2 ) and causes anatriuresis and diuresis in dogs( 58 ). Infusion of DNP does notcause any significant change in the circulating levels of ANP, BNP, or CNP( 58 ).

Richards et al. ( 81 ) havequestioned whether DNP actually exists in humans and mammals because it hasnot been characterized by HPLC linked to immunoassay, followed by purificationand analysis to establish the human amino acid sequence as has been done withthe above natriuretic peptides. The gene for DNP has not been cloned in thesnake or in any mammal as has been done for each of the other natriureticpeptides ( 81 ). Richards et al.suggest that DNP may be "snake BNP" because BNP varies markedly inamino acid sequence among species (and the BNP sequence in this snake isunknown). The peptides from the ANP prohormone are markedly conserved amongspecies ( 36, 104 ), and one would notsuspect that DNP is one of these peptides as their amino acid sequences aremarkedly different from DNP. Further experimentation with the above studiessuggested by Richards et al.( 81 ) should give us moreinsight with respect to this interesting peptide." a1 ]3 a* t$ L% `7 Q; _/ j
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IMMUNOCYTOCHEMICAL LOCALIZATION AT ANPs IN THE KIDNEY' d/ }- E0 {0 Y5 P: ~8 X
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The kidney is a prime target organ (along with vasculature) of thephysiological effects of ANPs( 10, 56, 104 ). Immunohistochemical studies have localized ANP, vessel dilator, and LANP to the sub-brush borderof the pars convuluta and pars recta of the proximal tubules of animal( 79 ) and human( 85 ) kidneys( Fig. 3 ). Immunofluorescentstudies reveal that each of these peptides has a strong inclination for theperinuclear region in both the proximal and distal tubules( 79, 85 ). Immunohistochemical studies localize urodilatin to the distal tubule, with no evidence ofurodilatin in the proximal tubule( 85 ). ANP mRNA studies haveconfirmed that ANP prohormone is synthesized in the kidney ( 34, 76, 97, 102 ). The amount of ANPprohormone present in the kidney, however, is only one one-ninetieth of thatproduced in the atria of the heart( 104 ). These studies takentogether suggest that because urodilatin( 93 ) is found mainly in the distal nephron ( 82, 85 ) and because it is part ofthe 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 upregulatedwithin the kidney in early renal failure in diabetic animals( 34 ) and in the remnant kidney of rats with reduced renal mass( 102 ).$ n$ L$ k" X: k) |
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Fig. 3. Vessel dilator immunoperoxidase staining in the rat kidney reveals strongstaining 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. Theinterstitial artery ( C ) had strong proANP-(31-67) staining ofthe 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 thecollecting duct cells. Magnification: x 940. Reprinted by permission(Blackwell Publishing, Ltd., 1992)( 79 ).; m7 H# u2 T, Q, |$ P9 B' U

INFLUENCE OF ARF ON THE CIRCULATING CONCENTRATION OF ANPs" f+ a' y8 I$ A

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 thecirculation in salt- and water-retaining states such as congestive heartfailure and renal failure compared with their concentrations in healthyindividuals. Thus in salt- and water-retaining states there is no decrease inproduction of these natriuretic and diuretic peptides, but rather there isincreased production (mainly from the ventricle of the heart) ( 32, 76 ) in an apparent attempt toovercome the salt and water retention via their natriuretic and diureticproperties ( 123 ). The diseasestate associated with the highest circulating concentrations of ANPs is renalfailure ( 29, 30, 89, 122, 124 ). One would suspect thatANPs are higher in renal failure vs. class IV congestive heart failurepatients because of the added pathophysiology of decreased degradation ofthese peptides with the decreased functioning of renal parenchyma( 124 ). However, Franz et al. ( 30 ) have shown that there isan increased excretion of ANPs in renal failure and that the increase invessel dilator excretion occurs even before serum creatinine levels begin torise. The circulating concentrations of ANPs in chronic renal failure (CRF)appear to reflect volume status( 50, 66, 80, 124 ). Despite increasedcirculating ANPs in sodium-retaining disease states, the kidney retains sodiumand is hyporesponsive to ANP, LANP, and BNP( 11, 54, 77, 109 ). The mechanism for theattenuated renal response to these natriuretic peptides is multifactoral andincludes renal hypoperfusion and activation of therenin-angiotensin-aldosterone and sympathetic nervous systems( 10, 36, 65 ).

Hemodialysis
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ANPs. These peptides have been suggested as possible indicators ofwhen to perform dialysis in persons with CRF( 50, 66, 80, 89, 124 ). However, other datasuggest that ANPs are not useful in predicting when hemodialysis is necessary( 29 ). Hemodialysis lowers thecirculating concentration of ANP by 34-42%, with the amount of decreaseappearing to be related to the volume status of the patients( 50, 121, 124 ). Hemodialysis does notdecrease the circulating concentrations of vessel dilator and LANP( 124 ). Part of the reason forthe difference in the effects of hemodialysis on ANPs is that vessel dilator and LANP crosses the dialysis membrane compared with15-25% of ANP crossing hemodialysis membranes( 124 ). Hemodialysis usingcellulose-triacete dialyzers reduces plasma levels of these peptides in ARFmore than hemodialysis therapy with polysulfone dialyzers( 29 ).3 ~6 w9 E( }" v4 Q0 _& m

BNP. Hemodialysis has been reported to both lower( 55 ) and have no effect oncirculating BNP levels ( 49 ).Before dialysis in persons with CRF, plasma BNP levels have no relationship toserum creatinine or mean blood pressure( 55 ). In those CRF patients inwhom plasma BNP levels decrease with dialysis, this decrease correlates withthe degree of postural blood pressure drop, but there is no correlation withthe fall in serum creatinine( 55 ). In none of the studiesof BNP and dialysis ( 13, 21, 49, 55 ) has BNP ever returned toits circulating concentration in healthy individuals. With volume repletion after hemodialysis, there is an exaggerated release of ANP, but changes in BNPare small and without any correlation with either atrial or ventricular volume( 21 ).! ^8 n. v6 m7 D8 q0 W& ], N

Renal Transplantation
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Successful transplantation of functioning kidneys decreases the markedlyelevated circulating levels of ANPs in persons with ARF to those in healthyindividuals ( 75, 78 ). Nonfunctioning renalallografts 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 theallograft kidney does not fully function immediately with respect to clearingthese peptides. The half-life of ANP in healthy persons is only 2.5-3.5min ( 1, 104 ). If the transplantedkidneys began to function immediately, one would have expected the circulatingconcentration 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 withthat of ANP ( 1, 104 ), which may explain whyit takes 3 more days for this peptide hormone to normalize in the circulation after successful renal transplantation. If one gives ANP (via infusion) at thetime of renal transplantion, this does not appear to have any beneficialeffect on the outcome of the renal allograft( 87 ).3 m  @- s! [% Z3 j
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PROTECTIVE AND THERAPEUTIC EFFECTS OF ANPs IN ARF

ANP and Urodilatin0 N% Q+ r4 Q  g& C

Several of the atrial peptides have been investigated as possible treatment(s) of ARF. ANP had encouraging results in early studies of ARF inanimals ( 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 ischemicARF attenuated renal tissue damage and preserved glomerular filtration rate(GFR). Nakamoto et al. ( 68 )and Shaw et al. ( 95 ) were ableto shorten the course of renal artery cross-clamping-induced ARF in rats with ANP. Conger et al. ( 20 ) founda marked improvement in GFR in a rat renal artery clamp model when ANP-III(0.2µg·kg - 1 ·min - 1 ) was given intravenously immediately after clamp release in combination withdopamine sufficient to maintain mean arterial pressure above 100 mmHg. In therat, ANP had no effect on GFR when given intravenously( 56 ) but did have an effect onGFR when given directly into the renal artery for 4 h( 95 ). The inability of ANP toincrease GFR when given intravenously could be restored if dopamine were givensimultaneously ( 20 ). In thedog, the improvement in renal perfusion only lasted for a short period after a180-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 improvementin renal perfusion on those days( 71 ). Thus in animals theimprovement 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 bodywt - 1 ·min - 1 for24 h to humans with ARF revealed that ANP did not cause significantimprovement and did not reduce the need for dialysis or reduce mortality( 3 ). ANP infusions wereassociated with decreased survival in the nonoliguric ARF subjects, whorepresented 75% of the subjects( 3 ). The usefulness of ANP fortreatment is hampered by its short half-life of 2.5 min( 1, 104 ) and by its very shortduration of action ( 20, 57, 59, 61, 77, 112 ). Of 504 ARF patientstreated with ANP, 46% developed hypotension, which would further limit itsusefulness in ARF ( 3 ). Use of several of the ANPs investigated to treat ARF has each resulted in severehypotension and bradycardia ( 3, 47 ). In addition to ANPresulting in 46% of renal failure patients becoming hypotensive( 3 ), urodilatin has also beenassociated 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 beeninvestigated in humans with CRF to determine whether it could preventradiocontrast-induced nephropathy, one cause of hospital-acquired ARF( 52 ). When ANP was given before and during a radiocontrast study in 247 patients, no beneficial effectwas found ( 52 ). Urodilatin hasbeen suggested as a possible treatment of renal failure( 63, 92, 96 ), but in double-blindtrials in ARF patients urodilatin was found to have no beneficial effect( 63 ).
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Vessel Dilator8 p6 V% x7 X% E' o2 V

Vessel dilator appears to be one of the ANPs with promising therapeuticpotential in the treatment of ARF. Vessel dilator (0.3µg·kg - 1 ·min - 1 via ip pump) decreases blood urea nitrogen and serum creatinine from 162± 4 and 8.17 ± 0.5 mg/dl, respectively, to 53 ± 17 and0.98 ± 0.12 mg/dl in ARF animals in which ARF was established for 2days (after vascular clamping) before vessel dilator was given( 19 ). At day 6 ofARF, mortality decreased to 14% with vessel dilator from 88% without vessel dilator ( 19 ). The ARF animalsthat did not receive vessel dilator had moderate (i.e., 25-75% of alltubules involved) to 75% of all tubules necrotic) ATN by day 8 after the ischemic event( Fig. 4 B ). As shown in Fig. 4 B, the tubulesof the animals were almost completely destroyed. The destruction of thetubules included both the proximal and distal tubules, with the proximaltubules being more severely affected ( Fig.4 B ). The glomerulus of the ARF animals was sparedcompared with the renal tubules, with the glomerulus appearing to be normal inthe ARF animals ( Fig. 4, A and B ).

Fig. 4. Renal histology of a normal Sprague-Dawley rat ( A ) with intactproximal tubular brush border (arrowhead). B : acute renal failure(ARF) rat at day 8 75% of tubules are necrotic). Theglomerulus (x) appears to be normal. C : ARF rat treated with vesseldilator from days 2-5 of ARF with kidney examined after day8 of ARF reveals brush border to be present in proximal tubule(arrowhead). No tubules are necrotic in this ARF animal treated with vesseldilator. The glomerulus (x) is intact. Magnification of hematoxylin and eosin: x 426 ( A and C ) and x 320 ( B ). Reprintedfrom Ref. 19.
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The addition of vessel dilator after renal failure had been present for 2days resulted in a marked improvement in renal histology, with scores rangingfrom 0 (i.e., no tubular necrosis) to 1  (i.e., 19 ). When the kidneys were examined at day 8 of renal failure, the brush borders ofthe proximal tubules in the ARF animals treated with vessel dilator werepresent ( Fig. 4 C ),which was similar with respect to the proximal tubules in healthy animals( Fig. 4 A ). In the ARFanimals not treated with vessel dilator, the brush borders of the tubules weredestroyed ( Fig. 4 B ).The glomeruli of vessel dilator-treated ARF animals also appeared normal( Fig. 4 C ). It shouldbe pointed out that the animals treated with vessel dilator did have severerenal failure before vessel dilator was begun on the second day of renalfailure ( 19 ). It is alsoimportant to note that the animals treated with vessel dilator that had asignificant 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, andkaliuretic peptide, as opposed to ANP, BNP, and urodilatin, have never causeda hypotensive episode when given to either healthy animals or humans( 61, 111, 112 ) or when given to humanswith sodium and water retention( 70, 109, 110 ).; y! h; H6 O/ ~. L% p

The ability of vessel dilator to reverse ischemic ARF is consistent withthe important concept, based on experiments at the cellular level and inhumans with ATN, that the pathophysiology of ischemic ARF is due to asublethal and reversible injury to renal tubular cells( 9, 64 ). This reversible injury isnow thought to contribute more predominately to renal tubular dysfunction thanpermanent tubular cell necrosis( 9, 64 ). Pathological similarities between humans and rats with ischemic ATN are that the injury is to theproximal brush border, with a predilection for the most severe injury to occurin the proximal straight (S3 segments) tubules( 64 ). As outlined above, itwas the proximal tubule brush borders that were mainly regenerated by vesseldilator even when given 2 days after ischemic ATN( 19 ). Part of the improvementby using vessel dilator may be due to its ability to cause intrarenalvasodilation because it is a strong vasodilator ( 113 ). The reason vesseldilator has greater benefical effects than ANP, BNP, CNP, and urodilatin inARF appears due, at least in part, to its ability to cause the endogenoussynthesis of renoprotective PGE 2, which ANP, BNP, CNP, andurodilatin do not have ( 18, 35 ).
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Prostaglandins have renoprotective effects in ARF( 2, 46, 121 ). An indication thatPGE 2 is renoprotective (by maintaining glomerular hemodynamics) isthe observation that cyclooxygenase inhibitors in congestive heart failure andvolume depletion states augment the reduction in renal blood flow and GFR( 27, 120 ). With respect to themechanism of the protective effects of prostaglandins in ARF, after ischemicinjury there is a dramatic decrease in perfusion in the outer medulla( 44 ), a region of renal tissuethat normally operates "on the verge of ischemia"( 12 ). Prostaglandins have afavorable effect on blood flow distribution to this region( 67 ). In addition, prostaglandins have distinct cytoprotective effects and improve microvascularpermeability in ischemic ARF( 15, 46 ). Prostaglandins are notstored in the kidney but rather have to be synthesized acutely secondarily toa stimulating agent such as vessel dilator ( 18, 35 ) for prostaglandins to havea positive beneficial effect in renal failure.

There is evidence that ADM is renoprotective in Dahl salt-sensitive rats inthat when they were perfused for 7 days, their glomerular injury score was 54%less ( P salt-sensitive rats( 72 ). The ADM-treatedsalt-sensitive rats, however, had considerably more ( P and anteriolar sclerosis and atrophic tubules aftertreatment than the control Dahl salt-resistant rats( 72 ).9 `7 Z* X# B- f' S+ m2 O
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CNP increases in the circulation in ARF( 42 ), but its effects in ARFare unknown. As above, CNP has no natriuretic effects in healthy humans( 6, 40, 42 ).
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DNP has been evaluated in persons with end-stage renal disease on dialysisand was found not to correlate ( P = 0.62) with the echocardiographicleft ventricular mass index, whereas ANP and BNP did correlate with the leftventricular mass index of these end-stage renal patients( 16 ). DNP has not beeninvestigated with respect to its possible therapeutic effects in renalfailure.# Q; B2 b' W9 L' C" e
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SUMMARY AND FUTURE DIRECTIONS
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ANPs are both synthesized( 34, 76, 102 ), and have some of theirmost potent biological effects, e.g., natriuresis and diuresis, within thekidney ( 8, 25, 26, 35, 37, 61, 118, 127 ). Vessel dilator, via itsability to ameliorate ARF and enhance tubule regeneration in ATN( 19 ), may prove useful in thefuture in the treatment of ARF. BNP and ADM, with their effects in glomerularhypertrophy ( 45 ) andglomerular 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 therapeuticpotential in ATN appears limited. Future studies with these peptide hormonesin humans with ARF and/or glomerular diseases are necessary to determinewhether the findings in animal models of ARF are applicable to the treatment of humans with ARF." t+ K3 z' T  n  q; N! d3 T1 o

DISCLOSURES7 J4 q( W( [8 \3 o! m
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This work was supported in part by grants from the National Institutes ofHealth, a Merit Award from the U.S. Department of Veteran Affairs, and aGrant-in-Aid from the American Heart Association, Florida-Puerto RicoAffiliate.
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ACKNOWLEDGMENTS

The author thanks Charlene Pennington for secretarial assistance and thenumerous coinvestigators without whom all of the investigations reportedherein could not have been completed., |. w2 r' [1 D$ }
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