Published online before print April 4, 2005, doi: 10.1161/01.HYP.0000161878.81141.62
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(Hypertension. 2005;45:940.)
© 2005 American Heart Association, Inc.
Original Articles |
Extrarenal ETB Plays a Significant Role in Controlling Cardiovascular Responses to High Dietary Sodium in Rats
From the Departments of Pediatrics (M.O., N.D.T.N., Y.-H.T., C.E.G.) and Pathology (P.D.K.), University of Michigan, Ann Arbor; Howard Hughes Medical Institute (M.Y.) and Departments of Pathology (S.C.W.), Transplant Surgery (Y.W., S.L.), and Molecular Genetics (R.C.W., M.Y.), The Donald W. Reynolds Cardiovascular Clinical Research Center (M.Y.), University of Texas Southwestern Medical Center, Dallas, Tex.
Correspondence to Masashi Yanagisawa, MD, PhD, Howard Hughes Medical Institute, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Y5-224, Dallas, TX 75235-9050. E-mail Masashi.Yanagisawa{at}UTSouthwestern.edu or Cheryl E. Gariepy, MD, Department of Pediatrics and Communicable Diseases, University of Michigan, Medical Science Research Building I, A520, Ann Arbor, MI 48109-0656. E-mail CGariepy@med.umich.edu
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Abstract |
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Endothelin-B receptor (ETB)-deficient rats have low-renin, salt-sensitive hypertension. We hypothesized this was caused by an absence of renal ETB signaling and performed a series of experiments to examine the effect of dietary sodium (Na) on endothelin-1 (ET1) expression and renal function in wild-type (WT) and ETB-deficient rats. We found that ETB deficiency, but not dietary Na, increases circulating and tissue (kidney and aorta) ET1 levels. Quantitative reverse-transcription polymerase chain reaction reveals that aortic and renal ET1 and endothelin-A receptor (ETA) mRNA, however, are similarly increased by dietary Na in ETB-WT and ETB-deficient rats. We then determined the effect of chronic ETA blockade on blood pressure (direct conscious measurements), urinary protein excretion, and creatinine clearance (Crcl). On a Na-deficient diet, ETB-deficient rats have mild proteinuria and impaired Crcl. On a high-Na diet, severe hypertension and renal dysfunction develop in ETB-deficient rats. Chronic ETA blockade prevents hypertension and renal injury. To determine the role of the renal versus the extrarenal endothelin system, we performed renal cross-transplantation. We found that ETB deficiency in the body is associated with renal injury and an impaired ability to excrete an Na load. We also found that ETB deficiency in the body affects blood pressure response to dietary Na. Expression of ET1 and ETA are regulated by dietary Na. ETB receptors outside of the kidney, likely by functioning as a clearance receptor for ET1, limit salt-sensitivity in rats.
Key Words: endothelin • natriuresis • proteinuria • sympathetic nervous system • transplantation
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Introduction |
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The endothelin-B (ETB) receptor-deficient rat is a model of salt-sensitive hypertension resulting from a naturally occurring mutation in a single locus. These rats were created through the transgenic rescue of the spotting lethal (sl) rat. Spotting lethal is a 301-bp deletion in the ETB gene that abrogates functional receptor expression.1 ETBsl/sl rats are rescued from their lethal intestinal phenotype via a dopamine-ß-hydroxylase (DßH)-ETB transgene. DßH-ETB;ETBsl/sl rats express ETB in adrenergic tissues but fail to express ETB in other sites where they are normally expressed.2–4 Although adult transgenic ETB wild-type (WT) (DßH-ETB;ETB+/+) rats are not responsive to dietary sodium (Na), ETB-deficient (DßH-ETB;ETBsl/sl) rats exhibit low-renin, amiloride-responsive, salt-sensitive hypertension.4
The functional role of ETB in vascular homeostasis is controversial because it has both pressor and depressor effects. ETB activation on vascular smooth muscle mediates endothelin-1 (ET1)-induced vasoconstriction, whereas ETB activation on vascular endothelium produces a depressor response by evoking the production of the endothelium-derived vasodilators nitric oxide and/or prostacyclin.5 ETB on the vascular endothelium also plays an important role in clearing circulating ET1, thereby reducing ETA-mediated pressor actions.5,6 In addition, ETB is distributed abundantly in the tubular epithelium of the renal medulla, where activation provokes natriuresis and diuresis.7,8
Our previous studies demonstrated that hypertension in ETB-deficient rats is resolved by administration of amiloride at doses specific for inhibition of the epithelial sodium channel.4 Several studies demonstrate that ETB activation can inhibit the epithelial sodium channel activity.9,10 These findings led us to hypothesize that salt-sensitive hypertension in ETB-deficient rats results from an absence of ETB-mediated inhibition of the epithelial sodium channel activity in the renal tubule. However, these rats are also sensitive of ETA blockade, suggesting that hypertension in these rats is due to increased activation of ETA.11
To evaluate these possibilities, we looked at the regulation of renal and vascular ET1 and ETA expression in response to dietary Na. We also examined the effect of chronic ETA blockade on cardiovascular and renal function. Finally, to examine the role of the intrarenal versus extrarenal endothelin system, we measured cardiovascular and renal parameters in rats having undergone renal cross-transplantation.
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Methods |
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For complete details of experimental procedures, please see the online supplement at http://hyper.ahajournal.org. Only male rats were used experimentally.
Chronic Dietary Treatment and ETA Blockade
Diets were purchased from Harlan Teklad (Winfield, Iowa). ETB-WT and ETB-deficient rats (age 10 weeks) were fed a sodium-deficient (DNa) diet (0.008% NaCl) for 24 hours, after which they were treated with a selective ETA antagonist ABT-627 (5 mg/kg twice daily by gavage; Abbott Laboratories, Abbott Park, Ill) or vehicle. We confirmed that this dose of ABT-627 effectively antagonizes the acute pressor effect of exogenous ET1 in ETB-WT and ETB-deficient rats. ABT-627 was orally administered in a volume of 1 mL/kg. One day after the start of ABT-627 treatment, the chow of half of the rats was changed to a high-sodium (HNa) diet (8% NaCl). Three weeks later, 24-hour urine samples were collected and rats underwent catheterization with blood sample collection.
Arterial Catheterization and Blood Pressure Measurement
A catheter was placed in the right femoral artery using standard surgical techniques as described elsewhere.4 Twenty-four hours later, the externalized arterial catheter was connected to a calibrated blood pressure (BP) transducer and the rats acclimated to the measurement environment for 1 hour. Rats were unrestrained and allowed free access to food and water while attached to the transducer. Pulsatile BP was recorded over 1 hour using the PowerLab system (ADInstruments, Colorado Springs, Colo).
Renal Transplantation
ETB-WT and ETB-deficient (age 10 to 12 weeks) rats underwent bilateral nephrectomy followed by unilateral renal transplantation or served as kidney donors. All renal transplant surgeries were performed with a standard technique described by Waynforth and Flecknell12 in a recipient and donor genotype-blinded fashion. Rats were allowed to recover from surgery for 2 weeks on a normal rodent chow diet and then placed on the DNa diet. Creatinine clearance (Crcl) and 24-hour urine protein were determined after 1 week on DNa diet.
Dietary Na Shift
Rats were placed in individual metabolic cages and given free access to DNa diet. Food and water intake were recorded daily. On day 7, all rats were given an equal weight of the DNa diet, determined by the minimum daily amount consumed by any rat in the previous week. Urine and blood sample were collected 24 hours later and chow changed to an equal amount of HNa diet. Blood and urine samples were collected 8 and 24 hours later. Food and water intake were also measured.
Histology
The left or transplanted kidney of each rat was preserved in phosphate-buffered 10% formalin, after which the tissues were embedded in paraffin, sectioned at 2 µm, and stained with hematoxylin and eosin or Masson’s trichrome. Slides were blindly evaluated and photographed by a renal pathologist (P.D.K.).
Acute Sympathetic Blockade
ETB-WT and ETB-deficient rats (age 10 weeks) were fed HNa diet and administered ABT-627 for 3 weeks. Catheters were placed in the right femoral artery and vein, and the rats were allowed to recover for 24 hours. After acclimatization to the measurement environment for 1 hour, the baseline of BP in each rat was recorded for 10 minutes, after which hexamethonium (30 mg/kg) was administered intravenously by bolus injection (1 mL/kg). BP was continuously monitored over the subsequent 1 hour and recorded as 10-minute averages.
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Results |
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DßH-ETB;ETBsl/sl Are ETB Deficient in the Kidney
In situ hybridization demonstrates reduced ETB-mRNA in the kidney of DßH-ETB;ETBsl/sl rats.4 To quantitate ETB deficiency in DßH-ETB;ETBsl/sl kidneys, we looked for functional ETB in kidney membrane fractions from DßH-ETB;ETBsl/sl and ETB+/+ rats by radioligand binding assay. ETB was identified by the binding of labeled ET1 in the presence of the ETA-selective antagonist FR139317.13 A significant number of ETB binding sites were detected in kidney membranes from ETB+/+ rats. The number of ETB binding sites in DßH-ETB;ETBsl/sl kidneys was significantly reduced compared with ETB+/+ kidneys. In the WT kidney, ETB accounts for 71±18% of total ET binding sites. In the DßH-ETB;ETBsl/sl kidney, we found
4% of the ETB binding sites in WT kidney (please see Figure I at http://hyper.ahajournals.org).
Circulating and Tissue ET1 Protein Levels Are Elevated in ETB-Deficient Rats
We measured circulating and tissue ET1 protein levels in ETB-WT and ETB-deficient rats on a DNa or HNa diet for 3 weeks. Circulating ET1 levels were 
5-fold elevated in ETB-deficient rats compared with ETB-WT rats and were not affected by dietary Na (Figure 1A). ET1 extracted from whole kidney similarly showed a dramatic increased associated with ETB deficiency that was not affected by dietary Na (Figure 1B). In the aorta, however, both dietary Na and ETB deficiency affected ET1 protein levels (Figure 1C).
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High Dietary Na Increases ET1 and ETA mRNA Levels in the Kidney and the Aorta
We performed quantitative real-time reverse-transcription polymerase chain reaction to determine the relative number of ET1 and ETA transcripts in the kidney and aorta in response to 3 weeks of either DNa or HNa diet in ETB-WT and ETB-deficient rats. HNa diet was associated with an increased in renal ET1 and aortic ETA transcripts in ETB-WT rats. Similar increases that did not reach statistical significance by t test were noted in the ETB-deficient rats. By ANOVA, HNa diet was also associated with an increase in the relative number of renal ET1 and ETA transcripts and aortic ETA transcripts. ETB genotype did not affect these responses to dietary Na (Figure 2).
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ETB Deficiency Is Associated With Renal Dysfunction and Mild Hypertension on DNa Diet
We measured BP under conscious and unrestrained conditions as well as 24-hour urinary protein and Crcl in ETB-WT and ETB-deficient rats fed either a DNa or a HNa diet with or without ABT-627 for 3 weeks. On DNa diet, ETB-deficient rats are mildly hypertensive and exhibit an elevated 24-hour urine protein and decreased Crcl compared with ETB-WT rats (Figure 3). Mean arterial pressure (MAP) is mildly increased in ETB-WT rats and dramatically increased in ETB-deficient rats in response to HNa diet (Figure 3A). Systolic and diastolic pressures were similarly affected by salt in the 2 genotypes. ETB-WT systolic pressures increased from 110±2 to 117±2 mm Hg (7%) and diastolic pressures increased from 86±2 to 98±2 mm Hg (13%). ETB-deficient systolic pressures increased from 128±3 to180±5 mm Hg (40%), and diastolic pressured increased from 101±3 to 152±3 mm Hg (50%). HNa diet increased urinary protein and Crcl in both genotypes, with severe proteinuria developing in ETB-deficient rats (Figure 3B and 3C).
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Chronic ETA Blockade Normalizes BP, Improves Crcl, and Prevents Worsening Proteinuria in ETB-Deficient Rats
ETA blockade was started 1 day before the specified diet and continued for 3 weeks. Chronic ETA blockade resulted in equal BPs in ETB-WT and ETB-deficient rats, regardless of dietary treatment. Although ETA blockade prevented the severe proteinuria seen in HNa vehicle-treated ETB-deficient rats, it did not alter the elevated urinary protein observed in DNa ETB-deficient rats. Chronic ETA blockade normalized Crcl in ETB-deficient rats fed either diet (Figure 3).
Hypertensive ETB-Deficient Rats Exhibit Normal Renal Histology
Kidneys from ETB-WT and ETB-deficient rats given DNa or HNa diet for 3 weeks in the presence or absence of chronic ETA blockade were harvested. Sections stained with hematoxylin and eosin were blindly read by a renal pathologist (P.D.K.). No significant renal abnormality or injury was identified in any of the groups by light microscopy (data not shown). Electron microscopy was not performed.
ETB Deficiency in the Renal Transplant Recipient Is Associated With Elevated Urinary Protein and BP Salt Sensitivity
We performed renal cross-transplantation between ETB-WT and ETB-deficient rats. After 2-week recovery on a normal chow diet, rats were changed to a DNa diet for 1 week and serum creatinine and 24-hour urine protein were measured. There were no differences in serum creatinine levels, survival (>90%), or growth rate after transplantation between the 4 groups illustrated in Figure 4. However, urine protein levels were elevated in ETB-deficient recipients, regardless or renal genotype (Figure 4A). Rats were then placed on either DNa or HNa diet for 3 weeks, followed by direct BP measurements. All rats that underwent transplantation were hypertensive and showed Na sensitivity. However, ETB-deficient recipients demonstrated greater responses to chronic HNa diet than ETB-WT recipients, regardless of renal genotype. Body genotype affected systolic and diastolic pressures in HNa rats (188±7/141±6 mm Hg for ETB-WT recipient of ETB-WT kidney, 197±10/152±6 mm Hg for ETB-WT recipient of ETB-deficient kidney, 222±13/187±10 mm Hg for ETB-deficient recipient of ETB-WT kidney, and 256±15/190±7 mm Hg for ETB-deficient recipient of ETB-deficient kidney; P<0.001 for affect of body genotype on both systolic and diastolic pressures by ANOVA). Renal ETB deficiency increased diastolic pressures slightly without affecting the MAP (P=0.04). On the DNa diet, systolic and diastolic pressures were affected by renal genotype only (155±4/119±4 mm Hg for ETB-WT recipient of ETB-WT kidney, 166±7/126±5 mm Hg for ETB-WT recipient of ETB-deficient kidney, 157±7/122±5 mm Hg for ETB-deficient recipient of ETB-WT kidney, and 189±11/145±6 mm Hg for ETB-deficient recipient of ETB-deficient kidney; P<0.02 for affect of renal genotype on both systolic and diastolic pressures by ANOVA). MAPs are shown in Figure 4B.
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P<0.05 compared with ETB-deficient recipients of an ETB-WT kidney on the DNa diet. *P<0.05 compared with ETB-WT recipients of the same genotype kidney on the HNa diet.
ETB-Deficient Recipients Had a Decreased Ability to Excrete Na Load
We matched oral Na intake per kilogram of body weight in the first 24 hours after introduction of the HNa diet and measured urinary Na excretion. ETB-WT recipients of an ETB-deficient kidney took in or consumed less Na than the other 3 groups (Figure II); therefore, their Na excretion was not analyzed. Both body and renal ETB genotype affected Na excretion over the first 24 hours of HNa diet, with body genotype being a greater source of the variation by ANOVA (Figure 5).
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Salt-Induced Hypertension in ETB-Deficient Rats Is Associated With Increased Sympathetic Tone
Heart rate was obtained while measuring direct pulsatile BPs under conscious and unrestrained conditions. Salt intake in ETB-deficient rats results in hypertension associated with tachycardia. In the transplantation experiments, we observed that, like the salt-induced hypertension, tachycardia is related to the ETB genotype of the recipient (Table I). To further investigate this finding, we subjected HNa diet-fed ETB-WT and ETB-deficient rats with and without chronic ETA blockade to acute sympathetic blockade with hexamethonium. The magnitude of the peak depressor response in ETB-deficient rats was greater that in ETB-WT rats. MAP of salt-fed ETB-deficient and ETB-WT rats under sympathetic blockade was not different. There was no difference in the depressor responses to hexamethonium between ABT-627–treated ETB-WT and ETB-deficient rats (Figure III).
Transplanted Kidneys Showed No Evidence of Immunologic Rejection
The ETB-WT and ETB-deficient rats used in these experiments were the offspring of heterozygous matings on an inbred Wistar-Kyoto genetic background. Transplantation was therefore expected to be well tolerated. On chronic DNa diet, only ETB-deficient kidneys transplanted to ETB-deficient rats showed focal ischemic collapse of glomeruli, without inflammation, by hematoxylin and eosin staining (data not shown). No renovascular damage was identified in the other 3 groups.
On chronic HNa diet, although transplanted ETB-WT or ETB-deficient kidneys harvested from ETB-WT rats had a normal histological appearance (Figure IVA and IVD), various vascular changes ranging from thickening of afferent arterial walls to fibrinoid necrosis and generalized mesangial sclerosis were observed in ETB-WT kidneys removed from ETB-deficient rats (Figure IVB and IVC). Severe vascular wall injury most commonly involved afferent arterioles near the vascular pole of glomeruli and spared larger-caliber arterioles near the corticomedullary junction. In addition, ETB-deficient kidneys from ETB-deficient rats uniformly exhibited severe vascular injury with extensive fibrinoid necrosis most frequently involving larger-caliber arterioles near the corticomedullary junction. Numerous protein and red blood cell casts, mesangial hypercellularity, and occasional crescents with protein-rich exudates were identified (Figure IVE and IVF).
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Discussion |
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HNa increases ET1 and ETA mRNA expression in the kidney and ETA expression in the aorta. There was a trend for HNa diet to increase ET1 mRNA in the aorta, but it did not reach statistical significance. These findings extend and are consistent with previous studies of the effect of dietary Na on expression of endothelin and its receptors.14,15 The levels of ET1 and ETA mRNA we observed were not related to the level of hypertension. Although we did not find any deleterious effect of increased ET1 and ETA expression in salt-fed ETB-WT rats, Yu et al found that longer treatment of Wistar-Kyoto rats with HNa diet leads to renal and left ventricular fibrosis associated with increased production of transforming growth factor-ß1.16 Increased expression of ET1 in response to HNa diet would be predicted from this result given its induction by transforming growth factor-ß.17 We speculate that chronic ETA blockade may ameliorate salt-induced fibrosis in these rats.
Circulating ET1 levels are not a reliable indicator of local production. ETB deficiency leads to increased levels of circulating ET1 that are unresponsive to the amount of dietary Na. Similar findings are reported with chronic ETB blockade14 and suggest that alternative methods of clearance become important when ET1 levels become very high. Whole-kidney ET1 protein levels correlate with circulating levels, not renal production or the level of renal ETA expression, indicating that the majority of the renal ET1 protein we measured is produced outside of the kidney and not bound to renal ETA. We suspect that the amount of ET1 protein of renal origin is relatively small in comparison with circulating levels. Changes in renal ET1 production are thus obscured by ET1 of extrarenal origin. In the aorta, HNa diet increases ET1 protein levels, suggesting that a significant amount of the measured ET1 is being produced locally and/or bound to ETA. ETB-deficient rats on a low-Na diet express more ETA protein in small mesenteric arteries compared with ETB-heterozygous rats.2 Together with our mRNA data, this finding suggests that ETB signaling may alter the turnover of ETA in the vasculature.
Proteinuria and decreased Crcl are found in ETB-deficient rats, even on DNa diet, and thus are not correlated with increased renal ET1 production or ETA expression. The improvement of Crcl with chronic ETA blockade suggests that increase activation of ETA contributes to renal dysfunction in ETB deficiency. Given the association of proteinuria with ETB deficiency in renal transplant recipients, high circulating ET1 or hemodynamic changes transmitted to the kidney, and not increased renal ET1 and ETA expression, are likely contributing to podocyte injury, the likely cause of the proteinuria not visible by light microscopy. Proteinuria was less responsive to chronic ETA blockade, suggesting that this injury may not be reversible.
High circulating ET1 may alter intrarenal hemodynamic responses and shift the pressure–natriuresis curve.18 In addition, paracrine ETA signaling in the vasculature could increase systemic arterial stiffness that is associated with reduced Crcl and proteinuria.19,20 Safer et al hypothesize that transmission of increased mechanical strain and shear stress may result in morphological and functional changes within the kidney.21 ETB-deficient recipients of an ETB-WT kidney on DNa diet exhibited relative Na retention compared with ETB-WT recipients of an ETB-WT kidney when switched to HNa diet. Because these animals have identical BPs on DNa, this finding supports the concept that ETB deficiency in the body impairs renal function independent of systemic BP.
Salt-induced hypertension in ETB-deficient rats is prevented by ETA blockade and is associated with a chronic increase in sympathetic activity. Increased sympathetic tone or an alteration in vascular responsiveness, as well as increased ETA activation, is reported in hypertensive humans and several models of experimental hypertension in rats.22–25 Increased sympathetic tone may be secondary to the hypertension, but ETA activation may be directly involved. ET1 is reported to act as an inhibitory and facilitory neuromodulator of the arterial baroreflex.26–28 Endothelin signaling is also active in central cardiovascular regulatory centers, including the nucleus of the solitary tract and the ventrolateral medulla.29,30 Increased sympathetic activity can produce Na retention,31 but this does not explain our results in rats that underwent transplantation, because we doubt that renal sympathetic innervation was re-established 4 weeks after transplantation. However, extrarenal autocrine/paracrine ETA signaling induced by HNa diet could increase sympathetic tone and contribute to the severity or maintenance of hypertension in ETB-deficient rats.
Perspectives
Activation of renal ETB increases Na excretion through direct effects on renal tubular reabsorption and by increasing medullary blood flow.9,32,33 Despite these effects, this and previous studies demonstrate that rats genetically deficient in ETB or undergoing chronic ETB blockade exhibit salt-sensitive hypertension responsive to ETA blockade, suggesting that Na retention and hypertension under these conditions results not from a lack of ETB-mediated natriuresis or diuresis in the kidney but from an increase in ETA signaling.11,15 This study goes further to demonstrate that although intrarenal ETB plays a significant role in determining BP in these animals on DNa diet, it plays a relatively minor role in determining BP in these animals on HNa diet. The absence of ETB outside of the kidney significantly contributes to salt-induced hypertension in rats. Extrarenal ETB deficiency is associated with renal injury and/or changes in renal blood flow that likely play a dominant role in the initiation of the salt-induced hypertension in ETB-deficient rats. Increased sympathetic tone, perhaps through salt-induced paracrine/autocrine ETA signaling outside of the kidney, may play a significant role in maintaining or exacerbating the hypertensive state. The mechanism by which the endothelin system affects sympathetic tone in the context of chronic HNa in this and other models of hypertension merits further investigation.
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Acknowledgments |
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This work was supported by National Institutes of Health R01 HL64720, The Donald W. Reynolds Cardiovascular Clinical Research Center at The University of Texas Southwestern Medical Center, the Perot Family Foundation, the W. M. Keck Foundation and the Tanabe Medical Frontier Conference. R. Wiseman was a Summer Undergraduate Research Fellow at the University of Texas Southwestern Medical Center. M. Yanagisawa is an Investigator of the Howard Hughes Medical Institute. ABT-627 was generously provided by Abbott Laboratories (Abbott Park, Ill).
Received January 17, 2005; first decision January 17, 2005; accepted February 28, 2005.
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 M. P. Schneider, E. W. Inscho, and D. M. Pollock Attenuated vasoconstrictor responses to endothelin in afferent arterioles during a high-salt diet Am J Physiol Renal Physiol, April 1, 2007; 292(4): F1208 - F1214. [Abstract] [Full Text] [PDF]
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Y. Ge, A. Bagnall, P. K. Stricklett, K. Strait, D. J. Webb, Y. Kotelevtsev, and D. E. Kohan Collecting duct-specific knockout of the endothelin B receptor causes hypertension and sodium retention Am J Physiol Renal Physiol, December 1, 2006; 291(6): F1274 - F1280. [Abstract] [Full Text] [PDF]
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 U. C. Kopp, M. Z. Cicha, and L. A. Smith Differential effects of endothelin on activation of renal mechanosensory nerves: stimulatory in high-sodium diet and inhibitory in low-sodium diet Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2006; 291(5): R1545 - R1556. [Abstract] [Full Text] [PDF]
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D. M. Pollock and M. P. Schneider Clarifying Endothelin Type B Receptor Function Hypertension, August 1, 2006; 48(2): 211 - 212. [Full Text] [PDF]
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 Y.-H. Tsai, M. Ohkita, and C. E. Gariepy Chronic high-sodium diet increases aortic wall endothelin-1 expression in a blood pressure-independent fashion in rats. Experimental Biology and Medicine, June 1, 2006; 231(6): 813 - 817. [Abstract] [Full Text] [PDF]
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 N. Dhaun, J. Goddard, and DavidJ. Webb The Endothelin System and Its Antagonism in Chronic Kidney Disease J. Am. Soc. Nephrol., April 1, 2006; 17(4): 943 - 955. [Abstract] [Full Text] [PDF]
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