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(Hypertension. 1998;31:397.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Endothelin-A Receptor Antagonism Attenuates the Hypertension and Renal Injury in Dahl Salt-Sensitive Rats
From Department of Physiology and Biophysics, Center for Excellence in Cardiovascular and Renal Research and Department of Anatomy (B.C.), University of Mississippi Medical Center, Jackson, Miss.
Correspondence to Joey P. Granger, PhD, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505. E-mail JPG{at}fiona.umsmed.edu
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Abstract |
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The aim of this study was to examine the role of endothelin-A (ETA) receptors in mediating the hypertension and renal injury associated with high salt intake in Dahl salt-sensitive (DS) rats. To achieve this goal, we examined the effects of chronic selective ETA antagonist (A-127722) treatment at a dose of 10 mg/kg/d on arterial pressure, renal function, and morphology in DS and Dahl salt-resistant (DR) rats placed on a high sodium (8% NaCl) diet (HSD) for 3 weeks. Placement of DS rats (n=13) on HSD for 3 weeks caused a progressive increase in systolic pressure (from 118±3 to 186±15 mm Hg). The increase in systolic pressure was significantly attenuated (from 125±4 to 167±12 mm Hg) in DS rats treated with A-127722 (n=13). Mean arterial pressure (MAP) measured directly at the end of the study was also significantly lower by 18 mm Hg (P<.02) in the DS rats treated with A-127722. The slope of the chronic pressure-natriuresis curve was shifted to the right in DS rats and to the left by chronic ETA receptor blockade in DS rats. The hypertension in DS rats was associated with marked proteinuria (from 4.1±1.1 to 74.3±5.3 mg/24 h/100 g body weight) that was significantly attenuated (from 5.7±1.2 to 55.2±6.5 mg/24 h/100 g body weight) in DS rats treated with A-127722. The percentage of glomeruli displaying fibrosis, hypercellularity, and hyalinization was also significantly reduced after treatment with A-127722 in DS rats. Arterial pressure, protein excretion, renal hemodynamics, and morphologic structure were not significantly changed in response to ETA receptor blockade in DR rats placed on HSD. These data indicate that endothelin-A receptor activation may play a role in the exacerbation of hypertension and development of renal injury in DS rats.
Key Words: endothelin receptors • kidney • rats • Dahl • hypertension
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Introduction |
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Endothelin-1 (ET-1) exerts a variety of actions within the kidney that, if sustained chronically, could contribute to the development of hypertension and progressive renal injury.1 ET-1 causes a dose-dependent decrease in glomerular filtration rate (GFR) and renal plasma flow (RPF) through stimulation of vascular smooth muscle and mesangial cell contraction.2,3 Long-term effects of ET on the kidney include stimulation of mesangial cell proliferation and extracellular matrix deposition as well as stimulation of vascular smooth muscle hypertrophy in renal resistance vessels.1,4 Previous studies have indicated that expression of ET is greatly enhanced in animal models of severe hypertension with renal vascular hypertrophy5,6 and in models of progressive renal injury.7,8 In addition, treatment with endothelin receptor antagonists attenuated the hypertension and small artery morphologic changes and improved kidney function in these models.9–12 Dahl salt-sensitive (DS) rats placed on a high sodium diet (HSD) are characterized by an attenuated pressure natriuresis, development of hypertension, and extensive renal lesions in the form of glomerulosclerosis, renal arteriolar and tubular injury, and progressive renal failure in late phases of the disease.13–16 However, the role of endothelin in mediating the salt-induced hypertension and renal injury in DS rats is still unclear.
There is evidence to support the hypothesis that endothelin may play a role in DS hypertension. Previous studies have demonstrated that prepro-ET mRNA and vascular responsiveness to ET are increased in the renal cortex of DS rats compared with Dahl salt-resistant (DR) rats.17 In addition, a positive correlation between ET generation in the renal cortex and the extent of glomerulosclerosis has been reported in DS hypertensive rats.18 Also supporting a role of ET in DS hypertension is a recent study from our laboratory indicating that acute intravenous infusion of the nonselective ETA-ETB receptor antagonist (SB 209670) reduced arterial pressure in DS rats. When the same antagonist was infused directly into the renal interstitium, it improved renal hemodynamic and excretory functions in DS rats but not in DR rats.19 Although these data indicate that ET may play a role in the attenuated renal hemodynamics in late stages of hypertension in DS rats, the role of ET in the initiation and maintenance of hypertension and renal injury in DS rats remains unclear. Furthermore, the contribution of each ET receptor subtype in mediating the development of hypertension and progressive deterioration in kidney function in DS rats is unknown. Since most of the mitogenic and vascular hypertrophic effects of endothelin are mediated mainly through activation of ETA receptors,1 we investigated the effects of chronic treatment with the orally active selective ETA antagonist (A-127722) on arterial pressure, urinary protein excretion, renal hemodynamics, and renal morphology in DS and DR rats placed on a HSD (8% NaCl) for 3 weeks.
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Methods |
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Experimental Design
Male DS and DR rats of the Rapp strain with an average weight of 225 to 250 g were purchased from Harlan Sprague-Dawley, Inc. Rats were fed a sodium-deficient (0.4% NaCl) diet (Harlan Teklad) for 1 week followed by a high-sodium (8% NaCl) diet (ICN) for 3 weeks. Four groups of rats were studied: DS control (n=13), DS treated with the ETA antagonist (A-127722) (n=13), DR control (n=11), and DR treated with A-127722 (n=12). A-127722 was diluted in distilled water at concentrations to deliver approximately 10 mg/kg/d, with the control group receiving tap water for 4 weeks. This dose of A-127722 has previously been shown to virtually abolish the pressor responses to exogenous ET-1.20 Furthermore, higher oral doses of A-127722 in rats (30 mg/kg) did not cause a greater degree of inhibition of the ET-1-induced pressor response than the 10 mg/kg/d dose.21 Experimental procedures were conducted in accordance with National Institutes of Health guidelines for use and care of animals, and the protocols were approved by the Animal Care and Use Committee at the University of Mississippi Medical Center.
Rats were placed in individual metabolic cages at the end of first, second, third, and fourth weeks of the study, and 24-hour measurements of water intake, urinary protein, and electrolyte excretion were obtained. Body weights were measured every week throughout the period of the study. Systolic blood pressure was measured during the 4-week period of the study by using the tail cuff method with automated sphygmomanometers (IITC Life Science, Inc.) with rats that were prewarmed in a chamber at 30°C and placed in individual restrainers. Systolic pressures were measured twice a week, and the average of three readings was recorded.
After 3 weeks on HSD, rats were instrumented for direct measurement of arterial pressure and renal function in the conscious state. Rats were anesthetized with sodium pentobarbital (40 mg/kg intraperitoneally) and instrumented with catheters in the femoral artery and vein (PE-50), and the urinary bladder was cannulated with a flare-tipped PE-90 tubing for urine collection. All catheters were tunneled to the back of the neck and exteriorized. The animals were allowed to recover for two days and then prepared for direct measurement of MAP and renal function in the conscious state as previously described.19 Briefly, rats were placed in individual restrainers, and the femoral vein catheter was connected to an infusion pump that delivered isotonic saline containing [125I] iothalamate (Glofil, 0.05 µCi · kg-1 · min-1; Cypros) and [131I] iodohippurate (0.1 µCi · kg-1 · in-1; Syncor International Corporation) at a fixed rate of 3 mL/h. Arterial pressure was monitored with a pressure transducer, and the data were displayed on a chart recorder for continuous recording of arterial pressure. After a 60-minute stabilization period, two 20-minute control clearances and steady-state arterial pressure measurements were obtained. Arterial pressure during each clearance period was the average recording of five readings obtained at times zero, 5, 10, 15, and 20 minutes.
Renal Histological Studies
The right kidney from each animal was removed and placed in 2% paraformaldehyde. After fixation, a midsagittal cut was made through the hilum of the kidney, dividing it into two equal halves. One half of each kidney was then embedded in paraffin and sections (6 to 8 µm) were stained with hematoxylin and eosin, periodic acid-schiff, Gomori trichrome, and Alcian blue. All tissue samples were evaluated by an investigator who had no prior knowledge of the group to which each rat belonged. At least 50 glomeruli were examined per kidney, and the percentage of glomeruli displaying damage was used as an index for assessing the glomerular damage between groups. In addition to examining glomerular damage, we also performed morphologic analysis to assess the degree of renal tubular damage. The method of Uehara et al18 was used to score the degree of renal tubular damage as follows: 0, no lesion, 1+, very mild focal dilatation; 2+, large number of dilated tubules with widening of the interstitium; 3+, fairly extensive dilatation of tubules with cystic formation and/or protein cast and widening of the interstitium; and 4+, complete atrophy of the tubules. Each animal was given a score (0 to 4+), and the individual scores were averaged for each group.
Analysis of Plasma and Urine
Urine volume was determined gravimetrically. Sodium and potassium concentrations in urine and plasma were measured by flame photometry (IL-943, Instrumentation Laboratory). Urinary protein concentration was measured by using the Bradford method22 and a commercially available dye reagent (Biorad). These measurements allowed the calculation of urinary protein excretion, urinary sodium excretion (UNaV), urine flow (UV), and fractional excretion of sodium (FENa). GFR and RPF were calculated from concentrations of 125I and 131I in plasma and urine.
Statistical Analysis
All data in the experiment are expressed as mean±SE. Arterial pressure and renal changes in response to high salt intake within each group were determined by using ANOVA for repeated measures followed by Dunnett’s test. Differences between groups were determined by using factorial ANOVA followed by Scheffe’s test. A value of P < 0.05 was considered statistically significant.
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Results |
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Effects of Long-Term ETA Receptor Blockade on Arterial Pressure and Pressure-Natriuresis in DS and DR Rats
Fig 1 illustrates the changes in systolic blood pressure in response to a HSD for 3 weeks in control DS and DR rats and in DS and DR rats that were chronically treated with A-127722. Baseline systolic pressure was not significantly different between control and treated DS and DR rats. After 1 week of HSD, there was a significant increase in systolic pressure in the control DS group, and the pressure progressively increased after 3 weeks by 57% (from 118±3 to 186±15 mm Hg). Systolic pressure in rats that were chronically treated with A-127722 was significantly lower (from 125±4 to 167±12 mm Hg, P<.05) than in control DS rats after 3 weeks on a HSD. Systolic pressure in DR rats did not increase significantly in response to the HSD and showed no statistically significant difference from that in DR rats that were treated with A-127722. MAP measured by an arterial catheter at the end of the study was significantly lower in DS rats treated with A-127722 (by 18 mm Hg, P<.02) than in DS controls, while the difference in MAP between DR control and treated groups was not significant. Fig 2 illustrates the relationship between sodium excretion and arterial pressure in DS and DR rats at the third week of salt intake. Chronic pressure natriuresis curve was steep, and a slight (nonsignificant) parallel shift to the left of the curve occurs in DR rats. However, the slope of the curve was shifted to the right in DS rats and significantly shifted to the left in DS rats receiving the ETA blocker. These data indicate that chronic ETA receptor blockade partially corrected the attenuated pressure natriuresis in DS rats.
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Renal Hemodynamics in Response to Chronic ETA Receptor Blockade in DS and DR Rats
Table 1 shows the renal function measurements in DS and DR rats at the end of the study. GFR and RPF in DS rats were 20% and 18% lower in DS rats than in DR rats. Treatment with A-127722 tended to improve GFR (2.86±0.22 mL/min versus 2.44±0.48 mL/min) and RPF (7.37±1.22 mL/min versus 6.02±0.59 mL/min) in DS rats as compared with control DS rats. However, these differences did not achieve statistical significance. No difference in GFR or RPF was observed between treated and nontreated DR rats.
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Individual weights of kidney and heart were also taken at the end of the study. The average weight of the heart was 0.41±0.02 and 0.38±0.01 g/100 g body weight in control DS rats and rats treated with A-127722, respectively. Kidney weight averaged 0.67±0.04 and 0.76±0.03 g/100 g body weight in control DS rats and those treated with A-127722, respectively. The differences in weights of kidneys and heart were not statistically significant between DS and DR rats and were not affected by chronic ETA receptor blockade in either group.
Effects of Long-Term ETA Receptor Blockade on Proteinuria and Renal Morphology in DS and DR Rats
Urinary protein excretion during the period of low-salt diet was not statistically different between control DS rats, control DR rats, and DS rats treated with A-127722 (Fig 3). However, urinary protein excretion in DR rats treated with A-127722 was significantly lower (P>.05) compared with the DS-treated group. Feeding a HSD to DR rats did not increase urinary protein excretion, and no differences in urinary protein excretion were observed between treated and control DR rats. However, in DS-controls, urinary protein excretion increased progressively (from 4.1±1.1 to 74.3±5.3 mg/24 h/100 g body weight, P<.001) after 3 weeks on a HSD. Urinary protein excretion also increased from 5.7±1.2 to 55.2±6.5 mg/24 h/100 g body weight in DS rats treated with A-127722. Although the differences in urinary protein excretion between control DS and treated groups were not statistically significant during the first and second weeks of HSD, the level of proteinuria achieved after 3 weeks by the DS-treated group was significantly lower (P<.05) than in DS controls.
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Fig 4 illustrates the percentage of glomeruli displaying fibrosis, hyalinization, or hypercellularity in DS and DR rats and the effect of chronic ETA blockade on these changes. The renal histological changes in response to HSD in DR rats were minimal and were not affected with ETA antagonism. In DS rats on a HSD diet, however, 51% of the glomeruli displayed fibrosis, 70% displayed hyalinization, and 63% displayed hypercellularity that appeared to result from mesangial cell proliferation and polymorphonuclear leukocyte infiltration. Chronic treatment with the ETA antagonist significantly reduced the percent of glomeruli with lesions to 9% with fibrosis, 26% with hyalinization, and 31% with hypercellularity. Tubular injury was severe in DS rats and was improved also in the DS group that was treated with the ETA blocker.
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Discussion |
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The results of this study indicate that chronic treatment with the ETA receptor blocker (A-127722) significantly reduced the severity of hypertension and attenuated glomerular and tubular damage in response to a high salt intake in DS rats. The finding that reduction in arterial pressure occurs only during the third week of a HSD supports the concept that the role of ET becomes more evident in late phases of hypertension when vascular endothelial damage occurs that leads to enhanced expression of ET-1 gene and exacerbation of the hypertensive process.4 Further support is derived from recent studies indicating that in animal models of severe hypertension such as DOCA-salt hypertensive rats and malignant DOCA-salt-SHR, the blood pressure-lowering response to endothelin antagonists occurs only in late stages of the disease when ET-1 gene is overexpressed in small arteries such as renal resistance vessels.9,10 Since the kidney is thought to play a key role in long-term regulation of arterial pressure,23 it is expected that most of the chronic hypertensive effects of endothelin are mediated via direct or indirect renal mechanisms. The renal vasculature is known to be extremely sensitive to the vasoconstrictor effects of ET-1,24 and this sensitivity is enhanced in DS rats.17 ET-1 induces a variety of short-term and long-term renal effects that could potentially lead to chronic hypertension, including reduction of renal hemodynamics, stimulation of vascular smooth muscle growth, and extracellular matrix deposition.1 The pressure natriuresis is a key mechanism for long-term control of arterial pressure in which the kidneys protect against any hypertensive stimuli by excreting more sodium to return the pressure back to normal.25 The pressure natriuresis mechanism is markedly attenuated in DS rats.14 Chronic ETA receptor blockade improved pressure natriuresis as indicated by a leftward shift of the slope of the pressure natriuresis curve in DS rats. These data indicate that an improvement in the kidney’s capability to excrete salt and water occurred in response to chronic ETA receptor blockade in DS rats.
Our observation that exacerbation of the hypertensive process in DS rats has an ETA-mediated component is not surprising, since most of the vasoconstrictive, mitogenic, and proliferative effects of endothelin are mediated through activation of ETA receptors.26,27 Benigni et al11 have reported that chronic treatment with the ETA receptor antagonist (FR 139137) significantly attenuated the increase in blood pressure and improved kidney function in rats with renal mass reduction. Selective ETA receptor blockade also attenuates hypertension and renal injury in mice with lupus nephritis.28 However, ETB receptors may play a role in mediating hypertension, since ETB receptors not only mediate vasodilation through release of nitric oxide and prostacyclin (ETB1) but also mediate renal vasoconstriction (ETB2) in rats.29 A recent study has indicated that chronic administration of the ETA receptor blocker (A-127722) did not affect the hypertension or proteinuria in rats with renal mass reduction.21 In addition, the ETB-mediated renal vasoconstrictor response was exaggerated in spontaneously hypertensive rats mostly because of increases in receptor number and affinity.30 The involvement of ETB receptor subtypes in mediating the renal dysfunction and increased arterial pressure in salt-sensitive hypertension remains to be determined.
Several lines of evidence support a role for endothelin in mediating chronic renal dysfunction in different animal models as well as in humans. Renal ET-1 gene expression has been shown to increase in a parallel fashion with the progression of renal disease in different models of renal injury, including reduced renal mass, diabetic nephropathy, lupus nephritis, and proliferative nephritis.8,31,32 Urinary excretion of ET has been reported to increase in rats with reduced renal mass.8,33 Plasma and urinary excretion of ET-1 have also been shown to be elevated in patients with chronic renal failure.34,35 The DS rat model typically develops malignant hypertension and marked renal pathological changes in the form of glomerulosclerosis, renal tubule dilatation, vascular hypertrophy, and renal insufficiency in response to the high salt intake.13–16 In the DS rat, renal ET-1 production has also been reported to be elevated and to correlate with the extent of glomerulosclerosis.18 These studies support our findings that chronic ETA receptor blockade protects against glomerular and tubular injury in DS rats. The overall average of glomeruli displaying damage was reduced from 62% to 22% in rats treated with the ETA antagonist. Although these data clearly indicate that ET is implicated in mediating the renal injury in DS rats, the underlying mechanisms are unclear. ET-1 exerts a potent proliferative effect on mesangial cells and increases the expression of collagen, laminin, fibronectin, and other cytokines that mediate extracellular matrix deposition and fibrosis within the kidney.36,37 Furthermore, ETA receptor antagonism reduces mesangial cell proliferation and attenuates the glomerular overexpression of genes encoding extracellular matrix components in rats with diabetic nephropathy.32 Whether the same correlation between renal injury components and ET receptor mRNA expression occurs in the kidneys of the DS rat is still unknown and needs further investigation.
Despite the observation that the chronic blockade of ETA receptors caused a slight improvement in renal hemodynamics in DS rats, a significant reduction of glomerular injury occurred. The cause of the difference between the histopathological and functional findings is unclear. However, since the renal hemodynamic differences were not statistically significant between DS and DR rats, it is possible that rats were examined in a stage of renal injury that was still compensated by the remaining functioning nephrons. Therefore, it appears that even though the effects of ET on arterial pressure in DS rats may occur in late stages of hypertension, intrarenal ET may promote renal injury early in the disease. Interestingly, ET-1 gene overexpression was found to occur in the early phase of proliferative nephritis in rats, and a direct relation between ET-1 and the initiation of glomerular lesion was reported in this model.31 Available data about the time course of changes in kidney ET-1 receptor subtype gene expression in models of progressive renal injury have been conflicting. In rats with renal mass reduction, a progressive increase in the ETB receptor gene expression occurs with no change in the expression of ETA receptors.12 However, ETA (but not ETB) receptor gene expression was upregulated coincidentally with maximal proteinuria and glomerular lesions in rats with proliferative nephritis.31 Therefore, it appears that the percent involvement of ETA versus ETB receptors may depend on the underlying renal disease, and further studies for quantifying the role of ETB receptor subtypes in mediating the deteriorated renal function in DS rats are still needed. An interesting question that emerges is whether the beneficial effect of the ETA blockade in reducing renal injury is mediated through reducing blood pressure or through direct renal mechanisms. Although our data cannot provide an answer, there is an evidence from some animal models of renal injury such as diabetic nephropathy and proliferative nephritis that ETA receptor gene expression is increased in the glomeruli and that treatment with ET blockers decreases the proteinuria and attenuates the renal morphologic lesions without significantly affecting the blood pressure.31,32,38
In summary, we found that DS rats that are placed on a HSD (8% NaCl) for 3 weeks develop severe hypertension, marked proteinuria, and glomerulotubular injury. Chronic blockade of ETA receptors attenuates the hypertension and proteinuria and ameliorates the glomerular and tubular damage associated with high salt intake in DS rats. We conclude that ET-A receptor activation may play a role in mediating the development of severe hypertension, proteinuria, and renal injury in DS rats that are placed on a HSD.
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Acknowledgments |
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We thank Dr Terry J. Opgenorth (Abbott Laboratories, Abbott Park, Ill) for kindly supplying the endothelin receptor antagonist (A-227722). The authors thank also Dr Raouf Khalil and Dr Barbara Alexander for critical review of the manuscript. We also thank Huimin Zhang for technical assistance and Gerry McAlpin for secretarial assistance. This work was supported by NIH grants HL38499 and HL51971.
Received September 17, 1997; first decision October 3, 1997; accepted October 20, 1997.
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  H. Guan, P. Wang, R. Hui, M. L. Edin, D. C. Zeldin, and D. W. Wang Adeno-Associated Virus-Mediated Human C-Reactive Protein Gene Delivery Causes Endothelial Dysfunction and Hypertension in Rats Clin. Chem., February 1, 2009; 55(2): 274 - 284. [Abstract] [Full Text] [PDF]
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 Y. Wang, D. Babankova, J. Huang, G. M. Swain, and D. H. Wang Deletion of Transient Receptor Potential Vanilloid Type 1 Receptors Exaggerates Renal Damage in Deoxycorticosterone Acetate-Salt Hypertension Hypertension, August 1, 2008; 52(2): 264 - 270. [Abstract] [Full Text] [PDF]
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 N. Dhaun, C. J. Ferro, A. P. Davenport, W. G. Haynes, J. Goddard, and D. J. Webb Haemodynamic and renal effects of endothelin receptor antagonism in patients with chronic kidney disease Nephrol. Dial. Transplant., November 1, 2007; 22(11): 3228 - 3234. [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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 G. D'Angelo, J. S. Pollock, and D. M. Pollock In vivo evidence for endothelin-1-mediated attenuation of {alpha}1-adrenergic stimulation Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1251 - H1258. [Abstract] [Full Text] [PDF]
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Y. Wang and D. H. Wang A Novel Mechanism Contributing to Development of Dahl Salt-Sensitive Hypertension: Role of the Transient Receptor Potential Vanilloid Type 1 Hypertension, March 1, 2006; 47(3): 609 - 614. [Abstract] [Full Text] [PDF]
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C. L. Laffer, R. J. Bolterman, J. C. Romero, and F. Elijovich Effect of Salt on Isoprostanes in Salt-Sensitive Essential Hypertension Hypertension, March 1, 2006; 47(3): 434 - 440. [Abstract] [Full Text] [PDF]
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Y. Wang, A. F. Chen, and D. H. Wang ETA receptor blockade prevents renal dysfunction in salt-sensitive hypertension induced by sensory denervation Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2005 - H2011. [Abstract] [Full Text] [PDF]
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G. D'Angelo, J. S. Pollock, and D. M. Pollock Endogenous endothelin attenuates the pressor response to acute environmental stress via the ETA receptor Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1829 - H1835. [Abstract] [Full Text] [PDF]
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Y. Wang and D. H. Wang Prevention of endothelin-1-induced increases in blood pressure: role of endogenous CGRP Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1868 - H1874. [Abstract] [Full Text] [PDF]
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J. A. Payne, B. T. Alexander, and R. A. Khalil Decreased Endothelium-Dependent NO-cGMP Vascular Relaxation and Hypertension in Growth-Restricted Rats on a High-Salt Diet Hypertension, February 1, 2004; 43(2): 420 - 427. [Abstract] [Full Text] [PDF]
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A. Ergul, V. Portik-Dobos, A. D. Giulumian, M. M. Molero, and L. C. Fuchs Stress upregulates arterial matrix metalloproteinase expression and activity via endothelin A receptor activation Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H2225 - H2232. [Abstract] [Full Text] [PDF]
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 J. P. Granger Endothelin Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2003; 285(2): R298 - R301. [Full Text] [PDF]
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L. Smith, J. A. Payne, M. H. Sedeek, J. P. Granger, and R. A. Khalil Endothelin-Induced Increases in Ca2+ Entry Mechanisms of Vascular Contraction Are Enhanced During High-Salt Diet Hypertension, March 1, 2003; 41(3): 787 - 793. [Abstract] [Full Text] [PDF]
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 A. L. Grubbs, M. P. Anstadt, and A. Ergul Saphenous Vein Endothelin System Expression and Activity in African American Patients Arterioscler. Thromb. Vasc. Biol., July 1, 2002; 22(7): 1122 - 1127. [Abstract] [Full Text] [PDF]
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J. B. Giardina, K. L. Cockrell, J. P. Granger, and R. A. Khalil Low-Salt Diet Enhances Vascular Reactivity and Ca2+ Entry in Pregnant Rats With Normal and Reduced Uterine Perfusion Pressure Hypertension, February 1, 2002; 39(2): 368 - 374. [Abstract] [Full Text] [PDF]
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J. R. Ballew and G. D. Fink Role of endothelin ETB receptor activation in angiotensin II-induced hypertension: effects of salt intake Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H2218 - H2225. [Abstract] [Full Text] [PDF]
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L. A. Barron, J. B. Giardina, J. P. Granger, and R. A. Khalil High-Salt Diet Enhances Vascular Reactivity in Pregnant Rats With Normal and Reduced Uterine Perfusion Pressure Hypertension, September 1, 2001; 38(3): 730 - 735. [Abstract] [Full Text] [PDF]
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 D. Casellas, A. Herizi, A. Artuso, A. Mimran, and B. Jover Candesartan prevents L-NAME-induced cardio-renal injury in spontaneously hypertensive rats beyond hypotensive effects Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1_suppl): S84 - S90. [Abstract] [PDF]
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 T. F. Luscher and M. Barton Endothelins and Endothelin Receptor Antagonists : Therapeutic Considerations for a Novel Class of Cardiovascular Drugs Circulation, November 7, 2000; 102(19): 2434 - 2440. [Abstract] [Full Text] [PDF]
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J. C. McGiff and J. Quilley 20-HETE and the kidney: resolution of old problems and new beginnings Am J Physiol Regulatory Integrative Comp Physiol, September 1, 1999; 277(3): R607 - R623. [Abstract] [Full Text] [PDF]
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G. H. Allcock, R. C. Venema, and D. M. Pollock ETA receptor blockade attenuates the hypertension but not renal dysfunction in DOCA-salt rats Am J Physiol Regulatory Integrative Comp Physiol, July 1, 1998; 275(1): R245 - R252. [Abstract] [Full Text] [PDF]
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