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(Hypertension. 2005;46:366.)
© 2005 American Heart Association, Inc.

Original Articles

Peroxisome Proliferator-Activated Receptor- Activation Reduces Salt-Dependent Hypertension During Chronic Endothelin B Receptor Blockade

Jan Michael Williams; Xueying Zhao; Mong H. Wang; John D. Imig; David M. Pollock

From the Department of Physiology (J.M.W., M.H.W., J.D.I., D.M.P.) and Vascular Biology Center (J.M.W., X.Z., J.D.I., D.M.P.), Medical College of Georgia, Augusta.

Correspondence to David M. Pollock, PhD, Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912-2500. E-mail dpollock{at}mail.mcg.edu

	Abstract

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Endothelin B (ET_B) receptor stimulation inhibits sodium transport in a similar fashion as 20-HETE. Clofibrate, a peroxisome proliferator-activated receptor- (PPAR-) agonist, increases protein expression of cytochrome P450 4A (CYP4A), which is responsible for 20-HETE synthesis in the kidney. Experiments were designed to determine whether clofibrate reduces hypertension associated with chronic ET_B receptor blockade. Male Sprague-Dawley rats received either normal-salt (0.8% NaCl) or high-salt (8% NaCl) diet for 10 days. Female rats were fed a high-salt (8% NaCl) diet for 10 days. During the last 7 days, rats of both sexes were divided into 3 treatment groups: (1) clofibrate in drinking water (80 mg per day), (2) ET_B receptor antagonist A-192621 in food (10 mg/kg per day), or (3) clofibrate and A-192621. During ET_B receptor blockade, clofibrate had no effect on mean arterial pressure (MAP) under normal salt conditions. In contrast, clofibrate significantly inhibited the increase in MAP produced by A-192621 in rats fed a high-salt diet (34±3 versus 19±4 mm Hg; P <0.05). Similar results were observed in female rats administered A-192621 and fed a high-salt diet. ET_B receptor blockade significantly decreased CYP4A protein expression in the renal cortex of rats on high salt. Clofibrate significantly increased renal cortical and medullary CYP4A protein expression in A-192621–treated male rats on high salt. Therefore, chronic PPAR- agonist treatment reduces salt-dependent hypertension produced by ET_B receptor blockade in male and female Sprague-Dawley rats. This suggests a possible relationship between ET_B receptor activation and the maintenance of CYP4A protein expression in the kidney of rats fed a high-salt diet.

Key Words: endothelin • blood pressure • hypertension, sodium-dependent

	Introduction

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Endothelin-1 (ET-1) is a vasoactive peptide that causes vasoconstriction and vasodilation by binding to ET_A receptors on vascular smooth muscle cells and ET_B receptors on endothelial cells, respectively.^1–3 In the kidney, ET-1 is synthesized from a variety of cells such as vascular endothelium, mesangial cells, tubular epithelial cells, and medullary interstitium.^4–10 The primary receptor subtype on renal tubular epithelial cells is the ET_B receptor.³ Studies have demonstrated that ET-1 stimulates sodium and water excretion through ET_B receptor activation.¹¹ Consistent with a pronatriuretic function, our laboratory has shown that blocking ET_B receptors causes salt-dependent hypertension along with elevated plasma ET-1 levels.^12,13 The latter effect is thought to be attributable to reduced clearance of ET-1 in the absence of ET_B receptor availability.

The role of cytochrome P450 (CYP450) hydroxylase metabolites in the maintenance of arterial pressure is complex because of their contrasting hypertensive and antihypertensive properties.¹⁴ Clofibrate, a peroxisome proliferator activated receptor- (PPAR-) agonist, has been shown to reduce arterial pressure in Dahl salt-sensitive rats on high salt diet by inducing the genes that code for CYP4504A (CYP4A) enzymes in the renal cortex.^15,16 CYP4A is the enzyme responsible for the synthesis of 20-HETE. Interestingly, 20-HETE has actions to reduce sodium transport and, like ET_B receptor activation, has been implicated in salt-dependent hypertension.^17–21

Previous studies have provided evidence that 20-HETE contributes to ET-1–mediated natriuretic responses.²² Blockade of CYP4A and 20-HETE prevented the increase in urinary sodium excretion produced by ET-1.²³ Similarly, inhibition of 20-HETE formation in isolated proximal tubules prevented the blockade of ion transport produced by ET-1, indicating that 20-HETE acts as a second messenger of ET-1 in the proximal tubule.²³ Because the ET-1–mediated diuretic and natriuretic effects are through ET_B activation, it is reasonable to presume that ET-1 stimulates 20-HETE formation through ET_B receptors. The purpose of the present study was to determine the influence of PPAR- activation and upregulation of CYP4A in the salt-sensitive hypertension produced by chronic ET_B receptor blockade.

	Methods

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Telemetry Blood Pressure Measurements
Telemetry transmitters (Data Sciences International) were implanted according to manufacturer specifications into male and female Sprague-Dawley rats (175 to 200 g; Harlan Laboratories; Indianapolis, Ind) as described previously.¹² In brief, a midline incision was used to expose the abdominal aorta, which was momentarily occluded to allow implantation of the transmitter catheter that was secured in place with tissue glue. The transmitter body was sutured to the abdominal wall while closing the incision. The skin was closed with staples that were removed 7 to 10 days later, after the incision was healed. Rats were returned to their individual cages and allowed to recover for 1 week before being used in experiments. Cages were placed on top of the telemetry receivers, and arterial pressure and heart rate measurements were recorded continuously, except on days when rats were placed in metabolic cages.

Protocol
Rats were given free access to chow that contained either normal (0.8%) or high (8%) NaCl for 10 days. After 3 days of baseline, rats were placed in metabolic cages for 24-hour urine collection. Then rats were divided into 3 groups: (1) clofibrate, a PPAR- agonist, at 80 mg per day in the drinking water; (2) A-192621, a selective ET_B receptor antagonist, at 10 mg/kg per day in the food; and (3) clofibrate and A-192621. The doses of A-192621 and clofibrate were chosen from previously published studies.^12,13,16 Rats were again placed in metabolic cages on the seventh day of drug treatment. After 7 days of treatment with A-192621 or clofibrate, rats were anesthetized with pentobarbital (65 mg/kg IP), and kidneys were removed and separated into the renal cortex and renal medulla before being frozen in liquid nitrogen.

Immunoblot Analysis of CYP4A Protein
Kidney cortex and medulla were homogenized in buffer containing 100 mmol/L Tris-HCl and 1.15% KCl, pH 7.4. Homogenates were centrifuged at 10 000g for 30 minutes. Protein was separated by electrophoresis on 10% stacking Tris-glycine gels before being were transferred electrophoretically to nitrocellulose membranes. The primary antibodies used were goat anti-rat CYP4A1 polyclonal antibody (1:2000; BD Gentest) and rabbit anti-rat CYP2C23 polyclonal antibody (1:5000; Dr Capedevila, Vanderbilt University, Nashville, Tenn). Blots were then washed in a PBS-0.1% Tween 20 solution and incubated with their respective secondary antibodies for 1 hour at room temperature and washed again. The secondary antibodies for CYP4A1 and CYP2C23 were donkey antigoat IgG-horseradish peroxidase (HRP; 1:40 000) and goat anti-rabbit IgG-HRP (1:100 000), respectively. Detection was accomplished with the use of enhanced chemiluminescence (ECL; Amersham Corp), and blots were exposed to x-ray film (Hyperfilm-ECL; Amersham Corp). CYP4A1 band intensity was measured densitometrically, and the values were normalized to expression of ß-actin.

Statistical Analysis
ANOVA for repeated measures, combined with post hoc tests, was used for statistical evaluation of mean values for every 12-hour telemetry measurement (SuperANOVA; Abacus Concepts Inc.). ANOVA combined with Newman-Keuls multiple comparison tests was used for statistical evaluation of mean values for 24-hour arterial pressure and heart rate telemetry measurements and CYP4A protein expression (Graph Pad Prism 4; Graph Pad Software, Inc.). Values are reported as means±SE with P <0.05 being considered significant.

	Results

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On a normal-salt diet, all groups of rats had a similar baseline arterial pressure averaging 106±2 mm Hg during the final 24 hours of blood pressure measurement before drug treatment (Figure 1). Clofibrate treatment had no effect on mean arterial pressure (MAP). Blockade of ET_B receptors with A-192621 (10 mg/kg per day) significantly increased MAP by 15±3 mm Hg on the final day compared with baseline (P <0.05) and was not statistically different from male rats treated with A-192621 plus clofibrate; MAP increased by 7±2 mm Hg in the latter group. There were no significant differences in heart rate between the groups of rats on a normal-salt diet (Table).

View larger version (17K): [in this window] [in a new window]   Figure 1. MAP in conscious male rats maintained on a normal-salt diet (0.8% NaCl diet) during treatment an ETB receptor antagonist A-192621 (10 mg/kg per day) or clofibrate (80 mg per day), a PPAR- agonist. The arrow indicates the beginning of the drug treatment period. Values are means±SE for 12-hour periods. *P <0.05 vs clofibrate group (n=4 per group).

View this table: [in this window] [in a new window]   Metabolic Cage and Telemetry Data of Rats Treated With Clofibrate, A-192621, and A-192621 Plus Clofibrate

As shown in Figure 2, placing male rats on a high-salt diet produced a small but significant increase in basal arterial pressures compared with male rats on a normal-salt diet; 24 hour MAP was 118±2 mm Hg by the third day on the high-salt diet. Treatment with A-192621 significantly increased MAP in male rats compared with baseline and compared with rats treated with clofibrate alone; the change in 24-hour MAP was 34±3 versus –8±1 mm Hg in A-192621 versus clofibrate-treated rats, respectively (P <0.05). The decrease in MAP produced by clofibrate treatment alone in rats on a high-salt diet was small but significant compared with baseline. Administration of clofibrate significantly inhibited the increase in MAP produced by A-192621; the change in 24-hour MAP was 19±4 mm Hg (P <0.05 versus A-192621 alone). There were no significant differences in heart rate among groups of rats on a high-salt diet (Table).

View larger version (19K): [in this window] [in a new window]   Figure 2. MAP in conscious male rats maintained on a high-salt diet (8.0% NaCl diet) during treatment with ETB receptor antagonist A-192621 (10 mg/kg per day) or clofibrate (80 mg per day), a PPAR- agonist. The high-salt diet started on day 0, and the arrow indicates the beginning of the drug treatment period. Values are means±SE for 12-hour periods. *P <0.05 vs clofibrate group and P <0.05 vs A-192621 (n=7 per group).

Similar to male rats, blockade of ET_B receptors in female rats on a high-salt diet significantly increased in MAP (Figure 3). The change in MAP from baseline was 29±4 mm Hg in female rats treated with A-192621 alone; that was significantly reduced in rats given A-192621 plus clofibrate. The change in MAP was 15±2 mm Hg in the latter group. Clofibrate alone did not have a significant effect on MAP in female rats on a high-salt diet. The different drug treatments had no effect on heart rate in female rats (Table).

View larger version (17K): [in this window] [in a new window]   Figure 3. MAP in conscious female rats maintained on a normal-salt diet (8.0% NaCl diet) during treatment with ETB receptor antagonist A-192621 (10 mg/kg per day) or clofibrate (80 mg per day), a PPAR- agonist. The high-salt diet started on day 0, and the arrow indicates the beginning of the drug treatment period. Values are means±SE for 12-hour periods. *P <0.05 vs clofibrate group and P <0.05 vs A-192621 (n=4 per group).

Before treatment with A-192621 or clofibrate, 24-hour food and water intake, as well as urine volume and sodium excretion, was not different among groups of rats on normal- or high-salt diets (data not shown). Similarly, at the end of the drug treatment period, food and water intake was not different among groups of rats on the same diet; nor were there any differences in urine volume and sodium excretion (Table).

In male rats on a high-salt diet, there was a tendency for clofibrate treatment to increase renal cortical CYP4A protein expression, but this did not reach statistical significance compared with untreated control rats (Figure 4A). Chronic A-192621 treatment significantly decreased renal cortical CYP4A protein expression compared with untreated control rats. Administration of clofibrate significantly increased cortical CYP4A protein expression in male rats on a high-salt diet treated with A-192621. Clofibrate treatment significantly increased CYP4A expression in the renal medulla of rats on high salt alone and rats fed a high-salt diet during chronic ET_B receptor blockade (Figure 4B). A-192621 treatment alone had no effect on renal medullary CYP4A expression. Neither clofibrate nor A-192621 treatments had any effect on CYP2C23 protein expression in the renal cortex or renal medulla (Figure 5A and 5B).

View larger version (24K): [in this window] [in a new window]   Figure 4. The ratio of renal cortical (A) and medullary (B) CYP4A protein expression normalized to ß-actin protein expression in male rats on a high-salt diet. Values are means±SE. *P <0.05 vs control group and P <0.05 vs A-192621 (n=4 per group).

View larger version (23K): [in this window] [in a new window]   Figure 5. Renal cortical (A) and medullary (B) CYP2C23 protein expression in male rats on a high-salt diet.

	Discussion

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Recently, studies from our laboratory provided evidence that blocking ET_B receptors causes a significant increase in arterial pressure in rats on a normal-salt diet and that this increase in arterial pressure is augmented by a high-salt diet.^12,13 Therefore, the lack of ET_B receptor function causes a salt-dependent hypertension. Similar to ET_B-deficient rats,^24,25 the hypertension can be attenuated with an ET_A receptor antagonist.^12,26 These results indicate that the elevation in arterial pressure is attributable to the blockade of the antihypertensive effects of ET_B receptors and to the stimulation of the prohypertensive effects of ET_A receptors. The important findings from the present study indicate that blocking ET_B receptors in rats on a high-salt diet decreased renal cortical CYP4A protein expression and that the administration of clofibrate, a PPAR- agonist, reversed the decrease in renal CYP4A expression and the increase in arterial pressure produced by chronic ET_B receptor blockade.

The current study examined whether the salt-dependent hypertension produced by chronic ET_B receptor blockade is related to a reduction in the protein levels of CYP4A enzymes. Previous studies have demonstrated that the induction of the renal CYP4A enzyme attenuates the development of hypertension in Dahl salt-sensitive rats^15,16,21 and that the inhibition of 20-HETE, a metabolite of CYP4A, causes hypertension.^19,27 Additionally, the antihypertensive actions of 20-HETE can be attributed to inhibition of sodium transport by the proximal tubule and thick ascending limb of the loop of Henle.^14,20,22 Blockade of ion transport in freshly isolated proximal tubules by ET-1 is attenuated by inhibiting 20-HETE synthesis.²² The significance of these findings and the current study provide support for the hypothesis that ET-1 increases CYP4A expression through the activation of ET_B receptors, which would result in an inhibition of sodium transport in the cortical region of the kidney via 20-HETE.

PPAR- receptors are highly expressed in the proximal tubules, but their functional role remains unclear.^28,29 Roman et al demonstrated that PPAR- activation increases CYP4A, leading to enhanced 20-HETE synthesis and to normalizing arterial pressure in Dahl salt-sensitive rats.^15,16,21 Our findings are somewhat similar because A-192621 caused a significant increase in MAP in rats fed a high-salt diet, and the administration of clofibrate inhibited this response. In contrast, clofibrate had no effect on arterial pressure in rats treated with A-192621 on a normal-salt diet.

All studies investigating the effects of chronic blockade of ET_B receptors have been conducted in male rats.^12,13 This is the first study to our knowledge that has examined chronic ET_B inhibition in female rats. A-192621 treatment in female rats on a high-salt diet increased MAP, which was very similar to the male rats on a high-salt diet. Conversely, female ET_B-deficient sl/sl rats on a high-sodium diet have significantly higher arterial pressures compared with their male counterparts.²⁴ This may be attributed to female ET_B-deficient rats not having functional ET_B receptors in their kidneys for their entire period of development. Clofibrate treatment significantly lowered MAP in A-192621–treated female rats on high-salt diet much to the same degree as male rats. Similarly, clofibrate has been shown to reduce arterial pressure in female Dahl S rats by inducing CYP4A protein expression in the renal cortex.¹⁵ Previous studies have demonstrated that androgens regulate expression of CYP450 enzymes, and androgens alone upregulate CYP450 enzymes.^30,31 In the present study, clofibrate was able to significantly increase CYP4A protein expression in male rats on a high-salt diet during chronic ET_B receptor blockade.

We cannot exclude the possible role of increased renal production of epoxyeicosatrienoic acids in mediating the decrease in arterial blood pressure in male rats on a high-salt diet during chronic ET_B blockade. PPAR- activation has been shown to induce renal CYP2C23 activity under pathological and nonpathological conditions.^32,33 Contrary to the effects of A-192621 treatment on CYP4A expression in rats on high salt, chronic ET_B blockade did not change CYP2C23 protein expression. Furthermore, clofibrate administration did not influence CYP2C23 expression in A-192621–treated rats on a high-salt diet. These data suggest that ET_B receptor activation does not regulate CYP2C23 enzyme expression in the kidney.

Our finding that chronic ET_B blockade did not change CYP4A protein expression in the renal medulla is somewhat unexpected, given the observed changes in cortical expression. There is an abundance of ET_B receptors located in the renal medulla that promote sodium and water excretion by increasing medullary blood flow or through direct inhibition of tubular transport.^34,35 Other studies have observed that ET increases production of prostaglandin E₂ (PGE₂) in several cell types within the renal medulla.^36–38 Furthermore, blockade of PGE₂ leads to a potentiation of ET-1–induced vasoconstriction.^36,39 Therefore, it would appear as though the primary mechanisms for inhibiting transport via ET_B receptors in the medulla are through the release of NO and PGE₂ production and may not be dependent on CYP450 metabolites. Further studies will need to clarify this possibility.

In conclusion, the downregulation of CYP4A protein expression in the cortex during chronic ET_B blockade may contribute to salt-dependent hypertension because the CYP4A metabolites have been shown to inhibit sodium transport from the lumen of the proximal tubule, the thick ascending limb, and the collecting duct.^22,40,41 An important finding from the current study was that inhibition of ET_B receptors significantly decreased CYP4A protein expression. These data suggest that ET-1 and ET_B receptors in rats on a high-salt diet function to maintain CYP4A enzyme expression and possibly 20-HETE production. These results indicate that chronic treatment with a PPAR- agonist can blunt the increase in arterial pressure produced by chronic ET_B receptor blockade, and ET-1, via the ET_B receptor, regulates CYP4A protein expression in the renal cortex. The specific mechanisms linking ET-1 and CYP4A have yet to be elucidated.

Perspectives
These findings suggest that CYP4A may play an important role in the development of hypertension during chronic ET_B receptor blockade. When chronically blocking ET_B receptors in rats on high-salt diet, CYP4A protein expression in the renal cortex was significantly decreased. This led us to speculate that the decrease in CYP4A expression translates to a decrease in 20-HETE synthesis that would increase tubular sodium reabsorption. Therefore, this study also provides further support for the hypothesis that 20-HETE may act as a second messenger of ET-1 to inhibit sodium transport in the cortical region of the kidney.

Escalante et al demonstrated that ET-1 and 20-HETE block ion transport in freshly isolated proximal tubules.²² Coadministration of 12,12-dibromododecenoic acid, an inhibitor of 20-HETE reduction, attenuated this effect. In addition, ET-1 stimulated the release of 20-HETE from isolated proximal tubules.²² These results provide the first line of evidence that 20-HETE may play a significant role in the natriuretic actions of ET-1. In the thick ascending limb, Plato et al provided evidence that ET-1 decreases sodium transport through the activation of ET_B receptors, which may contribute to the natriuretic effects of ET-1 observed in vivo.³⁵ Work from Roman’s laboratory has shown that 20-HETE production is decreased in the thick ascending limb of Dahl salt-sensitive rats and that the elevated Cl^– flux can be attenuated by adding 20-HETE.^42,43 Furthermore, the administration of clofibrate increased CYP4A activity and 20-HETE synthesis and improved pressure natriuresis in Dahl salt-sensitive rats.¹⁵ Together with the current study, these data provide a growing line of evidence that an interaction between ET-1 and a CYP4A metabolite, most likely 20-HETE, functions to reduce renal tubular sodium reabsorption in response to elevations in dietary salt intake.

	Acknowledgments

 
This study was supported by a predoctoral fellowship from the American Heart Association, southeast affiliate (J.M.W.), established investigator awards (D.M.P., J.D.I.), and National Institutes of Health grants HL64776 (D.M.P.), HL59699 (J.D.I.), HL74167 (D.M.P., J.D.I.), and HL70887 (M.H.W.). The authors would also like to thank Hiram Ocasio for his excellent technical assistance with telemetry measurements.

Received March 10, 2005; first decision April 7, 2005; accepted May 10, 2005.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Granger JP. Endothelin. Am J Physiol Regul Integr Comp Physiol. 2003; 285: R298–R301.[Free Full Text]

2. Rubanyi GM, Polokoff MA. Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev. 1994; 46: 325–415.[Medline] [Order article via Infotrieve]

3. Pollock DM. Renal endothelin in hypertension. Curr Opin Nephrol Hypertens. 2000; 9: 157–164.[CrossRef][Medline] [Order article via Infotrieve]

4. Marsden PA, Dorfman DM, Collins T, Brenner BM, Orkin SH, Ballermann BJ. Regulated expression of endothelin 1 in glomerular capillary endothelial cells. Am J Physiol Renal, Fluid & Electrolyte Physiol. 1991; 261: F117–F125.[Abstract/Free Full Text]

5. Sakamoto H, Sasaki S, Nakamura Y, Fushimi K, Marumo F. Regulation of endothelin-1 production in cultured rat mesangial cells. Kidney Int. 1992; 41: 350–355.[Medline] [Order article via Infotrieve]

6. Kohan DE. Production of endothelin-1 by rat mesangial cells: regulation by tumor necrosis factor. J Lab Clin Med. 1992; 119: 477–484.[Medline] [Order article via Infotrieve]

7. Schnermann JB, Zhu XL, Shu X, Yang T, Huang YG, Kretzler M, Briggs JP. Regulation of endothelin production and secretion in cultured collecting duct cells by endogenous transforming growth factor-beta. Endocrinology. 1996; 137: 5000–5008.[Abstract]

8. Todd-Turla KM, Zhu XL, Shu X, Chen M, Yu T, Smart A, Killen PD, Fejes-Toth G, Briggs JP, Schnermann JB. Synthesis and secretion of endothelin in a cortical collecting duct cell line. Am J Physiol Renal, Fluid & Electrolyte Physiol. 1996; 271: F330–F339.[Abstract/Free Full Text]

9. Kohan DE. Endothelin synthesis by rabbit renal tubule cells. Am J Physiol. 1991; 261: F221–F226.[Medline] [Order article via Infotrieve]

10. Wilkes BM, Ruston AS, Mento P, Girardi E, Hart D, Vander Molen M, Barnett R, Nord EP. Characterization of endothelin 1 receptor and signal transduction mechanisms in rat medullary interstitial cells. Am J Physiol Renal, Fluid & Electrolyte Physiol. 1991; 260: F579–F589.[Abstract/Free Full Text]

11. Vassileva I, Mountain C, Pollock DM. Functional role of ET_B receptors in the renal medulla. Hypertension. 2003; 41: 1359–1363.[Abstract/Free Full Text]

12. Pollock DM, Pollock JS. Evidence for endothelin involvement in the response to high salt. Am J Physiol Renal Physiol. 2001; 281: F144–F150.[Abstract/Free Full Text]

13. Williams JM, Pollock JS, Pollock DM. Arterial pressure response to the antioxidant tempol and ET_B receptor blockade in rats on a high-salt diet. Hypertension. 2004; 44: 770–775.[Abstract/Free Full Text]

14. Roman RJ. P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev. 2002; 82: 131–185.[Abstract/Free Full Text]

15. Alonso-Galicia M, Frohlich B, Roman RJ. Induction of P4504A activity improves pressure-natriuresis in Dahl S rats. Hypertension. 1998; 31: 232–236.[Abstract/Free Full Text]

16. Roman RJ, Ma YH, Frohlich B, Markham B. Clofibrate prevents the development of hypertension in Dahl salt-sensitive rats. Hypertension. 1993; 21: 985–988.[Abstract/Free Full Text]

17. Dos Santos EA, Dahly-Vernon AJ, Hoagland KM, Roman RJ. Inhibition of the formation of EETs and 20-HETE with 1-aminobenzotriazole attenuates pressure natriuresis. Am J Physiol Regul Integr Comp Physiol. 2004; 287: R58–R68.[Abstract/Free Full Text]

18. Zhang YB, Magyar CE, Holstein-Rathlou NH, McDonough AA. The cytochrome P-450 inhibitor cobalt chloride prevents inhibition of renal Na⁺,K⁺-ATPase and redistribution of apical NHE-3 during acute hypertension. J Am Soc Nephrol. 1998; 9: 531–537.[Abstract]

19. Hoagland KM, Flasch AK, Roman RJ. Inhibitors of 20-HETE formation promote salt-sensitive hypertension in rats. Hypertension. 2003; 42: 669–673.[Abstract/Free Full Text]

20. Hoagland KM, Flasch AK, Dahly-Vernon AJ, dos Santos EA, Knepper MA, Roman RJ. Elevated BSC-1 and ROMK expression in Dahl salt-sensitive rat kidneys. Hypertension. 2004; 43: 860–865.[Abstract/Free Full Text]

21. Wilson TW, Alonso-Galicia M, Roman RJ. Effects of lipid-lowering agents in the Dahl salt-sensitive rat. Hypertension. 1998; 31: 225–231.[Abstract/Free Full Text]

22. Escalante BA, McGiff JC, Oyekan AO. Role of cytochrome P-450 arachidonate metabolites in endothelin signaling in rat proximal tubule. Am J Physiol Renal Physiol. 2002; 282: F144–F150.[Abstract/Free Full Text]

23. Oyekan AO, McAward K, McGiff JC. Renal functional effects of endothelins: dependency on cytochrome P450-derived arachidonate metabolites. Biol Res. 1998; 31: 209–215.[CrossRef][Medline] [Order article via Infotrieve]

24. Taylor TA, Gariepy CE, Pollock DM, Pollock JS. Gender differences in ET and NOS systems in ET_B receptor-deficient rats: effect of a high salt diet. Hypertension. 2003; 41: 657–662.[Abstract/Free Full Text]

25. Gariepy CE, Ohuchi T, Williams SC, Richardson JA, Yanagisawa M. Salt-sensitive hypertension in endothelin-B receptor-deficient rats. J Clin Invest. 2000; 105: 925–933.[Medline] [Order article via Infotrieve]

26. Elmarakby AA, Loomis ED, Pollock JS, Pollock DM. ET_A receptor blockade attenuates hypertension and decreases reactive oxygen species in ET_B receptor deficient rats. J Cardiovasc Pharmacol. 2004; 44: S7–S10.[CrossRef][Medline] [Order article via Infotrieve]

27. Stec DE, Mattson DL, Roman RJ. Inhibition of renal outer medullary 20-HETE production produces hypertension in Lewis rats. Hypertension. 1997; 29: 315–319.[Abstract/Free Full Text]

28. Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology. 1996; 137: 354–366.[Abstract]

29. Kliewer SA, Forman BM, Blumberg B, Ong ES, Borgmeyer U, Mangelsdorf DJ, Umesono K, Evans RM. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci U S A. 1994; 91: 7355–7359.[Abstract/Free Full Text]

30. Nakagawa K, Marji JS, Schwartzman ML, Waterman MR, Capdevila JH. Androgen-mediated induction of the kidney arachidonate hydroxylases is associated with the development of hypertension. Am J Physiol Regul Integr Comp Physiol. 2003; 284: R1055–R1062.[Abstract/Free Full Text]

31. Sundseth SS, Waxman DJ. Sex-dependent expression and clofibrate inducibility of cytochrome P450 4A fatty acid omega-hydroxylases. Male specificity of liver and kidney CYP4A2 mRNA and tissue-specific regulation by growth hormone and testosterone. J Biol Chem. 1992; 267: 3915–3921.[Abstract/Free Full Text]

32. Vera T, Taylor M, Bohman Q, Flasch A, Roman RJ, Stec DE. Fenofibrate prevents the development of angiotensin II-dependent hypertension in mice. Hypertension. 2005; 45: 730–735.[Abstract/Free Full Text]

33. Muller DN, Theuer J, Shagdarsuren E, Kaergel E, Honeck H, Park JK, Markovic M, Barbosa-Sicard E, Dechend R, Wellner M, Kirsch T, Fiebeler A, Rothe M, Haller H, Luft FC, Schunck WH. A peroxisome proliferator-activated receptor-alpha activator induces renal CYP2C23 activity and protects from angiotensin II-induced renal injury. Am J Pathol. 2004; 164: 521–532.[Abstract/Free Full Text]

34. Gurbanov K, Rubinstein I, Hoffman A, Abassi Z, Better OS, Winaver J. Differential regulation of renal regional blood flow by endothelin-1. Am J Physiol Renal, Fluid & Electrolyte Physiol. 1996; 271: F1166–F1172.[Abstract/Free Full Text]

35. Plato CF, Pollock DM, Garvin JL. Endothelin inhibits thick ascending limb chloride flux via ET_B receptor-mediated NO release. Am J Physiol Renal Physiol. 2000; 279: F326–F333.[Abstract/Free Full Text]

36. Kohan DE, Padilla E, Hughes AK. Endothelin B receptor mediates ET-1 effects on cAMP and PGE2 accumulation in rat IMCD. Am J Physiol Renal, Fluid & Electrolyte Physiol. 1993; 265: F670–6.[Abstract/Free Full Text]

37. Kohan DE. Endothelins in the kidney: physiology and pathophysiology. Am J Kidney Dis. 1993; 22: 493–510.[Medline] [Order article via Infotrieve]

38. Zeidel ML, Brady HR, Kone BC, Gullans SR, Brenner BM. Endothelin, a peptide inhibitor of Na⁺,K⁺-ATPase in intact renaltubular epithelial cells. Am J Physiol Renal, Fluid & Electrolyte Physiol. 1989; 257: C1101–C1107.

39. Silldorff EP, Yang S, Pallone TL. Prostaglandin E2 abrogates endothelin-induced vasoconstriction in renal outer medullary descending vasa recta of the rat. J Clin Invest. 1995; 95: 2734–2740.[Medline] [Order article via Infotrieve]

40. Schwartzman M, Ferreri NR, Carroll MA, Songu-Mize E, McGiff JC. Renal cytochrome P450-related arachidonate metabolite inhibits Na⁺,K⁺-ATPase. Nature. 1985; 314: 620–622.[CrossRef][Medline] [Order article via Infotrieve]

41. Escalante B, Erlij D, Falck JR, McGiff JC. Effect of cytochrome P450 arachidonate metabolites on ion transport in rabbit kidney loop of Henle. Science. 1991; 251: 799–802.[Abstract/Free Full Text]

42. Zou AP, Drummond HA, Roman RJ. Role of 20-HETE in elevating loop chloride reabsorption in Dahl SS/Jr rats. Hypertension. 1996; 27: 631–635.[Abstract/Free Full Text]

43. Ito O, Roman RJ. Role of 20-HETE in elevating chloride transport in the thick ascending limb of Dahl SS/Jr rats. Hypertension. 1999; 33: 419–423.[Abstract/Free Full Text]

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