(Hypertension. 2002;39:690.)
© 2002 American Heart Association, Inc.
Scientific Contributions |
From the Vascular Biology Center, Department of Physiology, Medical College of Georgia, Augusta, Ga, and Department of Physiology, Tulane University School of Medicine, New Orleans, La (J.D.I. and X.Z.); Departments of Medicine and Biochemistry, Division of Nephrology, Vanderbilt University School of Medicine (J.H.C.), Nashville, Tenn; and Department of Entomology and the University of California at Davis Cancer Center, University of California at Davis (C.M., B.D.H.), Davis, Calif.
Correspondence to J.D. Imig, Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912-2500. E-mail jdimig{at}mail.mcg.edu
| Abstract |
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Key Words: renal blood flow endothelium-derived factors microcirculation cytochrome P450 kidney
| Introduction |
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The development of hypertension following the long-term administration of initially subpressor doses of Ang II has many of the same renal and vascular changes that are associated with human hypertension.1214 We established that an elevated vascular resistance in the juxtamedullary nephron region contributes to the blunted renal pressure-natriuresis response in Ang II hypertension.15 An enhanced renal microvascular reactivity that was selective for Ang II during the early phases of hypertension has also been observed.15,16 We recently investigated the role of EETs in Ang II hypertension because CYP450 epoxygenase metabolites have antihypertensive properties, and 11,12-EET has been proposed to be an endothelium-derived hyperpolarizing factor (EDHF) in the renal microcirculation.5,16,17 These investigations revealed that acute elevation of 11,12-EET levels reversed the enhanced preglomerular reactivity to Ang II during hypertension.16 Although 11,12-EET dilates the renal microvasculature and ameliorated the enhanced reactivity to Ang II in hypertension, the epoxide hydrolase product, 11,12-DHET, was found to have no vasodilatory actions.5 Increased EET hydration to inactive DHETs could contribute to the increased preglomerular vascular reactivity and resistance present in Ang II hypertension. Therefore, the present experimental studies were performed to determine epoxide hydrolase regulation in Ang II hypertension and the ability of epoxide hydrolase inhibitors to lower arterial blood pressure in these animals.
| Materials and Methods |
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Measurement of Blood Pressure
Systolic blood pressure was measured in conscious rats by tail-cuff plethysmography to monitor the progression of hypertension. In a separate series, indwelling femoral artery catheters were implanted to measure blood pressure in conscious animals as previously described.19 Blood pressure was measured between 9:00 AM and 12:00 PM before injection of epoxide hydrolase inhibitors or corn oil vehicle.
Kidney and Liver Epoxide Hydrolase Protein Levels in Ang II Hypertensive Rats
Kidney and liver samples were harvested and processed as previously described.16,20 Samples were separated by electrophoresis on a 3% to 8% stacking Tris-glycine gel, and proteins were transferred electrophoretically to a polyvinylidene fluoride (PVDF) membrane.16 The primary antibodies used were rabbit anti-mouse soluble epoxide hydrolase (sEH) antibody (1:2000; Dr Hammock, University of California, Davis) and rabbit anti-rat microsomal epoxide hydrolase (mEH) antibody (1:1000; Drs Oesch and Arand, University of Mainz, Germany). The blots were then washed and incubated with the goat anti-rabbit secondary antibody conjugated to horseradish peroxidase. Detection was accomplished using enhanced chemiluminescence Western blotting (ECL). Band intensity was measured densitometrically and the values were factored for ß-actin.
Renal Urinary EET and DHET Levels in Ang II Hypertensive Rats
Animals were housed in separate metabolic cages (Nalgene Corp., Rochester, NY) that efficiently separated urine from food and feces. Urine was collected in a conical tube containing 5 mg triphenylphosphine and cooled by dry ice. Samples were stored at -80°C until assayed for EET and DHET levels. Urinary EET and DHET levels were determined as previously described. Because the labile 5,6-EET suffers extensive decomposition during sample extraction and purification 5,6-EET levels were not determined.3 Urine samples are mixed with an equimolar mixture of 1-C14 labeled (54 µCi/µmol) 8,9-, 11,12-, and 14,15-EET (20 to 30 ng each) or 1-C14 labeled (54 µCi/µmol) 5,6-, 8,9-, 11,12-, and 14,15-DHET (20 to 30 ng each). Next, the samples were extracted, purified, derivatized, and quantified by negative ion chemical ionization/gas chromatography-mass spectroscopy (NICI/GS/MS) as described.16,17
Statistical Analysis
All data are presented as mean±SEM. The significance of differences between groups for the blood pressure data were evaluated with an ANOVA for repeated measures followed by a Duncans multiple range post hoc test. An unpaired 2-tailed t-test was applied to compare the sEH and mEH protein levels and urinary EET and DHET levels. A P value of <0.05 was considered significant.
| Results |
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The effect of NCND on systolic and arterial blood pressures in Ang II hypertensive rats is presented in Figure 1. Systolic blood pressure averaged 114±3 mm Hg before minipump implantation and increased significantly above control levels by day 10 to 187±6 mm Hg in animals receiving Ang II. Corn oil vehicle (0.5 mL, IP) treatment for 4 days did not change systolic blood pressure in Ang II hypertensive animals. NCND (3 mg/d, IP) decreased systolic blood pressure to 157±5 mm Hg on day 13 in animals receiving Ang II but did not alter blood pressure in normotensive animals. Measurement of blood pressure by indwelling arterial catheters in conscious animals with free movement in their cages confirmed that NCND had antihypertensive properties when administered to Ang II-infused rats (Figure 1, bottom panel). Administration of the mEH inhibitor dodecylamine (3 mg/d, 189±5 mm Hg, n=4), or the potential metabolite of the sEH inhibitor N-cyclohexylforamide (3 mg/d, 192±4 mm Hg, n=4) to Ang II hypertensive animals for 4 days did not lower systolic blood pressure.
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Figures 2 presents representative Western blots and densitometric analysis of epoxide hydrolase protein expression in the liver and kidney. Western blots and densitometric analysis demonstrate that kidney sEH protein expression was increased 2-fold 2 weeks after the start of Ang II infusion (Figure 2, top). The greater variability of sEH expression observed in the control Sprague-Dawley rats confirms previous findings that renal cortical sEH expression is low to barely detectable in Wistar-Kyoto (WKY) and Sprague-Dawley rats.11 Likewise, liver sEH protein expression was increased in Ang II hypertension, but this increase did not reach statistical significance (P=0.55) and was not as robust as that observed in the kidney. In contrast, kidney and liver mEH protein expression was not different between hypertensive and normotensive animals (Figure 2, bottom).
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Urinary EET and DHET levels were determined by NICI/GC/MS in normotensive and Ang II hypertensive rats. All 4 EET regioisomers were detected, but of the 4 DHET regioisomers only 14,15-DHET reached measurable levels. Urine was collected between days 11 and 12 for measurement of EET and DHET levels. Urinary excretion averaged 16.8±1.6 mL/day in normotensive rats and was slightly elevated (22.9±3.3 mL/day) in Ang II-infused rats. Administration of NCND to Ang II-infused rats resulted in a diuresis (34.1±1.2 mL/day; P<0.05) that corresponded with the decrease in systolic blood pressure on day 12. EET levels were decreased and 14,15-DHET levels increased 2 weeks following the start of Ang II infusion (Table 1 and Figure 3). Urinary EET levels in Ang II hypertension were significantly lower than those observed in normotensive animals, and averaged 5.7±1.2 and 10.8±1.9 ng/d (P<0.05) respectively. A significant 40% increase in urinary EETs (8.0±1.6; P<0.05) occurred in Ang II hypertensive rats treated with NCND (Table 1). Likewise, 14,15-DHET excretion decreased and averaged 4.7±1.3 ng/d in NCND-treated hypertensive animals (Figure 3).
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| Discussion |
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Epoxide hydrolase enzymes catalyze the conversion of epoxides to their corresponding diols by the addition of water.11,23,24 14,15-EET appears to be a better substrate than 11,12-EET for endothelial sEH, although both are turned over rapidly.23 In the renal microcirculation the predominant vasodilatory EETs are 11,12-EET and 14,15-EET,5,25 and increased conversion of these epoxides to their corresponding diol could reduce this antihypertensive attribute. Genetic polymorphisms for the mEH and sEH enzymes have been described in the human population,26,27 and a mEH gene polymorphism has recently been associated with preeclampsia.26 Linkage of these epoxide hydrolase gene polymorphisms to other cardiovascular diseases is not yet known. Nonetheless, we found that kidney and liver mEH were not altered 2 weeks following the start of Ang II infusion. This finding is in agreement with a previous report that renal mEH protein expression is not different between spontaneously hypertensive (SHR) and white Wistar-Kyoto (WKY) rats.11 In support of the concept that kidney sEH contributes to the long-term regulation of arterial blood pressure, we observed much larger increases in renal cortical compared with liver sEH in Ang II hypertensive animals.
The present findings demonstrate that sEH contributes significantly to the elevated blood pressure in Ang II-dependent hypertension. Besides elevating EET levels, sEH inhibition could lower blood pressure in other ways. sEH also converts the linoleic acid epoxides to their corresponding diols.24,28,29 Preliminary experiments have failed to reveal any significant influence of the linoleic acid epoxides, leukotoxin or iso-leukotoxin, on renal microvascular function (data not shown). These observations support the postulate that CYP450 epoxygenase metabolites derived from arachidonic acid are the primary epoxides involved in the regulation of renal hemodynamic function. Secondly, sEH inhibitors can alter incorporation of EETs into endothelial cell phospholipids, increase the conversion of 11,12-EET and 14,15-EET to chain shortened epoxy-fatty acids, and enhance the vasodilatory actions of EETs.23,30,31 The possible contribution of EET incorporation into endothelial cell membranes and chain shortened epoxy-fatty acids to the blood pressure lowering effects of NCND remain unknown. Nevertheless, the fact that NCND resulted in a diuresis, increased urinary EETs, and decreased urinary 14,15-DHET excretion rates supports the notion that elevation of renal vasodilatory and natriuretic EETs are partially responsible for the antihypertensive effect produced by sEH inhibition.
The ability of NCND to lower blood pressure in Ang II hypertension suggests that kidney sEH plays a central role in the development of hypertension. Two recent reports have provided evidence that sEH is important for the long-term regulation of arterial blood pressure. Sinal et al10 demonstrated that male sEH gene-disrupted mice have lower systolic blood pressures when compared with wild-type mice. Renal production of DHETs was decreased and EET formation increased in the sEH (-/-) mice, suggesting an important role for epoxygenase metabolism in the regulation of blood pressure.10 A pivotal role for the sEH enzyme in the pathogenesis of experimental hypertension has also been demonstrated. Yu et al11 showed that kidneys of the SHR have increased expression of sEH and urinary DHET excretion. Moreover, administration of a single dose of N,N'dicyclohexyl urea (DCU) decreased urinary DHET excretion and lowered blood pressure in the SHR.11 Blood pressure returned to a value similar to vehicle-injected SHR by 24 hours. In agreement with this finding, we did not observe a significant lowering of systolic blood pressure 24 hours after the administration of the first dose of NCND. In contrast, repeated administration of NCND resulted in a sustained antihypertensive effect. NCND administered once daily for up to 4 days lowered systolic blood pressure by 23 mm Hg by day 2, and this level was maintained to day 4. The sustained blood pressure lowering effect of NCND with time could be due to a build up of NCND or a bioactive metabolite of the drug with repeated administration. Further investigations will be needed to clearly define the mechanisms by which sEH inhibitors lower arterial blood pressure.
In summary, the current study demonstrated that kidney sEH protein levels were elevated in Ang II hypertension, and this was associated with increased levels of urinary 14,15-DHET. These studies demonstrate that increased renal sEH leads to increased EET hydration in Ang II hypertension. Administration of the selective sEH inhibitor, NCND, for 4 days lowered arterial blood pressure in Ang II hypertensive animals. Thus, the regulation of EETs and the sEH enzyme is a new target for therapeutic intervention in cardiovascular diseases.
| Acknowledgments |
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Received September 23, 2001; first decision October 29, 2001; accepted November 21, 2001.
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J. D. Imig Epoxide hydrolase and epoxygenase metabolites as therapeutic targets for renal diseases Am J Physiol Renal Physiol, September 1, 2005; 289(3): F496 - F503. [Abstract] [Full Text] [PDF] |
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J. M. Seubert, F. Xu, J. P. Graves, J. B. Collins, S. O. Sieber, R. S. Paules, D. L. Kroetz, and D. C. Zeldin Differential renal gene expression in prehypertensive and hypertensive spontaneously hypertensive rats Am J Physiol Renal Physiol, September 1, 2005; 289(3): F552 - F561. [Abstract] [Full Text] [PDF] |
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X. Fang, S. Hu, T. Watanabe, N. L. Weintraub, G. D. Snyder, J. Yao, Y. Liu, J. Y.-J. Shyy, B. D. Hammock, and A. A. Spector Activation of Peroxisome Proliferator-Activated Receptor {alpha} by Substituted Urea-Derived Soluble Epoxide Hydrolase Inhibitors J. Pharmacol. Exp. Ther., July 1, 2005; 314(1): 260 - 270. [Abstract] [Full Text] [PDF] |
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J. G. Maresh, H. Xu, N. Jiang, C. G. Gairola, and R. V. Shohet Tobacco smoke dysregulates endothelial vasoregulatory transcripts in vivo Physiol Genomics, May 11, 2005; 21(3): 308 - 313. [Abstract] [Full Text] [PDF] |
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O. Jung, R. P. Brandes, I.-H. Kim, F. Schweda, R. Schmidt, B. D. Hammock, R. Busse, and I. Fleming Soluble Epoxide Hydrolase Is a Main Effector of Angiotensin II-Induced Hypertension Hypertension, April 1, 2005; 45(4): 759 - 765. [Abstract] [Full Text] [PDF] |
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T. Vera, M. Taylor, Q. Bohman, A. Flasch, R. J. Roman, and D. E. Stec Fenofibrate Prevents the Development of Angiotensin II-Dependent Hypertension in Mice Hypertension, April 1, 2005; 45(4): 730 - 735. [Abstract] [Full Text] [PDF] |
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Y. Zhou, H.-H. Chang, J. Du, C.-Y. Wang, Z. Dong, and M.-H. Wang Renal epoxyeicosatrienoic acid synthesis during pregnancy Am J Physiol Renal Physiol, January 1, 2005; 288(1): F221 - F226. [Abstract] [Full Text] [PDF] |
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X. Fang, N. L. Weintraub, R. B. McCaw, S. Hu, S. D. Harmon, J. B. Rice, B. D. Hammock, and A. A. Spector Effect of soluble epoxide hydrolase inhibition on epoxyeicosatrienoic acid metabolism in human blood vessels Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2412 - H2420. [Abstract] [Full Text] [PDF] |
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S. Batkai, P. Pacher, D. Osei-Hyiaman, S. Radaeva, J. Liu, J. Harvey-White, L. Offertaler, K. Mackie, M. A. Rudd, R. D. Bukoski, et al. Endocannabinoids Acting at Cannabinoid-1 Receptors Regulate Cardiovascular Function in Hypertension Circulation, October 5, 2004; 110(14): 1996 - 2002. [Abstract] [Full Text] [PDF] |
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H. Jiang, J. C. McGiff, J. Quilley, D. Sacerdoti, L. M. Reddy, J. R. Falck, F. Zhang, K. M. Lerea, and P. Y-K Wong Identification of 5,6-trans-Epoxyeicosatrienoic Acid in the Phospholipids of Red Blood Cells J. Biol. Chem., August 27, 2004; 279(35): 36412 - 36418. [Abstract] [Full Text] [PDF] |
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E. A. Dos Santos, A. J. Dahly-Vernon, K. M. Hoagland, and R. J. Roman Inhibition of the formation of EETs and 20-HETE with 1-aminobenzotriazole attenuates pressure natriuresis Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2004; 287(1): R58 - R68. [Abstract] [Full Text] [PDF] |
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X. Zhao, T. Yamamoto, J. W. Newman, I.-H. Kim, T. Watanabe, B. D. Hammock, J. Stewart, J. S. Pollock, D. M. Pollock, and J. D. Imig Soluble Epoxide Hydrolase Inhibition Protects the Kidney from Hypertension-Induced Damage J. Am. Soc. Nephrol., May 1, 2004; 15(5): 1244 - 1253. [Abstract] [Full Text] [PDF] |
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A. E. Enayetallah, R. A. French, M. S. Thibodeau, and D. F. Grant Distribution of Soluble Epoxide Hydrolase and of Cytochrome P450 2C8, 2C9, and 2J2 in Human Tissues J. Histochem. Cytochem., April 1, 2004; 52(4): 447 - 454. [Abstract] [Full Text] [PDF] |
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Z. Yu, B. B. Davis, C. Morisseau, B. D. Hammock, J. L. Olson, D. L. Kroetz, and R. H. Weiss Vascular localization of soluble epoxide hydrolase in the human kidney Am J Physiol Renal Physiol, April 1, 2004; 286(4): F720 - F726. [Abstract] [Full Text] [PDF] |
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D. N. Muller, J. Theuer, E. Shagdarsuren, E. Kaergel, H. Honeck, J.-K. Park, M. Markovic, E. Barbosa-Sicard, R. Dechend, M. Wellner, et al. A Peroxisome Proliferator-Activated Receptor-{alpha} Activator Induces Renal CYP2C23 Activity and Protects from Angiotensin II-Induced Renal Injury Am. J. Pathol., February 1, 2004; 164(2): 521 - 532. [Abstract] [Full Text] [PDF] |
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T. Thum and J. Borlak Mechanistic Role of Cytochrome P450 Monooxygenases in Oxidized Low-Density Lipoprotein-Induced Vascular Injury: Therapy Through LOX-1 Receptor Antagonism? Circ. Res., January 9, 2004; 94 (1): e1 - e13. [Abstract] [Full Text] [PDF] |
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G. O. Ogungbade, L. A. Akinsanmi, H. Jiang, and A. O. Oyekan Role of epoxyeicosatrienoic acids in renal functional response to inhibition of NO production in the rat Am J Physiol Renal Physiol, November 1, 2003; 285(5): F955 - F964. [Abstract] [Full Text] [PDF] |
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K. M. Hoagland, A. K. Flasch, and R. J. Roman Inhibitors of 20-HETE Formation Promote Salt-Sensitive Hypertension in Rats Hypertension, October 1, 2003; 42(4): 669 - 673. [Abstract] [Full Text] [PDF] |
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S. I. Pomposiello, J. Quilley, M. A. Carroll, J. R. Falck, and J. C. McGiff 5,6-Epoxyeicosatrienoic Acid Mediates the Enhanced Renal Vasodilation to Arachidonic Acid in the SHR Hypertension, October 1, 2003; 42(4): 548 - 554. [Abstract] [Full Text] [PDF] |
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T. Watanabe, C. Morisseau, J. W. Newman, and B. D. Hammock IN VITRO METABOLISM OF THE MAMMALIAN SOLUBLE EPOXIDE HYDROLASE INHIBITOR, 1-CYCLOHEXYL-3-DODECYL-UREA Drug Metab. Dispos., July 1, 2003; 31(7): 846 - 853. [Abstract] [Full Text] [PDF] |
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J. W. Newman, C. Morisseau, T. R. Harris, and B. D. Hammock The soluble epoxide hydrolase encoded by EPXH2 is a bifunctional enzyme with novel lipid phosphate phosphatase activity PNAS, February 18, 2003; 100(4): 1558 - 1563. [Abstract] [Full Text] [PDF] |
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M. Fornage, C. A. Hinojos, B. W. Nurowska, E. Boerwinkle, B. D. Hammock, C. H.P. Morisseau, and P. A. Doris Polymorphism in Soluble Epoxide Hydrolase and Blood Pressure in Spontaneously Hypertensive Rats Hypertension, October 1, 2002; 40(4): 485 - 490. [Abstract] [Full Text] [PDF] |
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I. Fleming To Move or Not To Move?: Cytochrome P450 Products and Cell Migration Circ. Res., May 17, 2002; 90(9): 936 - 938. [Full Text] [PDF] |
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