OBJECTIVE: We examined the effects of treatment with soluble epoxide hydrolase inhibitor (sEHi) and epoxyeicosatrienoic acids (EETs) analogue (EET-A), given alone or combined, on blood pressure (BP) and ischemia/reperfusion myocardial injury in rats with angiotensin II (ANG II)-dependent hypertension. METHODS: Ren-2 transgenic rats (TGR) were used as a model of ANG II-dependent hypertension and Hannover Sprague-Dawley rats served as controls. Rats were treated for 14 days with sEHi or EET-A and BP was measured by radiotelemetry. Albuminuria, cardiac hypertrophy and concentrations of ANG II and EETs were determined. Separate groups were subjected to acute myocardial ischemia/reperfusion injury and the infarct size and ventricular arrhythmias were determined. RESULTS: Treatment of TGR with sEHi and EET-A, given alone or combined, decreased BP to a similar degree, reduced albuminuria and cardiac hypertrophy to similar extent; only treatment regimens including sEHi increased myocardial and renal tissue concentrations of EETs. sEHi and EET-A, given alone or combined, suppressed kidney ANG II levels in TGR. Remarkably, infarct size did not significantly differ between TGR and Hannover Sprague-Dawley rats, but the incidence of ischemia-induced ventricular fibrillations was higher in TGR. Application of sEHi and EET-A given alone and combined sEHi and EET-A treatment were all equally effective in reducing life-threatening ventricular fibrillation in TGR. CONCLUSION: The findings indicate that chronic treatment with either sEHi or EET-A exerts distinct antihypertensive and antiarrhythmic actions in our ANG II-dependent model of hypertension whereas combined administration of sEHi and EET-A does not provide additive antihypertensive or cardioprotective effects.

Center for Experimental Medicine Institute for Clinical and Experimental Medicine

Department of Biochemistry University of Texas Southwestern Medical Center Dallas Texas USA

Department of Developmental Cardiology Institute of Physiology Academy of Sciences of the Czech Republic Prague Czech Republic

Department of Entomology and UCD Cancer Center University of California Davis California

Department of Pharmacology and Toxicology Medical College of Wisconsin Milwaukee Wisconsin

Department of Renal and Body Fluid Physiology Mossakowski Medical Research Centre Polish Academy of Science Warsaw Poland

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Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007; 357:121–135. PubMed

Altamirano F, Wang ZV, Hill JA. Cardioprotection in ischaemia-reperfusion injury: novel mechanisms and clinical translation. J Physiol 2015; 17:3773–3788. PubMed PMC

Bulluck H, Yellon DM, Hausenloy DJ. Reducing myocardial infarct size: challenges and future opportunities. Heart 2016; 102:341–348. PubMed PMC

Heusch G Critical issues for the translation of cardioprotection. Circ Res 2017; 120:1477–1486. PubMed

Kloner RA, Hale SL, Dai W, Shi J. Cardioprotection: where to from here? Cardiovasc Drugs Ther 2017; 31:53–61. PubMed

Cabrera-Fuentes HA, Aragones J, Bernhagen J, Boening A, Boisvert WA, Botker HE, et al. From basic mechanisms to clinical applications in heart protection, new players in cardiovascular diseases and cardiac theranostics: meeting report from the third international symposium on ‘New frontiers in cardiovascular research’. Basic Res Cardiol 2016; 111:69. PubMed PMC

Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006; 3:e442. PubMed PMC

Heusch G, Libby P, Gersch B, Yellon D, Bohm M, Lopaschuk G, Opie L. Cardiovascular remodeling in coronary artery disease and heart failure. Lancet 2014; 383:1933–1943. PubMed PMC

Ferdinandy P, Hausenloy DJ, Heusch G, Baxter GF, Schulz R. Interaction of risk factors, comorbidities, and comedications with ischemia/reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning. Pharmacol Rev 2014; 66:1142–1174. PubMed

Sanada S, Komuro I, Kitakaze M. Pathophysiology of myocardial reperfusion injury: preconditioning, postconditioning, and translational aspects of protective measures. Am J Physiol 2011; 301: H1723–H1741. PubMed

Prisant LM. Hypertensive heart disease. J Clin Hypertens (Greenwich) 2005; 7:231–238. PubMed PMC

Alderman MH, Ooi WL, Cohen H, Madhavan S, Sealey JE, Laragh JH. Plasma renin activity: a risk factor for myocardial infarction in hypertensive patients. Am J Hypertens 1997; 10:1–8. PubMed

Mozaffari MS, Liu JY, Abebe W, Baban B. Mechanisms of load dependency of myocardial ischemia reperfusion injury. Am J Cardiovasc Dis 2013; 3:180–196. PubMed PMC

Agrawal V, Gupta JK, Qureshi SS, Vishwakarma VK. Role of cardiac renin angiotensin system in ischemia reperfusion injury and preconditioning of heart. Indian Heart J 2016; 68:856–861. PubMed PMC

Molgaard S, Faricelli B, Salomonsson M, Engstrom T, Treiman M. Increased myocardial vulnerability to ischemia-reperfusion injury in the presence of left ventricular hypertrophy. J Hypertens 2016; 34: 513–523. PubMed

Anderson PG, Bishop SP, Dignerness SB. Transmural progression of morphological changes during ischemia and reperfusion in the normal and hypertrophied heart. Am J Pathol 1987; 129:152–167. PubMed PMC

Minor T, Isselhard W, Sturz J. Recovery of healthy and hypertrophied hearts after global ischemia and gradual reperfusion. Ann Cardiol Angeol 1994; 43:395–399. PubMed

Snoeckx LH, van der Vusse GJ, Coumans WA, Willemsen PH, van der Nagel T, Reneman RS. Myocardial function in normal and spontaneously hypertensive rats during reperfusion after a period of global ischaemia. Cardiovasc Res 1986; 20:67–75. PubMed

Hearse DJ, Stewart DA, Green DG. Myocardial susceptibility to ischemic damage: a comparative study of disease models in the rat. Eur J Cardiol 1978; 7:437–450. PubMed

Ledvényiová-Farkašová V, Bernátová I, Balis P, Puzserova A, Bartekova M, Gablovsky I, Ravingerova T. Effects of crowding stress on tolerance to ischemia-reperfusion injury in young male and female hypertensive rats: molecular mechanisms. Can J Physiol Pharmacol 2015; 93:793–802. PubMed

Mozaffari MS, Schaffer SW. Effect of hypertension and hypertension-glucose intolerance on myocardial ischemic injury. Hypertension 2003; 42:1042–1049. PubMed

Saupe KW, Lim CC, Ingwall JS, Apstein CS, Eberli FR. Comparison of hearts with 2 types of pressure-overload left ventricular hypertrophy. Hypertension 2000; 35:1167–1172. PubMed

Wagner C, Ebner B, Tillack D, Strasser RH, Weinbrenner C. Cardioprotection by ischemic postconditioning is abrogated in hypertrophied myocardium of spontaneously hypertensive rats. J Cardiovasc Pharmacol 2013; 61:35–41. PubMed

Matsuhisa S, Otani H, Okazaki T, Yamashita K, Akita Y, Sato D, et al. Angiotensin II type 1 receptor blocker preserves tolerance to ischemia-reperfusion injury in Dahl salt-sensitive rat heart. Am J Physiol 2008; 294:H2473–H2479. PubMed

Neckář J, Kopkan L, Husková Z, Kolář F, Papoušek F, Kramer HJ, et al. Inhibition of soluble epoxide hydrolase by cis-4-[4–(3–adamantan–I–ylureido)cyclohexyl–oxy]benzoic acid exhibits antihypertensive and cardioprotective actions in transgenic rats with angiotensin II-dependent hypertension. Clin Sci 2012; 122:513–525. PubMed PMC

Alánová P, Husková Z, Kopkan L, Sporková A, Jíchová Š, Neckář J, et al. Orally active epoxyeicosatrienoic acid analog does not exhibit antihypertensive and reno- or cardioprotective actions in two-kidney, one-clip Goldblatt hypertensive rats. Vascul Pharmacol 2015; 73:45–56. PubMed

Ferdinandy P, Schulz R, Baxter GF. Interaction of cardiovascular risk with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning. Pharmacol Rev 2007; 59:418–458. PubMed

Husková Z, Kramer HJ, Vaňourková Z, Červenka L. Effects of changes in sodium balance on plasma and kidney angiotensin II levels in anesthetized and conscious Ren-2 transgenic rats. J Hypertens 2006; 24:517–527. PubMed

Kujal P, Čertíková-Chábová V, Vernerová Z, Walkowska A, Kompanowska-Jezierska E, Sadowski J, et al. Similar renoprotection after renin-angiotensin-dependent and -independent antihypertensive therapy in 5/6-nephrectomized Ren-2 transgenic rats: are there blood pressure-independent effects? Clin Exp Pharmacol Physiol 2010; 37: 1159–1169. PubMed

Halestrap AP, Richardson AP. The mitochondrial permeability transition: a current perspective on its identity and role in ischaemia/reperfusion injury. J Mol Cell Cardiol 2015; 78:129–141. PubMed

Ong SB, Dongworth RK, Cabrera-Fuentes HA, Hausenloy DJ. Role of the MPTP in conditioning the heart translability and mechanism. Br J Pharmacol 2015; 172:2074–2084. PubMed PMC

Javadov S, Jang S, Parodi-Rullán R, Khuchua Z, Kuznetsov AV. Mitochondrial permeability transition in cardiac ischemia-reperfusion: whether cyclophilin D is a viable target for cardioprotection? Cell Mol Life Sci 2017; 74:2795–2813. PubMed PMC

Gross GJ, Hsu A, Pfeiffer A, Nithipatikom K. Roles of endothelial nitric oxide synthase (eNOS) and mitochondrial permeability transition pore (MPTP) in epoxyeicosatrienoic acid (EET)-induced cardioprotection against infarction in intact rat hearts. J Mol Cell Cardiol 2013; 59:20–29. PubMed PMC

Oni-Orisan A, Alsaleh N, Lee CR, Seubert JM. Epoxyeicosatrienoic acids and cardioprotection: the road to translation. J Mol Cell Cardiol 2014; 74:199–208. PubMed PMC

Jamieson KL, Endo T, Darwesh AM, Samokhvalov V, Seubert JM. Cytochrome P450-derived eicosanoids and heart function. Pharmacol Ter 2017; 179:47–83. PubMed

Imig JD. Epoxyeicosatrienoic acids, hypertension, and kidney injury. Hypertension 2015; 65:476–482. PubMed PMC

Elmarakby AA. Reno-protective mechanisms of epoxyeicosatrienoic acids in cardiovascular disease. Am J Physiol 2012; 302:R321–R330. PubMed

Fan F, Muoya Y, Roman RJ. Cytochrome P450 eicosanoids in hypertension and renal disease. Curr Opin Nephrol Hypertens 2015; 24:37–46. PubMed PMC

Fleming I The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease. Pharmacol Rev 2014; 66:1106–1140. PubMed

Ai D, Shyy JYJ, Zhu Y. Linking an insect enzyme to hypertension: angiotensin II-epoxide hydrolase interactions. Kidney Int 2010; 77:88–92. PubMed

He J, Wang C, Zhu Y, Ai D. Soluble epoxide hydrolase: a potential target for metabolic diseases. J Diabetes 2016; 8:305–313. PubMed

Jamieson KL, Samokhvalov V, Akhnokh MK, Lee K, Cho WJ, Takawale A, et al. Genetic deletion of soluble epoxide hydrolase provides cardioprotective responses following myocardial infarction in aged mice. Prostaglandins Other Lipid Mediat 2017; 132:47–58. PubMed

Huang H, Morisseau C, Wang JF, Yang T, Falck JR, Hammock BD, Wang MH. Increasing or stabilizing renal epoxyeicosatrienoic acid production attenuates abnormal renal function and hypertension in obese rats. Am J Physiol 2007; 293:F342–F349. PubMed

Honetschlägerová Z, Sporková A, Kopkan L, Husková Z, Hwang SH, Hammock BD, et al. Inhibition of soluble epoxide hydrolase improves the impaired pressure-natriuresis relationship and attenuates the development of hypertension and hypertension-associated end-organ damage in Cyp1a1-Ren-2 transgenic rats. J Hypertens 2011; 29:1590–1601. PubMed PMC

Li J, Carroll MA, Chander PN, Falck JR, Sangras B, Stier CT. Soluble epoxide hydrolase inhibitor, AUDA, prevents early salt-sensitive hypertension. Front Biosci 2008; 13:3480–3487. PubMed

Lee CR, Imig JD, Edin ML, Foley J, DeGraff LM, Bradbury JA, et al. Endothelial expression of human cytochrome P450 epoxygenases lowers blood pressure and attenuates hypertension-induced renal injury in mice. FASEB J 2010; 24:3770–3781. PubMed PMC

Sporková A, Kopkan L, Varcabová A, Husková Z, Hwang SH, Hammock BD, et al. Role of cytochrome P450 metabolites in the regulation of renal function and blood pressure in 2-kidney, 1-clip hypertensive rats. Am J Physiol 2011; 300:R1468–R1475. PubMed PMC

Honetschlägerová Z, Husková Z, Vaňourková Z, Sporková A, Kramer HJ, Hwang SH, et al. Renal mechanisms contributing to the antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2 transgenic rats with inducible hypertension. J Physiol 2011; 589:207–219. PubMed PMC

Varcabová Š, Husková Z, Kramer HJ, Hwang SH, Hammock BD, Imig JD, et al. Antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2 transgenic rats is mediated by suppression of the intrarenal renin-angiotensin system. Clin Exp Pharmacol Physiol 2013; 40:273–281. PubMed PMC

Ma YH, Schwartzman ML, Roman RJ. Altered renal P-450 metabolism of arachidonic acid in Dahl salt-sensitive rats. Am J Physiol 1994; 267 (2 Pt 2):R579–R589. PubMed

Kaergel E, Muller DN, Honeck H, Theuer J, Shagdarsuren E, Mullaly A, et al. P450-dependent arachidonic acid metabolism and angiotensin II-induced renal damage. Hypertension 2002; 40:273–279. PubMed

Imig JD. Targeting epoxides for organ damage in hypertension. J Cardiovasc Pharmacol 2010; 56:329–335. PubMed PMC

Falck JR, Kodela R, Manne R, Atcha R, Puli N, Dubasi N, et al. 14,15-Epoxyeicosa-5,8,11-trienoic acid (14,15-EET) surrogates containing epoxide bioisosteres: influence upon vascular relaxation and soluble epoxide hydrolase inhibition. J Med Chem 2009; 52:5069–5075. PubMed PMC

Imig JD, Elmarakby A, Nithipatikom K, Wei S, Capdevila JH, Tuniki RV, et al. Development of epoxyeiocastrienoic acids analogs with in vivo antihypertensive actions. Front Physiol 2010; 1:157. PubMed PMC

Hye Khan MA, Pavlov TS, Christain SV, Neckář J, Staruschenko A, Gauthier KM, et al. Epoxyeicosatrienoic acid analogue lowers blood pressure through vasodilatation and sodium channel inhibition. Clin Sci 2014; 127:463–474. PubMed PMC

Hye Khan MA, Falck JR, Manthati VL, Campbell WB, Imig JD. Epoxyeicosatrienoic acid analog attenuates angiotensin II hypertension and kidney injury. Front Pharmacol 2014; 5:216. PubMed PMC

Jíchová Š, Kopkan L, Husková Z, Doleželová Š, Neckář J, Kujal P, et al. Epoxyeicosatrienoic acid analog attenuates the development of malignant hypertension, but does not reverse it once established: a study in Cyp1a1-Ren-2 transgenic rats. J Hypertens 2016; 34:2008–2025. PubMed PMC

Mullins JJ, Peter J, Ganten D. Fulminant hypertension in transgenic rats harboring the mouse Ren-2 gene. Nature 1990; 344:541–544. PubMed

Lee MA, Bohm M, Paul M, Bader M, Ganten U, Ganten D. Physiological characterization of the hypertensive transgenic rat TGR(mREN2)27. Am J Physiol 1996; 270 (6 Pt 1):E919–E929. PubMed

Dvořák P, Kramer HJ, Backer A, Malý J, Kopkan L, Vaněčková I, et al. Blockade of endothelin receptors attenuates end-organ damage in homozygous hypertensive Ren-2 transgenic rats. Kidney Blood Press Res 2004; 27:248–258. PubMed

Sporková A, Jíchová Š, Husková Z, Kopkan L, Nishiyama A, Hwang SH, et al. Different mechanisms of acute versus long-term antihypertensive effects of soluble epoxide hydrolase inhibition: Studies in Cyp1a1-Ren-2 transgenic rats. Clin Exp Pharmacol Physiol 2014; 41:1003–1013. PubMed PMC

Kurtz TW, Griffin KA, Bidani AK, Davisson RL, Hall JE. Recommendations for blood pressure measurements in humans and experimental animals. Part 2: Blood pressure measurements in experimental animals. Hypertension 2005; 45:299–310. PubMed

Jíchová Š, Doleželová Š, Kopkan L, Kompanowska-Jezierska E, Sadowski J, Červenka L. Fenofibrate attenuates malignant hypertension by suppression of the renin-angiotensin system: a study in Cyp1a1-Ren-2 transgenic rats. Am J Med Sci 2016; 352: 618–630. PubMed

Neckář J, Svatoňová A, Weissová R, Drahota Z, Zajíčková P, Brabcová I, et al. Selective replacement of mitochondrial DNA increases the cardioprotective effects of chronic continuous hypoxia in spontaneously hypertensive rats. Clin Sci 2017; 131:865–881. PubMed

Alánová P, Chytilová A, Neckář J, Hrdlička J, Míčová P, Holcerová K, et al. Myocardial ischemic tolerance in rats subjected to endurance exercise training during adaptation to chronic hypoxia. J Appl Physiol 2017; 122:1452–1461. PubMed

Walker MJ, Curtis MJ, Hearse DJ, Campbell RW, Janse MJ, Yellon DM, et al. The Lambeth Conventions: guidelines for the study of arrhythmias in ischaemia, infarction, and reperfusion. Cardiovasc Res 1988; 22:447–455. PubMed

Campbell WB, Fleming I. Epoxyeicosatrienoic acids and endothelium-dependent response. Pfluegers Arch 2010; 459:881–895. PubMed PMC

Imig JD, Zhao X, Falck JR, Wei S, Capdevila JH. Enhanced renal microvascular reactivity to angiotensin II in hypertension is ameliorated by the sulfonamide analog of 11,12-epoxyeicosatrienoic acid. J Hypertens 2001; 19:983–992. PubMed

Jacinto S, Mullins JJ, Mitchell KD. Enhanced renal vascular responsiveness to angiotensin II in hypertensive Ren-2 transgenic rats. Am J Physiol 1999; 276 (2 Pt 2):F315–F322. PubMed

Madhun ZT, Goldthwait DA, McKay D, Hopfer U, Douglas JG. An epoxygenase metabolite of arachidonic acid mediates angiotensin II-induced rises in cytosolic calcium in rabbit proximal tubule epithelial cells. J Clin Invest 1991; 88:456–461. PubMed PMC

Sakairi Y, Jacobson HR, Noland DT, Capdevila JH, Falck JR, Breyer MD. 5,6-EET inhibits ion transport in collecting duct by stimulating endogenous prostaglandin synthesis. Am J Physiol 1995; 268 (5 Pt 2): F931–F939. PubMed

Kobori H, Nangaku M, Navar LG, Nishiyama A. The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev 2007; 59:251–287. PubMed

Guyton AC, Hall JE, Coleman TG, Manning RD Jr, Norman RA Jr. The dominant role of the kidneys in long-term arterial pressure regulation in normal and hypertensive states In: Laragh JH, Brenner BM, editors. Hypertension: pathophysiology, diagnosis and management. New York, NY: Raven Press; 1995. pp. 1311–1328.

Cowley AW, Roman RJ. The role of the kidney in hypertension. JAMA 1996; 275:1581–1589. PubMed

Hall JE, Granger JP, Hall ME. Physiology and pathophysiology of hypertension In: Albeprn RJ, Caplan MJ, Moe OW, editors. Seldin and Giebisch’s the kidney physiology and pathophysiology, 5th ed. Academic Press; 2013. pp. 1319–1352.

Crowley SD, Coffman TM. The inextricable role of the kidney in hypertension. J Clin Invest 2014; 124:2341–2347. PubMed PMC

Mitchell KD, Navar LG. Intrarenal actions of angiotensin II in the pathogenesis of experimental hypertension In: Laragh JH, Brenner BM, editors. Hypertension: pathophysiology, diagnosis and management. New York, NY: Raven Press; 1995. pp. 1437–1449.

Yang T, Xu Ch. Physiology and pathophysiology of the intrarenal renin-angiotensin system: an update. J Am Soc Nephrol 2017; 28:1040–1049. PubMed PMC

Averina VA, Othmer HG, Fink GD, Osborn JW. A mathematical model of salt-sensitive hypertension: the neurogenic hypothesis. J Physiol 2015; 14:3065–3076. PubMed PMC

Feng W, Dell’Italia LJ, Sanders PW. Novel paradigms of salt and hypertension. J Am Soc Nephrol 2017; 28:1362–1369. PubMed PMC

Bernstein KE, Giani JF, Shen XZ, Gonzalez-Villalobos RA. Renal angiotensin-converting enzyme and blood pressure control. Curr Opin Nephrol Hypertens 2014; 23:106–112. PubMed PMC

Husková Z, Kopkan L, Červenková L, Doleželová Š, Vaňourková Z, Škaroupková P, et al. Intrarenal alterations of the angiotensin-converting enzyme type 2/angiotensin 1–7 complex of the renin-angiotensin system do not alter the course of malignant hypertension in Cyp1a1-Ren-2 transgenic rats. Clin Exp Pharmacol Physiol 2016; 43:438–449. PubMed

Garcia V, Schwartzman ML. Recent developments on the vascular effects of 20-hydroxyeicosatrienoic acid. Curr Opin Nephrol Hypertens 2017; 26:74–82. PubMed

Carlstrom M, Wilcox CS, Arendshorst WJ. Renal autoregulation in health and disease. Physiol Rev 2015; 95:405–411. PubMed PMC

Hye Khan MA, Liu J, Kumar G, Skapek SX, Falck JR, Imig JD. Novel orally active epoxyeicosatrienoic acid (EET) analogs attenuate cisplatin nephrotoxicity. FASEB J 2013; 27:2946–2956. PubMed PMC

ESH/ESC Task Force for the Management of Arterial Hypertension. 2013 Practice guidelines for the management of arterial hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC): ESH/ESC Task Force for the Management of Arterial Hypertension. J Hypertens 2013; 31:1925–1938. PubMed

Cooley DA, Reul GJ, Wukasch DC. Ischemic contracture of the heart: ‘stone heart’. Am J Cardiol 1972; 29:575–577. PubMed

Li N, Liu JY, Timofeyev V, Qiu H, Hwang SH, Tuteja D, et al. Beneficial effects of soluble epoxide hydrolase inhibitors in myocardial infarction model: insight gained using metabolomics approaches. J Moll Cell Cardiol 2009; 47:835–845. PubMed PMC

Wesphal C, Spallek B, Konkel A, Marko L, Qadri F, DeGraff LM, et al. CYP2J2 overexpresion protects against arrhythmia susceptibility in cardiac hypertrophy. PLosONE 2013; 8: e73490. PubMed PMC

Sirish P, Li N, Timofeyev V, Zhang XD, Wang L, Yang J, et al. Molecular mechanisms and new treatment paradigm for atrial fibrillation. Circ Arrhythm Electrophysiol 2016; 9:e003721. PubMed PMC

Glinge C, Sattler S, Jabbari R, Tfelt-Hansen J. Epidemiology and genetics of ventricular fibrillation during acute myocardial infarction. J Geriatr Cardiol 2016; 13:789–797. PubMed PMC

Ai D, Fu Y, Guo D, Tanaka H, Wang N, Tang C, et al. Angiotensin II up-regulates soluble epoxide hydrolase in vascular endothelium in vitro and in vivo. Proc Natl Acad Sci U S A 2007; 104: 9018–9023. PubMed PMC

Reckelhoff JF, Romero JC. Role of oxidative stress in angiotensin-induced hypertension. Am J Physiol 2003; 284:R893–R912. PubMed

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