title: Epoxyeicosatrienoic acid analog attenuates the development of malignant hypertension, but does not reverse it once established: a study in Cyp1a1-Ren-2 transgenic rats.
abstract: We evaluated the therapeutic effectiveness of a new, orally active epoxyeicosatrienoic acid analog (EET-A) in rats with angiotensin II (ANG II)-dependent malignant hypertension.
  
  
  
  Malignant hypertension was induced in Cyp1a1-Ren-2 transgenic rats by activation of the renin gene using indole-3-carbinol (I3C), a natural xenobiotic. EET-A treatment was started either simultaneously with I3C induction process (early treatment) or 10 days later during established hypertension (late treatment). Blood pressure (BP) (radiotelemetry), indices of renal and cardiac injury, and plasma and kidney levels of the components of the renin-angiotensin system (RAS) were determined.
  
  
  
  In I3C-induced hypertensive rats, early EET-A treatment attenuated BP increase (to 175 ± 3 versus 193 ± 4 mmHg, P < 0.05, on day 13), reduced albuminuria (15 ± 1 versus 28 ± 2 mg/24 h, P < 0.05), and cardiac hypertrophy as compared with untreated I3C-induced rats. This was associated with suppression of plasma and kidney ANG II levels (48 ± 6 versus 106 ± 9 and 122 ± 19 versus 346 ± 11 fmol ml or g, respectively, P < 0.05) and increases in plasma and kidney angiotensin (1-7) concentrations (84 ± 9 versus 37 ± 6 and 199 ± 12 versus 68 ± 9 fmol/ml or g, respectively, P < 0.05). Remarkably, late EET-A treatment did not lower BP or improve renal and cardiac injury; indices of RAS activity were not affected.
  
  
  
  The new, orally active EET-A attenuated the development of experimental ANG II-dependent malignant hypertension, likely via suppression of the hypertensiogenic axis and augmentation of the vasodilatory/natriuretic axis of RAS.
authors.affiliation: aCenter for Experimental Medicine, Institute for Clinical and Experimental Medicine bDepartment of Pathophysiology, 2nd Faculty of Medicine, Charles University cDepartment of Developmental Cardiology, Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic dSection of Nephrology, Medical Policlinic, Department of Medicine, University of Bonn, Bonn, Germany eDepartment of Renal and Body Fluid Physiology, Mossakowski Medical Research Centre, Polish Academy of Science, Warsaw, Poland fDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas gDepartment of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Šárka
authors.initials: Š
authors.lastname: Jíchová
authors.forename: Libor
authors.initials: L
authors.lastname: Kopkan
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Husková
authors.forename: Šárka
authors.initials: Š
authors.lastname: Doleželová
authors.forename: Jan
authors.initials: J
authors.lastname: Neckář
authors.forename: Petr
authors.initials: P
authors.lastname: Kujal
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Vernerová
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Kramer
authors.forename: Janusz
authors.initials: J
authors.lastname: Sadowski
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Kompanowska-Jezierska
authors.forename: Rami N
authors.initials: RN
authors.lastname: Reddy
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: John D
authors.initials: JD
authors.lastname: Imig
authors.forename: Luděk
authors.initials: L
authors.lastname: Červenka
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use*; D000419:Albuminuria / Q000188:drug therapy; D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D006974:Hypertension, Malignant / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control*; D007211:Indoles; D007668:Kidney / Q000378:metabolism; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic; D012083:Renin / Q000235:genetics; D012084:Renin-Angiotensin System / Q000187:drug effects; D013997:Time Factors
chemical_list: D007211:Indoles; D010446:Peptide Fragments; C535029:Ren2 protein, rat; D000804:Angiotensin II; D000803:Angiotensin I; C016517:indole-3-carbinol; D019363:Cytochrome P-450 CYP1A1; D012083:Renin; D015126:8,11,14-Eicosatrienoic Acid; C118790:angiotensin I (1-7)