title: Antihypertensive and renoprotective actions of soluble epoxide hydrolase inhibition in ANG II-dependent malignant hypertension are abolished by pretreatment with L-NAME.
abstract: OBJECTIVE
  The present study was performed to investigate in a model of malignant hypertension if the antihypertensive actions of soluble epoxide hydrolase (sEH) inhibition are nitric oxide (NO)-dependent.
  
  
  METHODS
  ANG II-dependent malignant hypertension was induced through dietary administration for 3 days of the natural xenobiotic indole-3-carbinol (I3C) in Cyp1a1-Ren-2 transgenic rats. Blood pressure (BP) was monitored by radiotelemetry and treatment with the sEH inhibitor [cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyl-oxy]-benzoic acid (c-AUCB)] was started 48 h before administration of the diet containing I3C. In separate groups of rats, combined administration of the sEH inhibitor and the nonspecific NO synthase inhibitor [Nω-nitro-L-arginine methyl ester (L-NAME)] on the course of BP in I3C-induced and noninduced rats were evaluated. In addition, combined blockade of renin-angiotensin system (RAS) was superimposed on L-NAME administration in separate groups of rats. After 3 days of experimental protocols, the rats were prepared for renal functional studies and renal concentrations of epoxyeicosatrienoic acids (EETs) and their inactive metabolites dihydroxyeicosatrienoic acids (DHETEs) were measured.
  
  
  RESULTS
  Treatment with c-AUCB increased the renal EETs/DHETEs ratio, attenuated the increases in BP, and prevented the decreases in renal function and the development of renal damage in I3C-induced Cyp1a1-Ren-2 rats. The BP lowering and renoprotective actions of the treatment with the sEH inhibitor c-AUCB were completely abolished by concomitant administration of L-NAME and not fully rescued by double RAS blockade without altering the increased EETs/DHETEs ratio.
  
  
  CONCLUSIONS
  Our current findings indicate that the antihypertensive actions of sEH inhibition in this ANG II-dependent malignant form of hypertension are dependent on the interactions of endogenous bioavailability of EETs and NO.
authors: Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors: Zuzana
authors: Z
authors: Honetschlägerová
authors: Kento
authors: K
authors: Kitada
authors: Zuzana
authors: Z
authors: Husková
authors: Alexandra
authors: A
authors: Sporková
authors: Libor
authors: L
authors: Kopkan
authors: Marcela
authors: M
authors: Bürgelová
authors: Šárka
authors: Š
authors: Varcabová
authors: Akira
authors: A
authors: Nishiyama
authors: Sung Hee
authors: SH
authors: Hwang
authors: Bruce D
authors: BD
authors: Hammock
authors: John D
authors: JD
authors: Imig
authors: Herbert J
authors: HJ
authors: Kramer
authors: Petr
authors: P
authors: Kujal
authors: Zdenka
authors: Z
authors: Vernerová
authors: Luděk
authors: L
authors: Červenka
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D055647:Rats, Transgenic; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D017392:Thiobarbituric Acid Reactive Substances; D000804:Angiotensin II; D019001:Nitric Oxide Synthase; D004851:Epoxide Hydrolases; D019331:NG-Nitroarginine Methyl Ester