title: Soluble epoxide hydrolase inhibition exhibits antihypertensive actions independently of nitric oxide in mice with renovascular hypertension.
abstract: OBJECTIVE
  The present study was performed to examine whether the blood pressure (BP)-lowering effects of soluble epoxide hydrolase (sEH) inhibition in two-kidney, one-clip (2K1C) Goldblatt hypertension are nitric oxide (NO) dependent.
  
  
  METHODS
  Mice lacking the endothelial NO synthase (eNOS) gene (eNOS-/-) and their wild-type controls (eNOS+/+) underwent clipping of one renal artery. BP was monitored by radiotelemetry and the treatment with the sEH inhibitor cis-4-[4-(3-adamantan-1-yl-ureido)cyclohex-yloxy]-benzoic acid (c-AUCB) was initiated on day 25 after clipping and lasted for 14 days. Renal concentrations of epoxyeicosatrienoic acids (EETs) and their inactive metabolite dihydroxyeicosatrienoic acids (DHETs) were measured in the nonclipped kidney. Renal NO synthase (NOS) activity was determined by measuring the rate of formation of L-[(14)C]citruline from L-[(14)C]arginine.
  
  
  RESULTS
  Treatment with the sEH inhibitor elicited similar BP decreases that were associated with increases in daily sodium excretion in 2K1C eNOS+/+ as well as 2K1C eNOS-/- mice. In addition, treatment with the sEH inhibitor increased the ratio of EETs/DHETs in the nonclipped kidney of 2K1C eNOS+/+ as well as 2K1C eNOS-/- mice. Treatment with the sEH inhibitor did not alter renal NOS activity in any of the experimental groups.
  
  
  CONCLUSIONS
  Collectively, our present data suggest that the BP-lowering effects of chronic sEH inhibition in 2K1C mice are mainly associated with normalization of the reduced availability of biologically active EETs in the nonclipped kidney and their direct natriuretic actions.
authors.affiliation: Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Libor
authors.initials: L
authors.lastname: Kopkan
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Husková
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sporková
authors.forename: Šárka
authors.initials: Š
authors.lastname: Varcabová
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Honetschlägerová
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hwang
authors.forename: Hsing-Ju
authors.initials: HJ
authors.lastname: Tsai
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: John D
authors.initials: JD
authors.lastname: Imig
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Kramer
authors.forename: Marcela
authors.initials: M
authors.lastname: Bürgelová
authors.forename: Alžběta
authors.initials: A
authors.lastname: Vojtíšková
authors.forename: Petr
authors.initials: P
authors.lastname: Kujal
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Vernerová
authors.forename: Luděk
authors.initials: L
authors.lastname: Červenka
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006978:Hypertension, Renovascular / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency*
chemical_list: D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse