title: Inhibition of the soluble epoxide hydrolase attenuates   monocrotaline-induced pulmonary hypertension in rats.
abstract: OBJECTIVE
  The soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs) to their less active dihydroxy derivatives. Because EETs have antiinflammatory properties, we determined whether or not inhibition of sEH attenuates disease development in the monocrotaline model of pulmonary hypertension in rats.
  
  
  METHODS
  sEH inhibition was achieved using 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (25 mg/l) and cis- 4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (5 mg/l) administered via drinking water starting 3 days prior to monocrotaline injection (60 mg/kg).
  
  
  RESULTS
  Monocrotaline induced the development of progressive pulmonary hypertension. sEH inhibition increased the plasma ratio of EETs to DHETs and attenuated the monocrotaline-induced increase in pulmonary artery medial wall thickness as well as the degree of vascular muscularization. Moreover, right ventricular pressure was significantly lower in the group treated with sEH inhibitors. Pulmonary sEH protein expression and sEH activity, as well as pulmonary cytochrome P450 epoxygenase activity were all impaired in monocrotaline-treated rats as compared with control animals. sEH inhibitors, however, increased the plasma ratio of EETs to dihydroxy epoxyeicosatrienoic acids. Monocrotaline induced the proliferation of pulmonary endothelial and vascular smooth muscle cells in vivo as determined by 5-Bromo-2'-deoxy-Uridine incorporation, and this effect was significantly blunted in animals treated with sEH inhibitors. Proliferation of cultured pulmonary smooth muscle cell, however, was not affected by EETs or sEH inhibitors suggesting that the in-vivo effects are a consequence of a direct EET-mediated protection against the inflammation induced by monocrotaline.
  
  
  CONCLUSIONS
  sEH inhibition reduces pulmonary vascular remodeling and the development of pulmonary hypertension in the monocrotaline model of primary pulmonary hypertension in rats.
authors.affiliation: Institut für Kardiovaskuläre Physiologie, Fachbereich Medizin der Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Revermann
authors.forename: Eduardo
authors.initials: E
authors.lastname: Barbosa-Sicard
authors.forename: Eva
authors.initials: E
authors.lastname: Dony
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fleming
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D008297:Male; D016686:Monocrotaline; D011651:Pulmonary Artery / Q000473:pathology; D051381:Rats; D011921:Rats, Inbred WKY
chemical_list: D016686:Monocrotaline; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid