title: Inhibition of soluble epoxide hydrolase as a novel approach to high dose diazepam induced hypotension.
abstract: BACKGROUND
  Hypotension is one of the dose limiting side effects of benzodiazepines (BZDs), in particular of diazepam (DZP) which is still widely used in the clinic. Currently, only one FDA approved antidote exists for BZD overdose and novel approaches are needed to improve management of DZP overdose, dependency and withdrawal.
  
  
  OBJECTIVE
  Here, we hypothesized that increasing bioactive lipid mediators termed epoxy fatty acids (EpFAs) will prevent hypotension, as was shown previously in a murine model of LPS-induced hypotension. Therefore, we first characterized the time and dose dependent profile of DZP induced hypotension in mice, and then investigated the reversal of the hypotensive effect by inhibiting the soluble epoxide hydrolase (sEH), an enzyme that regulates the levels of EpFAs.
  
  
  METHODS
  Following baseline systolic BP recording using tail cuffs, mice were administered a sEH inhibitor (TPPU) before DZP and BP was monitored. Blood and brain levels of DZP and TPPU were quantified to examine distribution and metabolism. Plasma EpFAs levels were quantified to determine TPPU target engagement.
  
  
  RESULTS
  In this murine model, DZP induced dose dependent hypotension which was more severe than midazolam. The temporal profile was consistent with the reported pharmacokinetics/pharmacodynamics of DZP. Treatment with TPPU reversed the hypotension resulting from high doses of DZP and decreased the sEH metabolites of EpFAs in the plasma demonstrating target engagement.
  
  
  CONCLUSIONS
  Overall, these findings demonstrate the similarity of a murine model of DZP induced hypotension to clinical observations in humans. Furthermore, we demonstrate that stabilization of EpFAs by inhibiting sEH is a novel approach to overcome DZP-induced hypotension and this beneficial effect can be enhanced by an omega three diet probably acting through epoxide metabolites of the fatty acids.
authors.affiliation: Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, USA.
authors.forename: Arzu
authors.initials: A
authors.lastname: Ulu
authors.affiliation: Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, USA.
authors.forename: Bora
authors.initials: B
authors.lastname: Inceoglu
authors.affiliation: Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Davis, USA.
authors.forename: Vikrant
authors.initials: V
authors.lastname: Singh
authors.affiliation: Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Vito
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Davis, USA.
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.affiliation: Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
keywords: DHETs; DZP; EETs; Soluble epoxide hydrolase inhibitors; hypotension; midazolam