We hypothesized that perinatal inhibition of soluble epoxide hydrolase (EPHX2), which metabolizes epoxyeicosatrienoic acids in the arachidonic acid (AA) cascade, with an orally active EPHX2 inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), would persistently reduce blood pressure (BP) in adult SHR despite discontinuation of AUDA at 4wk of age. Renal Ephx2 gene expression was enhanced in SHR vs. WKY from 2d to 24wk. Effects of perinatal treatment with AUDA, supplied to SHR dams until 4wk after birth, on BP in female and male offspring and renal oxylipin metabolome in female offspring were observed and contrasted to female SHR for direct effects of AUDA (8-12wk). Briefly, inhibition of EPHX2 was effective in persistently reducing BP in female SHR when applied during the perinatal phase. This was accompanied by marked increases in major renal AA epoxides and decreases in renal lipoxygenase products of AA. Early inhibition of EPHX2 induced a delayed increase in renal 5-HETE at 24wk, in contrast to a decrease at 2wk. Inhibition of EPHX2 in female SHR from 8wk to 12wk did not reduce BP, but caused profound decreases in renal 15(S)-HETrE, LTB4, TBX2, 5-HETE and 20-HETE, and increases in TriHOMEs. In male SHR BP reduction after perinatal AUDA was transient. Thus, Ephx2 transcription and EPHX2 activity in early life may initiate mechanisms that eventually contribute to high BP in adult female SHR. However, programmed BP-lowering effects of perinatal EPHX2 inhibition in female SHR cannot be simply explained by persisting reduction in renal EPHX2 activity, but rather by more complex and temporally dynamic interactions between the renal EPHX2, lipoxygenase and cyclooxygenase pathways.
- soluble epoxide hydrolase inhibitors
- perinatal treatment
- developmental plasticity
- Copyright © 2011, American Journal of Physiology - Endocrinology and Metabolism