title: Novel mechanism of brain soluble epoxide hydrolase-mediated blood pressure regulation in the spontaneously hypertensive rat.
abstract: The role of soluble epoxide hydrolase (sEH) in the central control of blood pressure (BP) has not been elucidated in spite of peripheral sEH overexpression being linked to hypertension. Thus, our objective was to investigate the involvement of brain sEH in BP control. sEH expression in the hypothalamus and brain stem, two cardioregulatory brain areas, was increased in the spontaneously hypertensive rat (SHR) compared to the Wistar Kyoto (WKY) rat. Inhibition of the enzyme by intracerebroventricular (icv) delivery of AUDA further increased both BP and heart rate (HR) by 32 +/- 6 mmHg and 54 +/- 10 bpm, respectively, (P<0.05) in the SHR. Analysis of waveform telemetry data revealed a decrease in spontaneous baroreceptor reflex gain following sEH inhibition, indicating the sustained increase in BP may be due to a decrease in baroreceptor reflex function. The hypertensive effect of sEH inhibition is likely a result of an increase in epoxyeicosatrienoic acid (EET)-mediated generation of ROS. This view is supported by the following: 1) Inhibition of EET formation attenuates AUDA-induced increase in BP; 2) delivery of an EET agonist increases BP and HR in the WKY rat, and 3) inhibition of NAD(P)H oxidase by gp91ds-tat prevents AUDA-induced increases in BP and HR. Finally, electrophysiological studies demonstrate that AUDA increased neuronal firing rate exclusively in the SHR, an effect completely abolished by gp91ds-tat. These observations suggest that EETs and sEH inhibition are involved in increasing BP in the SHR. We suggest that an increased expression of sEH is a futile central nervous system response in protection against hypertension.
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine and McKnight Brain Institute, Gainesville, Florida 32610, USA.
authors.forename: Kathleen W
authors.initials: KW
authors.lastname: Sellers
authors.forename: Chengwen
authors.initials: C
authors.lastname: Sun
authors.forename: Carlos
authors.initials: C
authors.lastname: Diez-Freire
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Waki
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Julian F
authors.initials: JF
authors.lastname: Paton
authors.forename: Mohan K
authors.initials: MK
authors.lastname: Raizada
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D017704:Baroreflex / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology*; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology*; D001933:Brain Stem / Q000166:cytology; D002478:Cells, Cultured; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism*; D006339:Heart Rate; D006706:Homeostasis / Q000502:physiology*; D006973:Hypertension / Q000201:enzymology* / Q000503:physiopathology; D007031:Hypothalamus / Q000166:cytology; D008297:Male; D009474:Neurons / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012995:Solubility
chemical_list: D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid