title: An orally active epoxide hydrolase inhibitor lowers blood pressure and provides renal protection in salt-sensitive hypertension.
abstract: The present study tested the hypothesis that increasing epoxyeicosatrienoic acids by inhibition of soluble epoxide hydrolase (sEH) would lower blood pressure and ameliorate renal damage in salt-sensitive hypertension. Rats were infused with angiotensin and fed a normal-salt diet or an 8% NaCl diet for 14 days. The sEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), was given orally to angiotensin-infused animals during the 14-day period. Plasma AUDA metabolite levels were measured, and they averaged 10+/-2 ng/mL in normal-salt angiotensin hypertension and 19+/-3 ng/mL in high-salt angiotensin hypertension on day 14 in the animals administered the sEH inhibitor. Mean arterial blood pressure averaged 161+/-4 mm Hg in normal-salt and 172+/-5 mm Hg in the high-salt angiotensin hypertension groups on day 14. EH inhibitor treatment significantly lowered blood pressure to 140+/-5 mm Hg in the normal-salt angiotensin hypertension group and to 151+/-6 mm Hg in the high-salt angiotensin hypertension group on day 14. The lower arterial blood pressures in the AUDA-treated groups were associated with increased urinary epoxide-to-diol ratios. Urinary microalbumin levels were measured, and ED-1 staining was used to determine renal damage and macrophage infiltration in the groups. Two weeks of AUDA treatment decreased urinary microalbumin excretion in the normal-salt and high-salt angiotensin hypertension groups and macrophage number in the high-salt angiotensin hypertension group. These data demonstrate that sEH inhibition lowers blood pressure and ameliorates renal damage in angiotensin-dependent, salt-sensitive hypertension.
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912-2500, USA. jdimig@mail.mcg.edu
authors.forename: John D
authors.initials: JD
authors.lastname: Imig
authors.forename: Xueying
authors.initials: X
authors.lastname: Zhao
authors.forename: Constantine Z
authors.initials: CZ
authors.lastname: Zaharis
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Olearczyk
authors.forename: David M
authors.initials: DM
authors.lastname: Pollock
authors.forename: John W
authors.initials: JW
authors.lastname: Newman
authors.forename: In-Hae
authors.initials: IH
authors.lastname: Kim
authors.forename: Takaho
authors.initials: T
authors.lastname: Watanabe
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000419:Albuminuria / Q000503:physiopathology; D000809:Angiotensins; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002452:Cell Count; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006973:Hypertension / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology* / Q000652:urine; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000517:prevention & control*; D007850:Lauric Acids / Q000494:pharmacology*; D008264:Macrophages / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride
chemical_list: C504897:12-(3-adamantan-1-ylureido)dodecanoic acid; D000809:Angiotensins; D007850:Lauric Acids; D012965:Sodium Chloride; D004851:Epoxide Hydrolases; D000218:Adamantane