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(Hypertension. 2005;46:975.)
© 2005 American Heart Association, Inc.

Part 2 Original Articles

An Orally Active Epoxide Hydrolase Inhibitor Lowers Blood Pressure and Provides Renal Protection in Salt-Sensitive Hypertension

John D. Imig; Xueying Zhao; Constantine Z. Zaharis; Jeffrey J. Olearczyk; David M. Pollock; John W. Newman; In-Hae Kim; Takaho Watanabe; Bruce D. Hammock

From the Vascular Biology Center (J.D.I., X.Z., C.Z.Z., J.J.O., D.M.P.), and the Departments of Physiology (J.D.I.), Pharmacology (X.Z.), and Surgery (D.M.P.), Medical College of Georgia, Augusta, and the Department of Entomology and Cancer Center (J.W.N., I.-H.K., T.W., B.D.H.), University of California at Davis.

Correspondence to John D. Imig, PhD, Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912-2500. E-mail jdimig{at}mail.mcg.edu

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.

Key Words: kidney • inflammation • endothelium-derived factors • albuminuria

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