Epoxide Hydrolase Inhibitor Lowers Blood Pressure in Salt-Sensitive Hypertension

Bruce Hammock, Ph.D.
University of California Davis
R37ES02710 and P42ES04699

Background: Although treatments for hypertension have improved dramatically over the past 30-40 years, chronic high blood pressure still results in renal failure. This is evident by the increasing incidence of end stage renal disease. The development of hypertension in laboratory animals after long-term administration of the peptide angiotensin has many of the same hallmarks as hypertension in humans. Animal models of angiotensin dependent hypertension show further elevation in blood pressure upon feeding high salt diets. High dietary salt is also associated with kidney damage in hypertensive patients and in angiotensis dependent hypertensive rats. The similarities between the human and rodent conditions make the animal model valuable in observing early kidney changes that ultimately result in end stage renal disease.

Inhibition of the enzyme soluble epoxide hydrolase (sEH) is known to lower blood pressure in angiotensin treated rats fed normal salt levels in their diets; however its potential for lowering salt-sensitive hypertension has not been tested. NIEHS-supported investigators at the University of California at Davis recently developed an sEH inhibitor known as adamantanyl-ureido dodecanoic acid (AUDA) which was shown to be potentially beneficial for treating chronic obstructive pulmonary disease and inflammation in the lungs. In the current study, they investigated its ability to lower blood pressure and ameliorate renal damage in salt-sensitive hypertension.

Advance: AUDA was given orally for two weeks to laboratory rats infused with angiotensin and fed either a normal salt diet or feed containing 8% sodium chloride. Arterial blood pressures in the normal- and high-salt diet animals averaged 161 and 172 respectively. In rats treated with AUDA, arterial blood pressures averaged 140 and 151 respectively in the normal- and high-salt diet animals. Two weeks of AUDA treatment also reduced the concentration of urinary microalbumin in both normal- and high-salt diet treated animals indicating that AUDA is effective in preventing renal damage.

Implications: This study shows that sEH inhibition by treatment with AUDA lowers blood pressure and lessens kidney damage in a laboratory animal model of angiotensin-dependent, salt-sensitive hypertension. These results added to those of previous studies provide sufficient evidence that sEH inhibition reduces hypertension-induced renal damage. These results also show that sEH inhibition with AUDA or similar compounds may be effective in treating human hypertension and preventing end stage renal disease.

Citation: Imig JD, Zhao X, Zaharis CZ, Olearczyk JJ, Pollock DM, Newman JW, Kim IH, Watanabe T, Hammock BD. An orally active epoxide hydrolase inhibitor lowers blood pressure and provides renal protection in salt-sensitive hypertension. Hypertension. 2005 Oct;46(4):975-81.