doi: 10.1161/hy0202.103788
(Hypertension. 2002;39:690.)
© 2002 American Heart Association, Inc.
Scientific Contributions |
Soluble Epoxide Hydrolase Inhibition Lowers Arterial Blood Pressure in Angiotensin II Hypertension
From the Vascular Biology Center, Department of Physiology, Medical College of Georgia, Augusta, Ga, and Department of Physiology, Tulane University School of Medicine, New Orleans, La (J.D.I. and X.Z.); Departments of Medicine and Biochemistry, Division of Nephrology, Vanderbilt University School of Medicine (J.H.C.), Nashville, Tenn; and Department of Entomology and the University of California at Davis Cancer Center, University of California at Davis (C.M., B.D.H.), Davis, Calif.
Correspondence to J.D. Imig, Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912-2500. E-mail jdimig{at}mail.mcg.edu
Epoxyeicosatrienoic acids (EETs) have antihypertensive properties and play a part in the maintenance of renal microvascular function. A novel approach to increase EET levels is to inhibit epoxide hydrolase enzymes that are responsible for conversion of biologically active EETs to dihydroxyeicosatrienoic acids (DHETs) that are void of effects on the preglomerular vasculature. We hypothesized that inhibition of soluble epoxide hydrolase (sEH) would lower blood pressure in angiotensin II (Ang II) hypertension. Rat renal cortical tissue was harvested and urine collected 2 weeks following implantation of an osmotic minipump containing Ang II (60 ng/min). Renal cortical sEH protein expression was significantly higher in Ang II hypertension compared with normotensive animals. Likewise, urinary 14,15-DHET levels were significantly increased in hypertensive compared with normotensive animals and averaged 8.1±1.3 and 2.7±1.1 ng/d; respectively. In additional experiments, the sEH inhibitor N-cyclohexyl-N-dodecyl urea (NCND; 3 mg/d) or vehicle (corn oil, 0.5 mL) was administered daily by intraperitoneal injection starting on day 10. Administration of NCND for 4 days lowered systolic blood pressure by 30 mm Hg in Ang II hypertensive animals, whereas the corn oil vehicle had no effect on blood pressure in normotensive or Ang II hypertensive animals. Measurement of blood pressure by indwelling arterial catheters in conscious animals with free movement in their cages confirmed that NCND had antihypertensive properties. Arterial blood pressure averaged 119±5 mm Hg in normotensive, 170±3 mm Hg in hypertensive and 149±10 mm Hg in NCND-treated, Ang II-infused animals. Administration of the potential metabolite of NCND, N-cyclohexylformamide to Ang II hypertensive rats did not lower the systolic blood pressure. These studies demonstrate that increased sEH expression in the Ang II hypertensive kidney leads to increased EET hydration. Moreover, sEH plays a role in the regulation of blood pressure, and inhibition of sEH during Ang II hypertension is antihypertensive.
Key Words: renal blood flow • endothelium-derived factors • microcirculation • cytochrome P450 • kidney
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