OBJECTIVE: The present study was performed to investigate in a model of malignant hypertension if the antihypertensive actions of soluble epoxide hydrolase (sEH) inhibition are nitric oxide (NO)-dependent. METHODS: ANG II-dependent malignant hypertension was induced through dietary administration for 3 days of the natural xenobiotic indole-3-carbinol (I3C) in Cyp1a1-Ren-2 transgenic rats. Blood pressure (BP) was monitored by radiotelemetry and treatment with the sEH inhibitor [cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyl-oxy]-benzoic acid (c-AUCB)] was started 48 h before administration of the diet containing I3C. In separate groups of rats, combined administration of the sEH inhibitor and the nonspecific NO synthase inhibitor [Nω-nitro-L-arginine methyl ester (L-NAME)] on the course of BP in I3C-induced and noninduced rats were evaluated. In addition, combined blockade of renin-angiotensin system (RAS) was superimposed on L-NAME administration in separate groups of rats. After 3 days of experimental protocols, the rats were prepared for renal functional studies and renal concentrations of epoxyeicosatrienoic acids (EETs) and their inactive metabolites dihydroxyeicosatrienoic acids (DHETEs) were measured. RESULTS: Treatment with c-AUCB increased the renal EETs/DHETEs ratio, attenuated the increases in BP, and prevented the decreases in renal function and the development of renal damage in I3C-induced Cyp1a1-Ren-2 rats. The BP lowering and renoprotective actions of the treatment with the sEH inhibitor c-AUCB were completely abolished by concomitant administration of L-NAME and not fully rescued by double RAS blockade without altering the increased EETs/DHETEs ratio. CONCLUSION: Our current findings indicate that the antihypertensive actions of sEH inhibition in this ANG II-dependent malignant form of hypertension are dependent on the interactions of endogenous bioavailability of EETs and NO.

• MeSH
• Angiotensin II physiology   MeSH
• Antihypertensive Agents pharmacology   therapeutic use   MeSH
• Epoxide Hydrolases antagonists & inhibitors   MeSH
• Hypertension drug therapy   physiopathology   MeSH
• Enzyme Inhibitors pharmacology   MeSH
• Blood Pressure drug effects   MeSH
• Rats MeSH
• Thiobarbituric Acid Reactive Substances metabolism   MeSH
• Kidney drug effects   physiopathology   MeSH
• NG-Nitroarginine Methyl Ester administration & dosage   pharmacology   therapeutic use   MeSH
• Rats, Transgenic MeSH
• Nitric Oxide Synthase antagonists & inhibitors   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Angiotensin II MeSH
• Antihypertensive Agents MeSH
• Epoxide Hydrolases MeSH
• Enzyme Inhibitors MeSH
• Thiobarbituric Acid Reactive Substances MeSH
• NG-Nitroarginine Methyl Ester MeSH
• Nitric Oxide Synthase MeSH