Antihypertensive and renoprotective actions of soluble epoxide hydrolase inhibition in ANG II-dependent malignant hypertension are abolished by pretreatment with L-NAME.

Abstract

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.

• Authors: Zuzana Honetschlägerová, Kento Kitada, Zuzana Husková, Alexandra Sporková, Libor Kopkan, Marcela Bürgelová, Šárka Varcabová, Akira Nishiyama, Sung Hee Hwang, Bruce D Hammock, John D Imig, Herbert J Kramer, Petr Kujal, Zdenka Vernerová, Luděk Červenka
• Journal: Journal of hypertension (J Hypertens) Vol. 31 Issue 2 Pg. 321-32 (Feb 2013) ISSN: 1473-5598 [Electronic] England
• PMID: 23307303 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antihypertensive Agents
• Enzyme Inhibitors
• Thiobarbituric Acid Reactive Substances
• Angiotensin II
• Nitric Oxide Synthase
• Epoxide Hydrolases
• NG-Nitroarginine Methyl Ester

Topics

• Angiotensin II (physiology)
• Animals
• Antihypertensive Agents (pharmacology, therapeutic use)
• Blood Pressure (drug effects)
• Enzyme Inhibitors (pharmacology)
• Epoxide Hydrolases (antagonists & inhibitors)
• Hypertension (drug therapy, physiopathology)
• Kidney (drug effects, physiopathology)
• NG-Nitroarginine Methyl Ester (administration & dosage, pharmacology, therapeutic use)
• Nitric Oxide Synthase (antagonists & inhibitors)
• Rats
• Rats, Transgenic
• Thiobarbituric Acid Reactive Substances (metabolism)