Soluble epoxide hydrolase inhibition prevents coronary endothelial dysfunction in mice with renovascular hypertension.

Abstract

OBJECTIVES:

The study addresses the hypothesis that endothelial dysfunction in experimental arterial hypertension can be related to an alteration in epoxyeicosatrienoic acids (EETs) pathway and can be prevented by the inhibition of EETs degradation by soluble epoxide hydrolase (sEH).

METHODS AND RESULTS:

Arterial hypertension was induced in FVB/N mice by renal artery stenosis ('two-kidney-one-clip', 2K1C). Seven weeks after surgery, increased aortic pressures (Millar tonometer; Millar Instruments, Houston, Texas, USA) and cardiac hypertrophy (echocardiography) were present in 2K1C mice as compared with control mice. Left coronary artery endothelium-dependent relaxations to acetylcholine were decreased in 2K1C mice without modification in the relaxing responses to NS309 and NS1619, the openers of calcium-activated potassium channels mediating the hyperpolarizing effect of EETs. The inhibitors of the EET-synthesizing enzymes cytochrome P450 epoxygenases, fluconazole and N-methylsulfonyl-6-(2-propargyloxyphenyl)-hexanamide (MSPPOH), reduced the coronary relaxations to acetylcholine in control but not in 2K1C mice. The sEH expression was increased in 2K1C mice. The sEH inhibitor 12-(3-adamantan-1-yl-ureido)dodecanoic acid administered for 2 weeks starting 5 weeks after surgery in 2K1C mice (25 mg/l in drinking water) reduced aortic pressures and cardiac hypertrophy, improved the coronary relaxations to acetylcholine and restored the inhibitory effect of fluconazole and MSPPOH on acetylcholine-induced relaxations, without modifying the relaxations to NS309 and NS1619.

CONCLUSION:

These results demonstrate that a reduced EET-mediated relaxations related to an increased degradation by sEH contributes to coronary endothelial dysfunction in 2K1C hypertensive mice. Inhibiting sEH prevents endothelial dysfunction by restoring EET-mediated relaxations and thus, could represent a promising pharmacological intervention to limit cardiovascular morbidity and mortality in arterial hypertension.

• Authors: Ji Gao, Jeremy Bellien, Elodie Gomez, Jean-Paul Henry, Brigitte Dautreaux, Frederic Bounoure, Mohamed Skiba, Christian Thuillez, Vincent Richard
• Journal: Journal of hypertension (J Hypertens) Vol. 29 Issue 6 Pg. 1128-35 (Jun 2011) ISSN: 1473-5598 [Electronic] England
• PMID: 21451419 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Enzyme Inhibitors
• N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide
• Fluconazole
• Epoxide Hydrolases

Topics

• Amides (pharmacology)
• Animals
• Blotting, Western
• Coronary Vessels (drug effects, enzymology)
• Echocardiography
• Endothelium, Vascular (drug effects, enzymology)
• Enzyme Inhibitors (pharmacology)
• Epoxide Hydrolases (antagonists & inhibitors)
• Fluconazole (pharmacology)
• Hypertension (physiopathology)
• Kidney (physiopathology)
• Male
• Mice