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

Arterial hypertension was induced in FVB mice using the two kidney-one clip (2K1C) model. Seven weeks after surgery, increased carotid artery pressures (Millar tonometer) and cardiac hypertrophy (echocardiography) were present in 2K1C mice as compared with control mice. Left coronary artery endothelium-dependent relaxations to acetylcholine was decreased in 2K1C mice without significant 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 cytochrome epoxygenases, which synthesize EETs, fluconazole and MSPPOH impaired the coronary relaxations to acetylcholine in control mice but not in 2K1C mice. Moreover, sEH expression was increased in 2K1C mice. The sEH inhibitor AUDA administered five weeks after surgery in 2K1C mice for two weeks (drinking water: 25mg/L) reduces arterial 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.

These results demonstrate that a reduced EETs-mediated relaxations related to an increased degradation by sEH contributes to coronary endothelial dysfunction in hypertensive mice. The inhibition of sEH prevents the endothelial dysfunction by restoring EETs availability appearing thus as a promising pharmacological intervention to limit cardiovascular morbidity and mortality in arterial hypertension.