Chronic ( − )-epicatechin improves vascular oxidative and inflammatory status but not hypertension in chronic nitric oxide-deficient rats

The present study analysed the effects of the flavanol ( − )-epicatechin in rats after chronic inhibition of NO synthesis with N^G-nitro-l-arginine methyl ester (l-NAME), at doses equivalent to those achieved in the studies involving human subjects. Wistar rats were randomly divided into four groups: (1) control-vehicle, (2) l-NAME, (3) l-NAME-epicatechin 2 (l-NAME-Epi 2) and (4) l-NAME-epicatechin 10 (l-NAME-Epi 10). Rats were daily given by oral administration for 4 weeks: vehicle, ( − )-epicatechin 2 or 10 mg/kg. Animals in the l-NAME groups daily received l-NAME 75 mg/100 ml in drinking-water. The evolution in systolic blood pressure and heart rate, and morphological and plasma variables, proteinuria, vascular superoxide, reactivity and protein expression at the end of the experiment were analysed. Chronic ( − )-epicatechin treatment did not modify the development of hypertension and only weakly affected the endothelial dysfunction induced by l-NAME but prevented the cardiac hypertrophy, the renal parenchyma and vascular lesions and proteinuria, and blunted the prostanoid-mediated enhanced endothelium-dependent vasoconstrictor responses and the cyclo-oxygenase-2 and endothelial NO synthase (eNOS) up-regulation. Furthermore, ( − )-epicatechin also increased Akt and eNOS phosphorylation and prevented the l-NAME-induced increase in systemic (plasma malonyldialdehyde and urinary 8-iso-PGF_2α) and vascular (dihydroethidium staining, NADPH oxidase activity and p22^phox up-regulation) oxidative stress, proinflammatory status (intercellular adhesion molecule-1, IL-1β and TNFα up-regulation) and extracellular-signal-regulated kinase 1/2 phosphorylation. The present study shows for the first time that chronic oral administration of ( − )-epicatechin does not improve hypertension but reduced pro-atherogenic pathways such as oxidative stress and proinflammatory status of the vascular wall induced by blockade of NO production.