Abstract--1. Flavonoids relaxed the contractions induced by noradrenaline, KCI or phorbol 12-myristate,13-acetate in rat aortic strips, the order of potency being: flavonols (quercetin, kaempferol, pentamethylquereetin)>flavones(luteolin, apigenin)>flavanols((+)-catechin, (-)-epicatechin) which correlates with the reported order of potency to inhibit protein kinase C.2. The relaxant effects of kaempferol and luteolin were slightly potentiated by isoprenaline and those of pentamethylquercetin, kaempferol and apigenin by sodium nitroprusside.3. It is concluded that the main vasodilatory mechanism of flavonoids seems to be the inhibition of protein kinase C. Inhibition of cyclic nucleotide phosphodiesterases or decreased Ca 2+ uptake may also contribute to their vasodilatory effects.

Hepatocytes release extracellular vesicles (EVs) loaded with signaling molecules and enzymes into the bloodstream. Although the importance of EVs in the intercellular communication is already recognized, the metabolic impact of the enzymes carried by these vesicles is still unclear. We evaluated the global effect of the enzymatic activities of EVs by performing untargeted metabolomic profiling of serum samples after their exposure to EVs. This approach revealed a significant change in the abundance of 94 serum metabolic signals. Our study shows that these vesicles modify the concentration of metabolites of different chemical nature including metabolites related to arginine metabolism, which regulates vascular function. To assess the functional relevance of this finding, we examined the levels of arginase-1 protein and its activity in the hepatic EVs carrying the exosomal markers CD81 and CD63. Remarkably, the arginase activity was also detected in EVs isolated from the serum in vivo, and this vesicular activity significantly increased under liver-damaging conditions. Finally, we demonstrated that EVs secreted by hepatocytes inhibited the acetylcholine-induced relaxation in isolated pulmonary arteries, via an arginase-dependent mechanism. In summary, our study demonstrates that the hepatocyte-released EVs are metabolically active, affecting a number of serum metabolites involved in oxidative stress metabolism and the endothelial function.

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