(-)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans

Abstract

Epidemiological and medical anthropological investigations suggest that flavanol-rich foods exert cardiovascular health benefits. Endothelial dysfunction, a prognostically relevant key event in atherosclerosis, is characterized by a decreased bioactivity of nitric oxide (NO) and impaired flow-mediated vasodilation (FMD). We show in healthy male adults that the ingestion of flavanol-rich cocoa was associated with acute elevations in levels of circulating NO species, an enhanced FMD response of conduit arteries, and an augmented microcirculation. In addition, the concentrations and the chemical profiles of circulating flavanol metabolites were determined, and multivariate regression analyses identified (-)-epicatechin and its metabolite, epicatechin-7-O-glucuronide, as independent predictors of the vascular effects after flavanol-rich cocoa ingestion. A mixture of flavanols/metabolites, resembling the profile and concentration of circulating flavanol compounds in plasma after cocoa ingestion, induced a relaxation in preconstricted rabbit aortic rings ex vivo, thus mimicking acetylcholine-induced relaxations. Ex vivo flavanol-induced relaxation, as well as the in vivo increases in FMD, were abolished by inhibition of NO synthase. Oral administration of chemically pure (-)-epicatechin to humans closely emulated acute vascular effects of flavanol-rich cocoa. Finally, the concept that a chronic intake of high-flavanol diets is associated with prolonged, augmented NO synthesis is supported by data that indicate a correlation between the chronic consumption of a cocoa flavanol-rich diet and the augmented urinary excretion of NO metabolites. Collectively, our data demonstrate that the human ingestion of the flavanol (-)-epicatechin is, at least in part, causally linked to the reported vascular effects observed after the consumption of flavanol-rich cocoa.

Figures

Fig. 1.

Time courses of FMD, RXNO, and total circulating flavanols. (A–C) Ingestion of a hFCD (917 mg of total flavanols; filled circles) exerted significant increases in FMD (A), RXNO (B), and circulating flavanols (C) compared with a low-flavanol control drink (lFCD = 37 mg; open circles; n = 10). lFCD ingestion slightly increased the sum of circulating flavanols (C) but had no effect on FMD and RXNO (mean values ± SEM). (D–F) AUCs of FMD, RXNO, and sum of circulating flavanols after ingestion of a lFCD (open symbols) or a hFCD (filled symbols). AUC of flavanol plasma concentration increased in all volunteers; in 9 of 10 individuals this was paralleled by an increase in AUC of FMD. (F) Mean values for AUCs of FMD (circles), RXNO (squares), and sum of circulating flavanols are significantly higher after hFCD (calculated from individual values presented in D and E). *, P < 0.05 vs. baseline at 0 h of respective day; #, P < 0.05 vs. respective time point on control day.

Fig. 2.

Plasma profile of flavanols/metabolites. Time course of epicatechin, catechin, and selected postabsorption metabolites after ingestion of a high-flavanol (917 mg) cocoa drink (see squares in Fig. 1C). Values depicted are means ± SEM. *, P < 0.05 vs. baseline at 0 h.

Fig. 3.

Proof-of-concept: Vascular response after oral ingestion of (–)-epicatechin. (A and C) FMD (A) and PAT (C) index significantly increased 2 h after ingestion of 1 or 2 mg/kg epicatechin in water (filled columns) but not water alone (open column; n = 3; cross-over). (B and D) Time course of FMD (B) and PAT (D) index after ingestion of water (open circles) or 1 mg/kg (–)-epicatechin in water (n = 3). Data represent means ± SEM. *, P < 0.05 vs. baseline at 0 h of respective day; #, P < 0.05 vs. respective time point on control day.