title: (-)-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.
authors.affiliation: Department of Nutrition, University of California, Davis, CA 95616, USA. hschroeter@ucdavis.edu
authors.forename: Hagen
authors.initials: H
authors.lastname: Schroeter
authors.forename: Christian
authors.initials: C
authors.lastname: Heiss
authors.forename: Jan
authors.initials: J
authors.lastname: Balzer
authors.forename: Petra
authors.initials: P
authors.lastname: Kleinbongard
authors.forename: Carl L
authors.initials: CL
authors.lastname: Keen
authors.forename: Norman K
authors.initials: NK
authors.lastname: Hollenberg
authors.forename: Helmut
authors.initials: H
authors.lastname: Sies
authors.forename: Catherine
authors.initials: C
authors.lastname: Kwik-Uribe
authors.forename: Harold H
authors.initials: HH
authors.lastname: Schmitz
authors.forename: Malte
authors.initials: M
authors.lastname: Kelm
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000818:Animals; D001011:Aorta / Q000473:pathology; D002099:Cacao / Q000378:metabolism*; D002320:Cardiovascular Physiological Phenomena; D002319:Cardiovascular System / Q000378:metabolism; D002392:Catechin / Q000737:chemistry / Q000502:physiology*; D004032:Diet; D004727:Endothelium / Q000378:metabolism; D047309:Flavones / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008297:Male; D015233:Models, Statistical; D015999:Multivariate Analysis; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011817:Rabbits; D012044:Regression Analysis; D012306:Risk; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D047309:Flavones; D009569:Nitric Oxide; D002392:Catechin; D019001:Nitric Oxide Synthase