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

Hagen Schroeter, Christian Heiss, Jan Balzer, Petra Kleinbongard, Carl L Keen, Norman K. Hollenberg, Helmut Sies, Catherine Kwik-Uribe, Harold H. Schmitz, Malte Kelm

Research output: Contribution to journalArticle

715 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1024-1029
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number4
DOIs
StatePublished - Jan 24 2006

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Catechin
Blood Vessels
Nitric Oxide
Eating
Vasodilation
Diet
Anthropology
Glucuronides
Insurance Benefits
Microcirculation
Nitric Oxide Synthase
Acetylcholine
Oral Administration
Atherosclerosis
Multivariate Analysis
Arteries
Regression Analysis
Rabbits
Food

Keywords

  • Cardiovascular disease
  • Endothelial function
  • Nitric oxide synthase

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

(-)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. / Schroeter, Hagen; Heiss, Christian; Balzer, Jan; Kleinbongard, Petra; Keen, Carl L; Hollenberg, Norman K.; Sies, Helmut; Kwik-Uribe, Catherine; Schmitz, Harold H.; Kelm, Malte.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 4, 24.01.2006, p. 1024-1029.

Research output: Contribution to journalArticle

Schroeter, H, Heiss, C, Balzer, J, Kleinbongard, P, Keen, CL, Hollenberg, NK, Sies, H, Kwik-Uribe, C, Schmitz, HH & Kelm, M 2006, '(-)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans', Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 4, pp. 1024-1029. https://doi.org/10.1073/pnas.0510168103
Schroeter, Hagen ; Heiss, Christian ; Balzer, Jan ; Kleinbongard, Petra ; Keen, Carl L ; Hollenberg, Norman K. ; Sies, Helmut ; Kwik-Uribe, Catherine ; Schmitz, Harold H. ; Kelm, Malte. / (-)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 4. pp. 1024-1029.
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AU - Schroeter, Hagen

AU - Heiss, Christian

AU - Balzer, Jan

AU - Kleinbongard, Petra

AU - Keen, Carl L

AU - Hollenberg, Norman K.

AU - Sies, Helmut

AU - Kwik-Uribe, Catherine

AU - Schmitz, Harold H.

AU - Kelm, Malte

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N2 - 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.

AB - 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.

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