title: Interactions between cocoa flavanols and inorganic nitrate: additive effects on endothelial function at achievable dietary amounts.
abstract: Dietary intervention studies have shown that flavanols and inorganic nitrate can improve vascular function, suggesting that these two bioactives may be responsible for beneficial health effects of diets rich in fruits and vegetables. We aimed to study interactions between cocoa flavanols (CF) and nitrate, focusing on absorption, bioavailability, excretion, and efficacy to increase endothelial function. In a double-blind randomized, dose-response crossover study, flow-mediated dilation (FMD) was measured in 15 healthy subjects before and at 1, 2, 3, and 4 h after consumption of CF (1.4-10.9 mg/kg bw) or nitrate (0.1-10 mg/kg bw). To study flavanol-nitrate interactions, an additional intervention trial was performed with nitrate and CF taken in sequence at low and high amounts. FMD was measured before (0 h) and at 1h after ingestion of nitrate (3 or 8.5 mg/kg bw) or water. Then subjects received a CF drink (2.7 or 10.9 mg/kg bw) or a micro- and macronutrient-matched CF-free drink. FMD was measured at 1, 2, and 4 h thereafter. Blood and urine samples were collected and assessed for CF and nitric oxide (NO) metabolites with HPLC and gas-phase reductive chemiluminescence. Finally, intragastric formation of NO after CF and nitrate consumption was investigated. Both CF and nitrate induced similar intake-dependent increases in FMD. Maximal values were achieved at 1 h postingestion and gradually decreased to reach baseline values at 4 h. These effects were additive at low intake levels, whereas CF did not further increase FMD after high nitrate intake. Nitrate did not affect flavanol absorption, bioavailability, or excretion, but CF enhanced nitrate-related gastric NO formation and attenuated the increase in plasma nitrite after nitrate intake. Both flavanols and inorganic nitrate can improve endothelial function in healthy subjects at intake amounts that are achievable with a normal diet. Even low dietary intake of these bioactives may exert relevant effects on endothelial function when ingested together.
authors.affiliation: Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, and. Electronic address: ana.rodriguez-mateos@med.uni-duesseldorf.de.
authors.forename: Ana
authors.initials: A
authors.lastname: Rodriguez-Mateos
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Hezel
authors.affiliation: Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, and.
authors.forename: Hilal
authors.initials: H
authors.lastname: Aydin
authors.affiliation: Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, and; Cardiovascular Research Institute Düsseldorf, University of Düsseldorf, Düsseldorf 40225, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Kelm
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Jon O
authors.initials: JO
authors.lastname: Lundberg
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Eddie
authors.initials: E
authors.lastname: Weitzberg
authors.affiliation: Molecular Nutrition Group, School of Chemistry, Food and Pharmacy, University of Reading, Reading, UK.
authors.forename: Jeremy P E
authors.initials: JP
authors.lastname: Spencer
authors.affiliation: Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, and.
authors.forename: Christian
authors.initials: C
authors.lastname: Heiss
mesh_terms: D000328:Adult; D006801:Humans; D008297:Male; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001916:Brachial Artery / Q000187:drug effects / Q000502:physiology; D002099:Cacao / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000008:administration & dosage / Q000097:blood / Q000652:urine; D005753:Gastric Mucosa / Q000378:metabolism; D009566:Nitrates / Q000008:administration & dosage / Q000097:blood / Q000652:urine; D009569:Nitric Oxide / Q000032:analysis / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D005419:Flavonoids; D009566:Nitrates; D009569:Nitric Oxide
keywords: Bioavailability; Cocoa flavanols; Endothelial function; Free radicals; Interactions; NO; Nitrate