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 ringsex vivo, thus mimicking acetylcholine-induced relaxations.Ex vivoflavanol-induced relaxation, as well as thein vivoincreases 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.

Guidelines and Expert Consensus Documents aim to present management and recommendations based on the relevant evidence on a particular subject in order to help physicians to select the best possible management strategies for the individual patient suffering from a specific condition, taking into account not only the impact on outcome, but also the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes for textbooks. The legal implications of medical guidelines have been discussed previously.¹

A specific difference-spectrophotometric method was used to measure nitric oxide (NO) release into the coronary effluent perfusate of isolated, constant-flow-perfused guinea pig hearts. Authentic NO applied into the coronary circulation decreased vascular resistance dose dependently and enhanced coronary release of cyclic GMP (cGMP) fivefold. Increasing oxygen tension in aqueous solutions from 150 to 700 mm Hg decreased NO half-life (5.6 seconds) by 32%. During single passage through the intact coronary system, 86% of the infused NO was converted to nitrite ions. Oxidation of NO was more than 30 times faster within the heart than in aqueous solution. Endogenously formed NO was constantly released into the coronary effluent perfusate at a rate of 161 +/- 11 pmol/min. The NO scavenger oxyhemoglobin and methylene blue increased coronary resistance and decreased cGMP release (basal release, 342 +/- 4 fmol/min), whereas superoxide dismutase reduced coronary resistance. L-Arginine (10(-5) M) slightly decreased coronary perfusion pressure and enhanced release of cGMP. NG-Monomethyl L-arginine (10(-4) M) reduced basal release of NO and cGMP by 26% and 31%, respectively, paralleled by a coronary vasoconstriction. Bradykinin in the physiological range from 5 x 10(-11) M to 10(-7) M dilated coronary resistance vessels, which was paralleled by the release of NO and cGMP. Onset of NO release preceded onset of coronary vasodilation in all cases. Upon stimulation with bradykinin, amounts of endogenously formed NO were within the same range as the dose-response curves for exogenously applied NO both for changes in coronary resistance and cGMP release. Acetylcholine (10(-5) M), ATP (10(-5) M), and serotonin (10(-8) M) increased the rate of NO and cGMP release, resulting in coronary vasodilation. Our data suggest the following: 1) NO, the most rapidly acting vasodilator presently known, is metabolized within the heart mainly to nitrite and exhibits a half-life of only 0.1 second; 2) in the unstimulated heart, basal formation of NO may play an important role in setting the resting tone of coronary resistance vessels; 3) the kinetics and quantities of NO formation suggest that NO is causally involved in the bradykinin-induced coronary vasodilation; and 4) amounts of NO formed within the heart stimulated with ATP, acetylcholine, and serotonin are effective for vasodilation.