Inhibition of endothelial NADPH oxidase as target of flavonoids in nitric acid metabolism

The foregoing article was focused on the modulation by dietary flavonoids of generation and biological role of plasma lipoproteins and the consequences as to the risk for cardiovascular diseases. The objective of the second article of this series is to gain deeper insight into the cellular and molecular action of flavonoids and other dietary polyphenols and their bioactive species, respectively. A decade ago, the beneficial effects of flavonoids were believed to be attributable to free radical-scavenging properties, which are observed in numerous in vitro assays. Evidence for a direct antioxidant activity in vivo, however, is poor. By estimation of parameters in vivo or ex vivo believed to be appropriate, many efforts were undertaken to demonstrate an attenuation of free radical-mediated processes upon intake of dietary polyphenols. The outcome of such studies was throughout disappointing, i.e. the effects were either lacking or only marginal, even though some authors interpreted their data in an exaggerated manner as “positive”. This tendency was promoted by the pressure of the investigators to achieve positive results for obtaining financial support, enabling them to sustain polyphenol research. Moreover, in many studies the selection of clinical parameters was far from reasonable. As an example, the widely used “thiobarbituric acid-reactive substance” (TBARS) assay provides unreliable data for several reasons, which will not be discussed in detail here. For detection of lipid peroxidation in vivo the plasma level of F2 isoprostanes may be the parameter of choice, since these arachidonic acid oxygenation products actually originate from non-enzymatic free radical-mediated attack and can be unequivocally discriminated from eicosanoids generated by enzymes of the arachidonic acid cascade [Roberts & Fessel, 2004; Basu, 2004]. For this reason, we conducted in Magdeburg a clinical study on the effect of intake of a high-flavanol cocoa beverage on plasma F2 isoprostanes [Wiswedel et al, 2004]. Although the volunteers were subjected to physical exercise by treadmill as a free radical-generating process, sizable lowering of the F2 isoprostane level was not observed. By contrast, the same type of high-flavanol cocoa exerted clear-cut beneficial effects in other clinical trials (see Section 3). Detailed statistical analysis of the data from the Magdeburg study, however, revealed that the cocoa flavanols prevented the increase in F2 isoprostanes induced by the low-flavanol control drink, an effect interpreted as postprandial oxidative stress [Sies et al, 2005a].