Conjugated Linoleic Acid Modulates Clinical Responses to Oral Nitrite and Nitrate.

Dietary NO3 - (nitrate) and NO2 - (nitrite) support ˙NO (nitric oxide) generation and downstream vascular signaling responses. These nitrogen oxides also generate secondary nitrosating and nitrating species that react with low molecular weight thiols, heme centers, proteins, and unsaturated fatty acids. To explore the kinetics of NO3 - and NO2 - metabolism and the impact of dietary lipid on nitrogen oxide metabolism and cardiovascular responses, the stable isotopes Na15 NO3 and Na15 NO2 were orally administered in the presence or absence of conjugated linoleic acid (cLA). The reduction of 15 NO2 - to 15 NO was indicated by electron paramagnetic resonance spectroscopy detection of hyperfine splitting patterns reflecting 15 NO-deoxyhemoglobin complexes. This formation of 15 NO also translated to decreased systolic and mean arterial blood pressures and inhibition of platelet function. Upon concurrent administration of cLA, there was a significant increase in plasma cLA nitration products 9- and 12-15 NO2 -cLA. Coadministration of cLA with 15 NO2 - also impacted the pharmacokinetics and physiological effects of 15 NO2 - , with cLA administration suppressing plasma NO3 - and NO2 - levels, decreasing 15 NO-deoxyhemoglobin formation, NO2 - inhibition of platelet activation, and the vasodilatory actions of NO2 - , while enhancing the formation of 9- and 12-15 NO2 -cLA. These results indicate that the biochemical reactions and physiological responses to oral 15 NO3 - and 15 NO2 - are significantly impacted by dietary constituents, such as unsaturated lipids. This can explain the variable responses to NO3 - and NO2 - supplementation in clinical trials and reveals dietary strategies for promoting the generation of pleiotropic nitrogen oxide-derived lipid signaling mediators. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01681836.