Conjugated Linoleic Acid Modulates Clinical Responses to Oral Nitrite and Nitrate

Abstract

Dietary nitrate (NO3−) and nitrite (NO2−) support nitric oxide (·NO) 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 Na15NO3 and Na15NO2 were orally administered in the presence or absence of conjugated linoleic acid (cLA). The reduction of 15NO2− to 15NO was indicated by electron paramagnetic resonance spectroscopy detection of hyperfine splitting patterns reflecting 15NO-deoxyhemoglobin complexes. This formation of 15NO 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 12-15NO2-cLA. Co-administration of cLA with 15NO2− also impacted the pharmacokinetics and physiological effects of 15NO2−, with cLA administration suppressing plasma NO3− and NO2− levels, decreasing 15NO-deoxyhemoglobin formation, NO2− inhibition of platelet activation, and the vasodilatory actions of NO2−, while enhancing the formation of 9- and 12-15NO2-cLA. These results indicate that the biochemical reactions and physiologic responses to oral 15NO3− and 15NO2− 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.

The discovery of nitro-fatty acids as products of metabolic and inflammatory reactions and mediators of adaptive cell signaling

“…More recently, the clinical administration of 15 N-labeled nitrite and nitrate has convincingly shown that fatty acid nitration occurs in humans during digestion (Fig. 1) (80,81). This observation in turn motivated the proposal that the cardiovascular benefits of a Mediterranean-like diet, rich in both vegetable-derived NO 2 − and NO 3 − and marine or olive oil-derived unsaturated fatty acids, could be (in part) ascribed to increased NO 2 -FA generation and the downstream elevation of vasoactive and anti-inflammatory lipid mediators (82).…”

Electrophilic characteristics and aqueous behavior of fatty acid nitroalkenes

“…The endogenous formation of NO 2 -FA [ [3] , [4] , [5] ] will be strongly influenced by diet, which may contain pre-formed NO 2 -FA or a combination of precursor fatty acids and sources of the organic nitrates required for fatty acid nitration (i.e., NO 2 − coming from animal and plant-derived products or NO 2 − -based preservatives) [ 22 ]. Clinical studies have revealed that dietary supplementation of organic nitrates, with and without co-administration of conjugated linoleic acid (cLA), resulted in a sustained level of NO 2 -cLA only when cLA was co-administered [ 23 ]. This indicates that cLA is rate limiting and its simultaneous presence in the gastric compartment together with NO 2 − and its precursor nitrate (NO 3 − ) is needed for the formation of the NO 2 -cLA.…”

The effect of the electrophilic fatty acid nitro-oleic acid on TRP channel function in sensory neurons

“…Thus endogenous nitrated fatty acids may have a role in modulating the activity of nociceptive afferents and, in turn, influence the development and/or resolution of inflammatory responses and pain. The demonstration that oral administration of nitrated fatty acids or their precursors can produce significant blood, tissue and urine levels of these substances [3,43–45] raises the possibility that nitro-lipid therapies may be developed to target pathophysiological mechanisms and disorders which involve TRP channels [46] and that passage of these substances from the urine into the bladder wall might be effective in treating certain types lower urinary tract dysfunctions.…”