The key to understanding why niacin is helpful in treating our symptoms may lie in its antiinflammatory properties
"In addition to lipid effects, recent research also suggested that niacin beneficially affects vascular inflammatory processes involved in atherogenesis. The findings from these studies indicate for the first time that niacin inhibits vascular inflammation by decreasing endothelial reactive oxygen species (ROS) production resulting in decreased endothelial expression of redox-sensitive genes, vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemotactic protein-1 (MCP-1), and monocyte/macrophage adhesion and accumulation, key events in early atherogenesis (25). These in vitro studies describe a novel mechanistic role for niacin in decreasing atherosclerosis beyond its conventional role as a lipid-regulating agent."
"Flushing symptoms occur following vasodilatation of small capillaries under the skin, a response that can be mediated via histamine/bradykinin or prostaglandins. Flushing is not unique to niacin; it has also been reported frequently by patients taking phosphodiesterase inhibitors, selective serotonin reuptake inhibitors (SSRIs), selective oestrogen receptor modulators (SERMs), adenosine and tretinoin. Topical and oral administration of niacin has not been associated with increases in blood levels of either histamine or bradykinin, suggesting that niacin-induced flushing is not mediated by mast cells (26,27). The release of histamine or bradykinin causes a substantial rise in nitric oxide, which leads to increased intracellular release of cyclic guanosine monophosphate (cGMP) and vasodilatation. Elimination of endothelial nitric oxide synthase (eNOS), an enzyme critical for NO production, did not stop niacin-induced flushing in mice (12), providing further support that the histamine/bradykinin pathway is not involved in niacin-induced flushing.
Prostaglandins (PGs), specifically forms D2 and E2, have been identified as participants in the niacin-induced flushing response (28,29). PGs, prostacylcins, thromboxanes and leukotrienes, collectively considered eicosanoids, are hormone-like chemical messengers derived from arachidonic acid. PGs have numerous biological effects, including essential roles in platelet aggregation, neurotransmitter release, and inflammatory and vasomotor responses. Individual prostaglandins can have both positive and negative effects (i.e. pro-inflammatory or anti-inflammatory, vasodilatory or vasoconstrictive) depending upon their concentration, relative proportion to other prostaglandins and expression of receptor types. As prostaglandins are rapidly metabolised and have short half-lives, their metabolic effects are typically localised and can be variable in different parts of the body."
"Through their downstream receptors, PGD2, PGE2 and PGI2 can all exhibit vasodilatory effects on smooth muscle cells in the vasculature, among other effects. Through the DP1 receptor, PGD2 inhibits platelet aggregation and mediates smooth muscle relaxation/contraction. Although PGD2 is known to have vasodilatory properties in the vascular endothelium, it can behave as a vasoconstrictor at higher concentrations and in separate tissues (35). PGD2 can also act through the chemoattractant CRTH2 (DP2) receptor, whose biological role appears to be regulating inflammatory allergic and asthmatic responses (36). PGE2 is perhaps the most widely produced prostaglandin, and as the highest-affinity agonist for the EP receptor family, it exerts the most diverse and versatile effects (37). The EP2 receptors are localised to smooth muscle in the trachea, GI tract and vascular system. They, along with EP4 receptors, are relaxant receptors and induce vasodilatation of various blood vessels through increasing cAMP. The PGE2-EP4 receptor pathway may also mediate some anti-inflammatory effects and facilitate mobilisation, migration and maturation of Langerhans cells in the skin (38). Prostacyclin is the major arachidonic acid product in vascular tissues (39). PGI2 is produced in blood vessels where it is a potent vasodilator and inhibitor of platelet aggregation through the IP receptor (34)."
"Several prostaglandins with vasodilatory properties are influenced by niacin. Specifically, levels of PGD2, PGE2, PGI2 and their metabolites have been shown to be increased as quickly as 12?45 min after niacin treatment (15,26,32,43). Their respective receptors, DP, EP2 and EP4 and IP, can all induce relaxation of blood vessels. After oral niacin treatment, PGD2 levels in the venous blood draining the skin are 14?1200 times higher than the levels in arterial blood (44). The production of PGI2 and PGD2 decreases after repetitive administration of niacin in parallel with the development of flushing tolerance (15). Further, methylnicotinate, which can deliver niacin transdermally, applied to a subject?s arm releases PGD2 only in the exposed arm, with no change in the untreated arm (44). Langerhans cells express PGD2 and PGE2 synthase enzymes (13), indicating they can produce PGD2 and PGE2 to activate receptors on blood vessels that lead to vasodilatation and contribute to flushing side effects. PUMA-G-deficient mice still flush when administered PGD2 (12). Likewise, humans pretreated with the NSAID indomethacin still flush when challenged with PGE (28). Separate deletions of the DP1, EP2 and EP4 in mice result in 40%, 20% and 40% reductions in flushing response, respectively, relative to normal mice after niacin administration (12). In comparison, deletions of COX in mice completely eliminate flushing after niacin treatment (12). Mice that do not express the IP receptor still flush after niacin (12). These experiments indicate that PGD2 and PGE2, signalling through the DP1, EP2 and EP4 receptors, are likely responsible for the flushing side effects of niacin."
"Besides COX, arachidonic acid can be metabolised by a family of enzymes called lipoxygenases to produce leukotrienes (LT), a group of inflammatory lipid mediators. They are released from neutrophils, eosinophils, mast cells and macrophages to play a role in innate immunity (45). Leukotrienes mediate asthma effects, mucus secretion and bronchoconstriction/bronchodilation. Leukotriene B4 (LTB4) applied directly to the skin can cause vasodilatation that is not decreased by COX inhibitors, indicating that the vasodilatation is not mediated by prostaglandins (46). The downstream mechanism of LTB4-mediated vasodilatation is currently unknown. Patients treated with niacin have shown evidence of increases in leukotriene E4 (LTE4) but not LTB4 (47). Any potential effects of LTE4 on niacin-induced flushing have not been reported, and its role in vasodilatation is unclear."
The mechanism and mitigation of niacin-induced flushing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779993/
