Nicotinic Acid Activates the Capsaicin Receptor TRPV1

Abstract

Objective Nicotinic acid (a.k.a. niacin or vitamin B3), widely used to treat dyslipidemias, represents an effective and safe means to reduce the risk of mortality from cardiovascular disease. Nonetheless, a substantial fraction of patients discontinue treatment due to a strong side effect of cutaneous vasodilation, commonly termed flushing. In the present study we tested the hypothesis that nicotinic acid causes flushing partially by activating the capsaicin receptor TRPV1, a polymodal cellular sensor that mediates the flushing response upon consumption of spicy food. Approach and Results We observed that the nicotinic acid-induced increase in blood flow was substantially reduced in Trpv1−/− knockout mice, indicating involvement of the channel in flushing response. Using exogenously expressed TRPV1, we confirmed that nicotinic acid at sub-millimolar to millimolar concentrations directly and potently activates TRPV1 from the intracellular side. Binding of nicotinic acid to TRPV1 lowers its activation threshold for heat, causing channel opening at physiological temperatures. Activation of TRPV1 by voltage or ligands (capsaicin and 2-APB) is also potentiated by nicotinic acid. We further demonstrated that nicotinic acid does not compete directly with capsaicin but may activate TRPV1 through the 2-APB activation pathway. Using live-cell fluorescence imaging, we observed that nicotinic acid can quickly enter the cell through a transporter-mediated pathway to activate TRPV1. Conclusions Direct activation of TRPV1 by nicotinic acid may lead to cutaneous vasodilation that contributes to flushing, suggesting a potential novel pathway to inhibit flushing and improve compliance.

Heating Up the Cutaneous Flushing Response

“…16 However, TRPV1 is also expressed on many non-neuronal cells including keratinocytes where its activation can regulate cell function. 17 Ma et al 15 now show that nicotinic acid-induced flushing is strongly reduced in mice lacking TRPV1. In addition, they demonstrate that nicotinic acid, when applied intracellularly, results in a left shift of the temperature dependence of TRPV1, causing a fraction of TRPV1 channels to be activated at normal body temperature.…”

“…In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Ma et al 15 propose the transient receptor potential (TRP) channel TRPV1 as a new direct target of nicotinic acid, mediating nicotinic acid-induced flushing. TRPV1, also known as the capsaicin receptor 1, is a cation channel activated by temperatures >43°C and by low pH, as well as by several compounds including capsaicin, the pungent component of hot chili peppers.…”

“…Given this low potency, it cannot be excluded that the regulation of TRPV1 in in vitro experiments is rather because of the physicochemical properties of nicotinic acid, and the authors report about a strong drop in the intracellular pH after addition of high doses of nicotinic acid, which by itself may alter TRPV1 activity. When studying the human TRPV1 channel in vitro, Ma et al 15 however found that nicotinic acid has a higher potency toward the human TRPV1 and that intracellular application of nicotinic acid at concentrations that can be reached in the plasma of treated patients increases the temperature sensitivity of human TRPV1 in vitro. Although the mouse experiments in vivo and the extremely low potency of nicotinic acid toward the murine TRPV1 in vitro are difficult to reconcile, the higher sensitivity of the human TRPV1 makes it a potential target for nicotinic acid in treated patients.…”

“…Any new insight into the mechanisms underlying, in particular, the unpleasant sensory component of flushing is of great importance to find new ways to mitigate flushing and to increase patient compliance. The work by Ma et al 15 will certainly inspire studies to explore further the involvement of TRPV1 in drug-induced flushing and to search for new ways to blunt the flushing response.…”

Measuring niacin-associated skin toxicity (NASTy) stigmata along with symptoms to aid development of niacin mimetics

“…Niacin may activate the capsaicin receptor, TRPV1, in dermal macrophages, binding the receptor intracellularly. Interestingly, TRPV1 inhibition mitigates dermal hyperemia post niacin (61,62). Perhaps secondary hyperemia follows TRPV1 activation after niacin presents intracellularly, explaining the several-hour delay.…”