Nicotinic acid (niacin or Vitamin B3) has been widely used to treat dyslipidemias and 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. As a multi-component complex biological event, the molecular mechanism of flushing is not completely understood yet. In the present study, we tested the hypothesis that nicotinic acid causes flushing by activating the capsaicin receptor TRPV1, a polymodal cellular sensor that mediates a similar flushing response upon consumption of spicy food.
Indeed, 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 could quickly enter the cell through a transporter-mediated pathway and potently activates TRPV1 from the intracellular side, but very weakly activates its homolog TRPV3 while inhibiting TRPV2 and TRPV4. 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 is also potentiated by nicotinic acid. Furthermore, nicotinic acid does not compete directly with capsaicin but may activate TRPV1 through the 2-APB activation pathway. In conclusion, direct activation of TRPV1 by nicotinic acid may lead to a cutaneous vasodilation that contributes to flushing, suggesting a potential novel pathway to inhibit flushing and improve compliance.