Perpetrator of Nicotinic Acid Flush Response Identified

To determine why nicotinic acid generates this flushing response, investigators at Duke University (Durham, NC, USA) worked with both human cell cultures and a mouse model of hypercholesterolemia.

They reported in the April 6, 2009, issue of the Journal of Clinical Investigation that in a human cell line-based signaling assay, nicotinic acid stimulation led to pertussis toxin-sensitive lowering of cAMP and recruitment of beta-arrestins to the cell membrane. The recruitment of beta-arrestin caused an activating conformational change in the molecule with subsequent beta-arrestin-dependent signaling to the ERK/MAPK (extracellular signal-regulated kinase/mitogen activated protein kinase) pathway. In addition, nicotinic acid promoted the binding of beta-arrestin1 to activated cytosolic phospholipase A2 as well as beta-arrestin1-dependent activation of cytosolic phospholipase A2 and release of arachidonate, the precursor of prostaglandin D2, which is the vasodilator responsible for the flushing response.

Mice that had been genetically engineered to lack the gene for beta-arrestin displayed reduced cutaneous flushing in response to nicotinic acid, although the improvement in serum free fatty acid levels was similar to that observed in wild-type mice.

The authors concluded that, "These data suggest that the adverse side effect of cutaneous flushing is mediated by beta-arrestin1, but lowering of serum free fatty acid levels is not." Therefore, development of a drug that raises HDL levels like nicotinic acid without activating beta-arrestin is a top priority.

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