New study cautions use of drugs to block 'niacin flush'

April 9, 2012

Niacin, or vitamin B3, is the one approved drug that elevates "good" cholesterol (high density lipoprotein, HDL) while depressing "bad" cholesterol (low density lipoprotein , LDL), and has thereby attracted much attention from patients and physicians. Niacin keeps fat from breaking down, and so obstructs the availability of LDL building blocks.

Patients often stop taking niacin because it causes uncomfortable facial flushing, an effect caused by the release of a fat called or (PG)D2. PGD2 is the primary cause of the unwanted vasodilation, the "niacin flush." The dilation occurs when blood vessels widen from relaxed within .

PGD2, formed by an enzyme called COX-2 and released by immune and , acts on a muscle cell-surface receptor called DP1 to cause the flushing. In fact, a combination of a DP1- blocking drug and niacin is being evaluated in a large clinical trial to determine its effectiveness in reducing heart attacks, as opposed to other drugs that reduce LDL cholesterol.

In work published in the this month, first authors Wenliang Song, MD, research assistant professor, and Jane Stubbe, PhD, postdoctoral fellow, in the Perelman School of Medicine, University of Pennsylvania, and their colleagues now question the wisdom of blocking DP1 in patients prone to cardiovascular disease, especially those taking niacin.

Drawing evidence from studies in mice and humans, they show that platelets -- complicated cells circulating in the bloodstream that stick together in the first phase of blood clotting -- make PGD2, which acts as a brake via DP1 on their own activation. This is surprising as PGD2 is made in platelets by COX-1, the target inhibited by low-dose aspirin.

COX-1 in platelets also makes thromboxane (Tx)A2, another fat that activates platelets. As low-dose aspirin is cardioprotective by thinning blood, the benefit from shutting down platelet TxA2 trumps the potential risk of suppressing platelet PGD2 production.

To gather more information on the potential risks from blocking DP1, the Penn investigators used mice lacking the DP1 receptor. However, unlike humans, mice do not express DP1 in their platelets. "Frankly, because of this, we did not expect to detect any signal of cardiovascular hazard in the mice," notes senior author Garret FitzGerald, MD, director of the Institute for Translational Medicine and Therapeutics.

However, deletion of DP1 made mice somewhat more susceptible to hardening of the arteries, the formation of aneurysm, thrombosis, and in some cases, high blood pressure. The researchers suggest that these findings are reflective of DP1 expression in vascular and immune cells in mice, just as in humans, despite its absence on mouse platelet cells.

Turning back to humans, the Penn investigators discovered that niacin evoked COX-1- dependent formation of both TxA2 and PGD2 in platelets and that a DP1 blockade enhanced the effect of TxA2 on platelet activation.

Taken together, these interwoven findings suggest that blocking the effects of PGD2 on DP1 is likely to be undesirable in patients with heart disease, and perhaps in particular, those taking niacin. That possibility is not addressed by the design of the large ongoing trial of the niacin/DP1 antagonist combination, say the researchers.

Should such a hazard exist, FitzGerald expects it to be confined to those patients not taking low-dose aspirin, along with . "This potential hazard of blocking one aspect of PGD2 action, the one dependent on DP1, contrasts nicely with our recent report that blocking its other receptor, DP2, may be beneficial in limiting male-pattern baldness" said FitzGerald.

Explore further: Niacin does not reduce heart attack, stroke risk in stable CV patients

Related Stories

Niacin does not reduce heart attack, stroke risk in stable CV patients

November 15, 2011
In patients whose bad cholesterol is very well-controlled by statins for a long time period, the addition of high-dose, extended release niacin did not reduce the risk of cardiovascular events, including heart attack and ...

Research identifies inhibitor causing male pattern baldness and target for hair-loss treatments

March 21, 2012
Researchers from the Perelman School of Medicine at the University of Pennsylvania have identified an abnormal amount a protein called Prostaglandin D2 in the bald scalp of men with male pattern baldness, a discovery that ...

Recommended for you

Engineered protein treatment found to reduce obesity in mice, rats and primates

October 19, 2017
(Medical Xpress)—A team of researchers with pharmaceutical company Amgen Inc. report that an engineered version of a protein naturally found in the body caused test mice, rats and cynomolgus monkeys to lose weight. In their ...

New procedure enables cultivation of human brain sections in the petri dish

October 19, 2017
Researchers at the University of Tübingen have become the first to keep human brain tissue alive outside the body for several weeks. The researchers, headed by Dr. Niklas Schwarz, Dr. Henner Koch and Dr. Thomas Wuttke at ...

Cancer drug found to offer promising results in treating sepsis in test mice

October 19, 2017
(Medical Xpress)—A combined team of researchers from China and the U.S. has found that a drug commonly used to treat lung cancer in humans offers a degree of protection against sepsis in test mice. In their paper published ...

Tracing cell death pathway points to drug targets for brain damage, kidney injury, asthma

October 19, 2017
University of Pittsburgh scientists are unlocking the complexities of a recently discovered cell death process that plays a key role in health and disease, and new findings link their discovery to asthma, kidney injury and ...

Study reveals key molecular link in major cell growth pathway

October 19, 2017
A team of scientists led by Whitehead Institute has uncovered a surprising molecular link that connects how cells regulate growth with how they sense and make available the nutrients required for growth. Their work, which ...

Inflammation trains the skin to heal faster

October 18, 2017
Scars may fade, but the skin remembers. New research from The Rockefeller University reveals that wounds or other harmful, inflammation-provoking experiences impart long-lasting memories to stem cells residing in the skin, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.