How COX Inhibitors Cause Heart Problems

[Angel]

The removal of COX-2 inhibitors from the market has had researchers trying to find out how the drugs cause heart problems. Now they may have an answer.

COX-2 inhibitors were developed to be as effective as nonsteroidal anti-inflammatory drugs (NSAIDS) in relieving inflammatory pain but without the side effect of gastrointestinal bleeding. But they were taken off the market in 2004 after they were linked to a higher incidence of heart attacks. A new study may explain the reason for the increase.

COX-2 inhibitors are believed to work by suppressing COX-2-derived prostacyclin (PGI2) and prostaglandin E2 (PGE2) -- substances that help prevent platelet clumping in blood vessels and vessel relaxation and/or constriction, respectively. The challenge has been to find a way to suppress PGI2 and PGE2 while avoiding cardiovascular problems.

Now researchers from the University of Pennsylvania School of Medicine in Philadelphia show selective inhibition, knockout, or mutation of COX-2, or deletion of the receptor for COX-2-derived PGI2 accelerates the formation of blood clots and elevates blood pressure in mice. These responses were weakened by COX-1 knock down, which mimics the benefits of low-dose aspirin.

Researchers also propose inhibitors of microsomal PGE synthase-1 (mPGES-1) as an alternative treatment -- one with the anti-inflammatory benefits of NSAIDS and COX-2 inhibitors but without the cardiovascular risks. mPGES-1 depresses PGE2 but avoids heart problems associated with COX-2-mediated PGI2 suppression.