Painkillers called COX-2 inhibitors may increase the risk of heart attacks by raising blood pressure and making the blood more likely to clot, researchers said on Thursday.

They do so by the same mechanisms that they use to reduce pain and inflammation, said University of Pennsylvania School of Medicine researcher Dr. Garret FitzGerald, who led the study.

But the finding shows that a new generation of anti-inflammatory drugs could avoid the problem, FitzGerald reported in the Journal of Clinical Investigation.

“Although these results are in mice, not people, they raise an exciting possibility which can be tested in humans,” FitzGerald said.

The COX-2 inhibitors were originally designed to be a safer long-term treatment than aspirin and other analgesics for arthritis and similar pain. They fell under a cloud when it was found they could raise the risk of heart problems.

Merck and Co. pulled its drug Vioxx from the market in September 2004 after a study showed it doubled the risk of heart attack and stroke in people who took Vioxx for at least 18 months. A jury on Tuesday awarded $9 million in punitive damages to a New Jersey man who blamed Vioxx for his heart attack and more than 7,000 other people have sued.

Pfizer Inc. suspended sales of its COX-2 inhibitor Bextra and now includes a strong “black box” warning for its COX-2 Celebrex, the only such drug now on the market.

FitzGerald has for years had a theory that COX-2 drugs depress a protective fat called prostacyclin, while leaving unaltered a harmful one called thromboxane.

He and collaborator Colin Funk, now at Queen’s University, Ontario, genetically manipulated mice and tested them.

PROVING THE THEORY

They found that disrupting the COX-2 gene, interfering with the enzyme through different genetic routes, and genetically disrupting prostacyclin’s effects all made the mice prone to blood clots and raised blood pressure.

“One does not need additional explanations to understand what we have seen in clinical trials,” Funk said in a statement.

“COX-2 inhibitors confer a small, but absolute cardiovascular risk using the same mechanism by which they relieve pain and inflammation,” he said.

Aspirin, long known to reduce the risk of heart attacks and stroke, interfered with the process.

It might be possible to take aspirin alongside a COX-2 but that would make no sense because the whole point of COX-2 inhibitors is to avoid the serious risk of stomach bleeding caused by aspirin, FitzGerald said.

“I think aspirin would do exactly what you might expect -  attenuate, but not abolish the risk,” FitzGerald said in an e-mail.

FitzGerald and Funk tested another enzyme, called microsomal prostaglandin E synthase or mPGES-1.

COX, or cyclooxygenase, is an enzyme that comes in two forms -  COX-1 and COX-2. Aspirin and other analgesics such as ibuprofen, known as non-steroidal anti-inflammatory drugs or NSAIDS, affect both COX-1 and COX-2 but have well-known side effects including sometimes fatal internal bleeding.

But some research has shown that interfering with mPGES-1 works as well as NSAIDS in reducing pain and inflammation and some big drug companies are working on developing drugs that do this.

FitzGerald and his colleagues showed that deleting mPGES-1 did not cause clotting or raise blood pressure in the mice.

“Selective inhibitors of mPGES-1 may retain much of the benefit of drugs like Vioxx and Celebrex, while diminishing the risk of heart attack and stroke by having precisely the opposite effect on prostacyclin,” FitzGerald said.

Journal of Clinical Investigation, April, 2006.