Finding might explain a danger of Viagra. (Blood-Clot Surprise).

For a fraction of 1 percent of the men who take sildenafil, the impotence-fighting pill known as Viagra, sex comes with nasty side effects: heart attack and sometimes death. However, scientists have never linked the deaths directly to the drug, leaving open the possibility that the physical stress of amorous activity could be the problem.

Now, researchers studying the blood component called platelets have stumbled upon evidence that might implicate the drug instead of the sex.

Platelets are tiny cell-like disks that collect and form blood clots at the site of an injury. Overactive platelets can clog blood vessels, causing heart attack or stroke. Sildenafil increases blood concentrations of a compound that both increases blood flow to the penis and stimulates production of an enzyme called cGMP-dependent protein kinase, or PKG. Researchers have long known that PKG keeps platelets from sticking together. In fact, scientists initially developed sildenafil to treat heart disease.

Researchers at the University of Illinois College of Medicine in Chicago now report that PKG plays a dual role, first spurting platelet aggregation and then, only minutes later, limiting clot size. The initial clot promotion, reported in the Jan. 10 Cell, suggests that a PKG booster such as sildenafil could send some men with already damaged heart vessels into cardiac arrest.

"We know of hundreds of [sildenafil-related] cardiac deaths, but they have never been causally linked to the drug's effects," says Xiaoping Du, a molecular biologist at the medical school. "Our results provide a possible mechanism" for such a link, says Du.

He and his colleagues first tested PKG's effects in hamster cells that had been engineered to produce human blood proteins. PKG enhanced the action of the protein that hooks platelets together during clot formation. Also, wounded tails of mice lacking PKG bled four times as long as those of normal mice did.

The researchers next treated human platelets with compounds to quell or stimulate the enzyme. Platelet binding changed with PKG concentrations. Also, sildenafil made platelets clingier only when natural blood-clotting stimulants were present. After several minutes of exposure to PKG, however, platelets became less sticky.

"The data are quite convincing that [PKG] can both activate and inhibit platelet function," says molecular cardiologist Edward F. Plow of the Cleveland Clinic Foundation in Ohio, and they "should raise caution about using [sildenafil]."

Hematologist Jose A. Lopez at Baylor College of Medicine in Houston warns against overextending the laboratory results. For most people, he says, the drug appears to be "pretty safe--safer than lots of other things people take."

If the drug substantially increased heart attack risk, adds Geoffrey Cook, spokesman for Viagra-maker Pfizer in New York City, clinical trials of the drug would have revealed it because many sildenafil users have cardiovascular disease.