Low-dose aspirin might prevent the cardiovascular damage known to arise from use of the painkiller rofecoxib (Vioxx)

Sep 20 2005

Low-dose aspirin might prevent the cardiovascular damage known to arise from use of the painkiller rofecoxib (Vioxx), suggest new findings from mouse studies by Duke University Medical Center researchers.

Their findings that a chemical imbalance might underlie such damage could also lead to the development of anti-inflammatory drugs without the adverse side effects, the researchers said.

The researchers reported their findings in Cell Metabolism.

Earlier studies in humans have found that cox-2 inhibitors such as rofecoxib cause a decline in prostacyclin, a chemical that normally keeps blood vessels open and prevents blood clots. That decline occurs without a change in concentration of thromboxane, a related agent that constricts vessels and promotes clot formation.

The new study found that, in a strain of mice prone to high blood pressure, an inability to respond to prostacyclin led to cardiac complications, including hypertension, enlarged hearts and severe scarring of the heart. Moreover, they showed, unrestrained action of thromboxane in the mice accentuated the intensity of cardiac damage caused by the high blood pressure.

"The current results suggest that such a chemical imbalance in patients taking selective cox-2 inhibitor painkillers may present a cardiovascular hazard -- particularly for people already predisposed to high blood pressure," said senior author of the study Thomas Coffman, M.D., chief of nephrology in the department of medicine.

Cox-2 inhibitors and other non-steroidal anti-inflammatory drugs (NSAIDS) -- including aspirin and ibuprofen -- all reduce inflammation and pain by blocking the function of the so-called cox enzymes, cox-1 and cox-2. Cox enzymes normally produce prostanoids-- a family of chemicals, including prostaglandins and thromboxanes, with many important functions throughout the body.

Prostaglandins produced by both enzymes promote inflammation, pain, and fever, while others made by cox-1 protect the stomach from the damaging effects of acid. Two important prostanoids produced by the cox-1 and cox-2 enzymes, respectively, are thromboxane and prostacyclin.

Traditional NSAIDs relieve pain and inflammation by simultaneously blocking the function of both cox enzymes, Coffman explained. However, the effects of such drugs on cox-1 can leave the stomach unprotected, causing gastrointestinal bleeding. Drugs such as rofecoxib, celecoxib (Celebrex) and valdecoxib (Bextra) avoid the gastrointestinal side effects by acting only on cox-2.

A 2004 study, however, found an increased rate of heart attack and stroke in patients treated with the specific cox-2 inhibitor rofecoxib for more than 18 months. The study also found that patients taking the drug showed a more immediate rise in blood pressure. The findings led Merck, the manufacturer of Vioxx, to withdraw the drug from the market last year.

While earlier research has implicated the abnormal chemical profile in the vascular disease associated with cox-2 inhibitors, its role in the development of high blood pressure remained unclear, Coffman said. Hypertension is the most common cardiovascular complication associated with cox-2 inhibition, he added.

To examine the consequences of prostacyclin decline for blood pressure and cardiac damage, the team manipulated mice such that they completely lacked the receptors that normally respond to the vessel dilator. The mice belonged to a strain particularly vulnerable to developing increased blood pressure when fed a diet high in salt.

"Hypertension is the most common cardiovascular complication associated with cox-2 inhibition, yet not everybody who takes the drugs develops high blood pressure," Coffman said. "The mice appear to have characteristics similar to the subset of patients who are prone to experience this side effect."

In the absence of the prostacyclin receptor, mice exhibited elevated blood pressure, the team reported. The animals also suffered exaggerated cardiac fibrosis and heart enlargement. Fibrosis, or scarring of the heart, can lead to arrhythmias and organ failure as the heart loses its ability to pump blood to the body's tissues.

Mice lacking both the prostacyclin and the thromboxane receptors continue to suffer from high blood pressure, but do not develop the other cardiac complications, they found. The results reveal the adverse cardiovascular consequences of thromboxane when left unconstrained by prostacyclin, the team reported. Furthermore, the findings point to the imbalance of blood vessel agents as the culprit behind the most serious cardiac complications in the animals.

The mice represent an extreme example of what might happen in patients taking cox-2 inhibitors, Coffman said. While prostacyclin activity can be substantially reduced in patients taking the painkillers, the animals lacked this important blood component altogether, he explained.

"Our data suggests that therapies that block unrestrained thromboxane actions – for example, low doses of aspirin -- might protect against end-organ damage without affecting blood pressure in patients taking cox-2 inhibitors," Coffman said. "However, the practical utility of such an approach would depend on whether such a therapy would retain the gastrointestinal protection afforded by cox-2 inhibitors alone."

The researchers will next explore the effects of cox-2 inhibitors themselves in the salt-sensitive mice. Further study of the animals might also reveal the genetic factors that underlie the predisposition of particular individuals to develop high blood pressure and cardiac complications during therapy with cox-2 inhibitors.

Collaborators on the study include Helene Francois, Krairerk Athirakul, David Howell, Rajesh Dash, Lan Mao and Howard Rockman, of Duke; Hyung-Suk Kim and Beverly Koller of University of North Carolina, Chapel Hill; and Garret Fitzgerald of University of Pennsylvania.

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