Durham, N.C. -- Low-dose aspirin might prevent the cardiovasculardamage known to arise from use of the painkiller rofecoxib (Vioxx®),suggest new findings from mouse studies by Duke University MedicalCenter researchers. Their findings that a chemical imbalance mightunderlie such damage could also lead to the development ofanti-inflammatory drugs without the adverse side effects, theresearchers said.
The researchers reported their findings in the September 14, 2005, issue of Cell Metabolism.
Earlier studies in humans have found that cox-2 inhibitors suchas rofecoxib cause a decline in prostacyclin, a chemical that normallykeeps blood vessels open and prevents blood clots. That decline occurswithout a change in concentration of thromboxane, a related agent thatconstricts vessels and promotes clot formation.
The new study found that, in a strain of mice prone to highblood pressure, an inability to respond to prostacyclin led to cardiaccomplications, including hypertension, enlarged hearts and severescarring of the heart. Moreover, they showed, unrestrained action ofthromboxane in the mice accentuated the intensity of cardiac damagecaused by the high blood pressure.
"The current results suggest that such a chemical imbalance inpatients taking selective cox-2 inhibitor painkillers may present acardiovascular hazard -- particularly for people already predisposed tohigh 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-inflammatorydrugs (NSAIDS) -- including aspirin and ibuprofen -- all reduceinflammation and pain by blocking the function of the so-called coxenzymes, cox-1 and cox-2. Cox enzymes normally produce prostanoids-- afamily of chemicals, including prostaglandins and thromboxanes, withmany important functions throughout the body.
Prostaglandins produced by both enzymes promote inflammation,pain, and fever, while others made by cox-1 protect the stomach fromthe damaging effects of acid. Two important prostanoids produced by thecox-1 and cox-2 enzymes, respectively, are thromboxane andprostacyclin.
Traditional NSAIDs relieve pain and inflammation bysimultaneously blocking the function of both cox enzymes, Coffmanexplained. However, the effects of such drugs on cox-1 can leave thestomach unprotected, causing gastrointestinal bleeding. Drugs such asrofecoxib, 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 attackand stroke in patients treated with the specific cox-2 inhibitorrofecoxib for more than 18 months. The study also found that patientstaking the drug showed a more immediate rise in blood pressure. Thefindings led Merck, the manufacturer of Vioxx, to withdraw the drugfrom the market last year.
While earlier research has implicated the abnormal chemicalprofile in the vascular disease associated with cox-2 inhibitors, itsrole in the development of high blood pressure remained unclear,Coffman said. Hypertension is the most common cardiovascularcomplication associated with cox-2 inhibition, he added.
To examine the consequences of prostacyclin decline for bloodpressure and cardiac damage, the team manipulated mice such that theycompletely lacked the receptors that normally respond to the vesseldilator. The mice belonged to a strain particularly vulnerable todeveloping increased blood pressure when fed a diet high in salt.
"Hypertension is the most common cardiovascular complicationassociated with cox-2 inhibition, yet not everybody who takes the drugsdevelops high blood pressure," Coffman said. "The mice appear to havecharacteristics similar to the subset of patients who are prone toexperience this side effect."
In the absence of the prostacyclin receptor, mice exhibitedelevated blood pressure, the team reported. The animals also sufferedexaggerated cardiac fibrosis and heart enlargement. Fibrosis, orscarring of the heart, can lead to arrhythmias and organ failure as theheart loses its ability to pump blood to the body's tissues.
Mice lacking both the prostacyclin and the thromboxanereceptors continue to suffer from high blood pressure, but do notdevelop the other cardiac complications, they found. The results revealthe adverse cardiovascular consequences of thromboxane when leftunconstrained by prostacyclin, the team reported. Furthermore, thefindings point to the imbalance of blood vessel agents as the culpritbehind the most serious cardiac complications in the animals.
The mice represent an extreme example of what might happen inpatients taking cox-2 inhibitors, Coffman said. While prostacyclinactivity can be substantially reduced in patients taking thepainkillers, the animals lacked this important blood componentaltogether, he explained.
"Our data suggests that therapies that block unrestrainedthromboxane actions -- for example, low doses of aspirin -- mightprotect against end-organ damage without affecting blood pressure inpatients taking cox-2 inhibitors," Coffman said. "However, thepractical utility of such an approach would depend on whether such atherapy would retain the gastrointestinal protection afforded by cox-2inhibitors alone."
The researchers will next explore the effects of cox-2inhibitors themselves in the salt-sensitive mice. Further study of theanimals might also reveal the genetic factors that underlie thepredisposition of particular individuals to develop high blood pressureand cardiac complications during therapy with cox-2 inhibitors.
Collaborators on the study include Helene Francois, KrairerkAthirakul, David Howell, Rajesh Dash, Lan Mao and Howard Rockman, ofDuke; Hyung-Suk Kim and Beverly Koller of University of North Carolina,Chapel Hill; and Garret Fitzgerald of University of Pennsylvania.
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