Participating in the research are, from left, Reyadh Redha, research assistant, Linda Davis, research assistant, Rich Breyer, Ph.D., Dr. Chuan-Ming Hao, Dr. Zhonghua Qi and Dr. Matt Breyer. Dr. Jason Morrow and Robert Langenbach, Ph.D. are not pictured. (photo by Dana Johnson)
Balance of COX enzymes helps blood pressure: study
Researchers at Vanderbilt University Medical Center have found some surprising evidence that a balance between the two cyclooxygenase (COX) enzymes is important in maintaining blood pressure.
The enzymes are best known for the role they play in arthritis: The blockbuster drugs Celebrex and Vioxx reduce pain and inflammation by selectively inhibiting COX-2. But because they spare the closely related COX-1, which protects the stomach lining, they don’t cause gastrointestinal bleeding and ulcers — a major problem with older arthritis drugs like Motrin and Aleve that block both enzymes.
Unfortunately, the COX-2 inhibitors don’t avoid other side effects of standard arthritis therapy, notably high blood pressure, salt and water retention (edema) and congestive heart failure in some patients, and some recent studies suggest that in some people, they may increase the risk of blood clots that can cause heart attacks and strokes.
Researchers previously thought that inhibition of COX-2 was exclusively responsible for the rise in blood pressure.
In a study in mice, however, Dr. Matthew D. Breyer and his colleagues found that both enzymes played a role in the blood pressure-raising effects of angiotension II, a hormone that constricts blood vessels. Blood pressure rose higher when COX-2 was blocked, but it unexpectedly fell in animals given an experimental drug that selectively inhibited COX-1, the researchers reported in this month’s Journal of Clinical Investigation.
The results indicate that the uninhibited COX-1 enzyme tends to accentuate the effects of angiotension II on blood pressure, whereas COX-2 normally acts as a “buffer,” lowering blood pressure.
Further study is needed, but the findings suggest that older arthritis drugs might in some cases be better than COX-2 inhibitors for patients with severe heart disease who are not at risk for gastrointestinal bleeding, said Breyer, professor of Medicine, and Molecular Physiology & Biophysics. “It also opens up the possibility that COX-1 selective inhibitors (which have not yet been brought to market) could be useful therapeutically in people,” he added. “We might have a new class of anti-hypertensive drugs.”
The lead author for the study was research fellow Dr. Zhonghua Qi, who set up the techniques for measuring blood pressure and renal effects in the mice.
Other authors included Dr. Chuan-Ming Hao, research assistant professor of Medicine; Breyer’s brother, Richard M. Breyer, Ph.D., associate professor of Medicine and Pharmacology; Dr. Jason D. Morrow, F. Tremaine Billings Professor of Medicine and professor of Pharmacology; research assistant Reyadh Redha; and Robert I. Langenbach, Ph.D., microbiologist in the Laboratory of Environmental Carcinogenesis and Mutagenesis at the National Institute of Environmental Health Sciences in Research Triangle Park, N.C.
The COX enzymes exert a wide variety of physiological effects through the production of locally acting hormones called prostaglandins in different tissues. In platelets, for example, COX-1 produces a kind of prostaglandin, called thromboxane, that causes the blood cells to clump. That’s why people at risk of heart attacks are encouraged to take aspirin — to block COX-1 and prevent the formation of blood clots. COX-2 produces a different kind, prostacyclin, which prevents clumping.
If the delicate balance between the two enzymes is disrupted, for example, by blocking COX-2 to treat arthritis, the tendency of COX-1 to cause platelet clumping and formation of blood clots will be unopposed — possibly increasing the risk of heart attack or stroke, Breyer said.
This could account for results observed in a large clinical trial of COX-2 inhibitors — where a four-fold increase in the number of heart attacks was seen among people who took the drugs, compared to those who took older arthritis medications.
Similarly, there is some evidence in animal studies that blocking both COX enzymes is necessary for gastrointestinal bleeding and ulcers to occur; blocking only COX-1 or COX-2 won’t cause the side effect, Breyer said. The theory is that COX-1 is important in maintaining normal stomach lining, while COX-2 helps heal microscopic damage when it occurs. “If you block both, then you cause injury and you block the healing, and that’s when you get the problem,” he said.
An imbalance between the COX enzymes also may play a role in salt and water retention, which can put pressure on the heart and cause congestive heart failure in some patients who take arthritis drugs, Breyer said.
In particular, COX-2 appears to be important in the kidney for proper elimination of salt and water. In mice given angiotensin II to raise their blood pressure, the Vanderbilt researchers found that infusion of a COX-2 inhibitor reduced blood flow in the kidney, urine volume and salt excretion. Infusion of a COX-1 inhibitor had no statistically significant effect, although Breyer said he suspects that the enzyme may play a role here as well.
People who regularly take aspirin and other non-steroidal, anti-inflammatory drugs have a reduced risk of colorectal cancer, and researchers at Vanderbilt and elsewhere are trying to determine the role of the COX enzymes play in this and other forms of cancer. The enzymes also may be involved in the development of Alzheimer’s disease.
As doctors learn more about the complicated interplay between COX-1 and COX-2, they may have to adjust their treatments accordingly. “We’re going to have to figure out who’s at risk (for various complications), and tailor our therapy,” Breyer said.
The research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases.