University of Florida researchers have identified a drug compound that dramatically lowers blood pressure, improves heart function and - in a remarkable finding - prevents damage to the heart and kidneys in rats with persistent hypertension.
The findings, which appear in the American Heart Association journal Hypertension, could lead to a new class of antihypertensive drugs designed to address two major problems associated with cardiovascular disease: high blood pressure and the tissue damage associated with it, known as fibrosis.
"When people have heart attacks (or suffer from hypertension) the blood vessels get more rigid," said study author David Ostrov, Ph.D., an assistant professor in the UF College of Medicine's department of pathology, immunology and laboratory medicine. "We discovered a compound that reverses the fibrosis that makes the blood vessels more rigid."
The American Heart Association estimates that 72 million people in the United States have high blood pressure, a major risk factor for stroke, heart attack and death.
Angiotensin-converting enzyme plays a key role in the development of high blood pressure. It produces angiotensin II, a potent hormone that triggers the condition and contributes to the development of cardiovascular disease by constricting blood vessels, causing blood pressure to rise. That's why millions of Americans with hypertension and cardiovascular disease take ACE inhibitors. But these drugs have limited capacity to repair heart function and to reverse tissue damage.
In contrast, the enzyme ACE2 not only lowers levels of angiotensin II but also converts it to a hormone that helps protect the cardiovascular system.
"Only recently has it come to be appreciated that ACE and ACE2 play a very important role in balancing the activity of the other one to maintain normal blood pressure," Ostrov said. "They work in harmony."
Hypothesizing that activating ACE2 could be beneficial, UF scientists set out to discover a compound that enhances the enzyme's activity.
Researchers used one of the world's most powerful supercomputers to process 140,000 prospective drug compounds in a matter of weeks. The computer predicted which molecules would be most likely to enhance the activity of ACE2, rotating them in thousands of different orientations to see how they would bind to certain pockets on the enzyme's surface.
"This project had a very small likelihood of succeeding because it's much easier to inhibit activity rather than to enhance it. By analogy, it's easier to break something than to build it," Ostrov said. "If you consider the structure of an enzyme's active site it's easy to see that if you plug up the active site it's not going to work. But how can one make the enzyme actually work better" This seemed to be a very significant challenge we were probably not likely to overcome. We tried anyway."
And it worked.