Navigation Links
UF scientists discover compound that could lead to new blood pressure drugs

GAINESVILLE, Fla. 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 todays (May 1) edition of 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 Medicines 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. Thats 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 enzymes activity.

Researchers used one of the worlds 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 enzymes surface.

This project had a very small likelihood of succeeding because its much easier to inhibit activity rather than to enhance it. By analogy, its easier to break something than to build it, Ostrov said. If you consider the structure of an enzymes active site its easy to see that if you plug up the active site its 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.

That in itself is a significant accomplishment because no one has ever specifically identified a compound that enhances the activity of an enzyme using a rational structure-based approach, he said. In other words, no one has ever done this before on purpose. People have discovered molecules that enhance the activity of enzymes by trial and error, but no group has ever done it in a specifically pointed way like this.

Ostrov said the enzyme exists in two forms: like a Pac-Man with a mouth that has chomped closed, and like a Pac-Man with a mouth that remains wide open. The molecule that worked best fit in a structural pocket in the enzymes open conformation.

So in other words, stabilizing the open conformation may be the reason why we enhance the activity of the enzyme, he said.

After hitting on the lead compound, UF researchers then tested it in hypertensive rats that had developed fibrosis of the heart and kidney. The animals received the drug for two weeks. Tissue samples from treated animals revealed a significant decrease in fibrosis of the heart, kidney and blood vessels, said Ostrov, who described the findings as striking and reproducible.

The study was funded by grants from the National Institutes of Health and the American Heart Association and was a collaborative effort of the UF colleges of Medicine, Pharmacy and Liberal Arts and Sciences. Researchers also included Mohan Raizada, Ph.D., distinguished professor of physiology and functional genomics, Michael J. Katovich, Ph.D., a professor of pharmacodynamics, and Ronald K. Castellano, an assistant professor of chemistry, among others.

Early results also show the compound inhibits inflammation, which has significant implications for a number of human diseases, including autoimmune diseases such as type 1 diabetes and rheumatoid arthritis as well as other diseases involving fibrosis, such as Alzheimers, Ostrov said.

Additional research will continue to explore the compounds effectiveness in animals and humans.


Contact: Melanie Fridl Ross
University of Florida

Related biology news :

1. UIC scientists discover how some bacteria survive antibiotics
2. Scientists aim to boost world energy supplies -- with microbes!
3. Scientists determine drug target for the most potent botulinum neurotoxin
4. Scientists make chemical cousin of DNA for use as new nanotechnology building block
5. Scientists find stem cells for the first time in the pituitary
6. Brown scientists say biodiversity is crucial to ecosystem productivity
7. Scientists urged to make a stand on climate change
8. Scientists clarify a mechanism of epigenetic inheritance
9. Scientists to explore global change-public health connection
10. Scientists test device to track medication adherence in patients with HIV/AIDS
11. Scientists discover how nanocluster contaminants increase risk of spreading
Post Your Comments:
(Date:4/15/2016)... , April 15, 2016  A new ... make more accurate underwriting decisions in a fraction ... timely, competitively priced and high-value life insurance policies ... screenings. With Force Diagnostics, rapid testing ... lifestyle data readings (blood pressure, weight, pulse, BMI, ...
(Date:4/13/2016)... physicians supporting Medicaid patients in Central Florida ... telehealth thanks to a new partnership with higi.   ... can routinely track key health measurements, such as blood ... they opt in, share them with IMPOWER clinicians through ... location at no cost. By leveraging this data, IMPOWER ...
(Date:3/29/2016)... Florida , March 29, 2016 ... the "Company") LegacyXChange "LEGX" and SelectaDNA/CSI Protect are pleased ... in ink used in a variety of writing instruments, ... Buyers of originally created collectibles from athletes on LegacyXChange ... forensic analysis of the DNA. Bill ...
Breaking Biology News(10 mins):
(Date:6/23/2016)... ... June 23, 2016 , ... ... of its second eBook, “Clinical Trials Patient Recruitment and Retention Tips.” Partnering with ... in this eBook by providing practical tips, tools, and strategies for clinical researchers. ...
(Date:6/23/2016)... HOUSTON , June 23, 2016 ... agreement with the Cy-Fair Sports Association to serve ... of the agreement, Houston Methodist Willowbrook will provide ... education and connectivity with association coaches, volunteers, athletes ... partner with the Cy-Fair Sports Association and to ...
(Date:6/23/2016)... ... 2016 , ... Supplyframe, the Industry Network for electronics hardware ... . Located in Pasadena, Calif., the Design Lab’s mission is to bring together ... built and brought to market. , The Design Lab is Supplyframe’s physical representation ...
(Date:6/23/2016)... 23, 2016 Andrew ... Published recently in ... journal from touchONCOLOGY, Andrew D Zelenetz , ... cancer care is placing an increasing burden on ... biologic therapies. With the patents on many biologics ...
Breaking Biology Technology: