Groundbreaking research by a Mercer University College of Pharmacy professor could unlock new treatment options for people with drug-resistant high blood pressure. This condition disproportionately affects African Americans and a portion of the general population, leading to increased risks of heart attack and stroke.
Dr. Raquibul Hasan, assistant professor of pharmaceutical sciences, was awarded a two-year $154,000 grant from the American Heart Association this spring to further his work in this area. He also is in the process of applying for additional research funding, including a $3 million grant from the National Institutes of Health.
More than 50 percent of adults in the United States have high blood pressure — also known as hypertension. This condition develops over time and is a “silent killer” that, without proper treatment, damages the blood vessels. This can cause harm to the heart, kidneys, eyes and other parts of the body, increasing the risk for medical conditions like heart attack and stroke, Dr. Hasan said.
People with hypertension are generally treated by taking one of several medications on the market. However, about half of these patients still aren’t able to adequately control their blood pressure, despite the use of prescriptions, because of other factors at play in their bodies — one of the most potent and common being a chemical known as endothelin-1 or ET-1.
The production of ET-1 can be triggered by a variety of cardiovascular risk-factors or behaviors that cause inflammation. In addition to drug-resistant high blood pressure, high levels of ET-1 can contribute to pulmonary hypertension, obesity, kidney disease and other conditions.
“ET-1 is considered the body’s most potent vessel constrictor,” Dr. Hasan said. “When you make more of this chemical, it not only immediately constricts your blood vessels but also causes severe long-term damage to the blood vessels, heart and kidneys. Moreover, ET-1 happens to be a common mediator chemical for a number of different diseases. Unfortunately, efforts to reduce the formation of this chemical in the body were not really successful in the past. However, we think we have a compound that can potentially accomplish that.”
Currently available drugs only block the receptors of ET-1, but an ideal drug needs to block both ET-1 production and the receptors, he said. Dr. Hasan and his research team have identified a compound that appears to be able to do both, which would be the first in-class drug to achieve this. In essence, the compound blocks the ET-1-producing enzyme, reducing ET-1 production, and also inhibits the receptors, so it cannot work anywhere in the body. This two-step action is expected to be very effective in minimizing the damage.
“Although the detrimental role of the endothelin system in cardiovascular diseases has been known for about three decades, currently available drugs can only block the ET-1 receptors and are less effective in preventing endothelin-related cardiovascular diseases,” Dr. Hasan explained. “Our test drug can simultaneously inhibit both ET-1 receptors and the ET-1-synthesizing enzyme ECE-1, and therefore possesses huge potential. The project is a significant step forward in the fight against drug-resistant high blood pressure, a condition that affects millions of people worldwide.”
The compound identified by Dr. Hasan for this new drug is naturally produced by the body’s gut bacteria. In normal circumstances, these bacteria serve as the body’s natural defense against disease. However, certain factors like high salt intake can kill these beneficial bacteria, reducing the body’s defense against conditions like high blood pressure. Additionally, some people may be compromised because they naturally have lower counts of this bacteria.
Over the last decade or so, more understanding has emerged of gut bacteria and its role in shaping people’s health, Dr. Hasan said.
“We are only recently realizing the importance of the gut bacterial flora in regulating the function of other organs and in various diseases, and this project shows that biochemicals made by gut bacteria can impact the blood vessels, and hypertension, in a meaningful way,” said Dr. Nader Moniri, associate dean for research and professor of pharmaceutical sciences. He and Dr. Mahavir Chougule, associate professor of pharmaceutical sciences, are co-investigators on the American Heart Association grant project.
With the funding from the American Heart Association and any additional funding received, Dr. Hasan’s research team will conduct a series of studies to determine if the drug can slow the development of high blood pressure and prevent cardiovascular diseases like heart attack and stroke, he said. He will modify different chemical groups within the compound to see how to make it most effective.
Dr. Hasan’s research team is also involved in a few other projects related to ET-1, including its role in obesity, diabetes and insulin resistance.
