UC Davis researchers have discovered that a new class of drugs that lowers blood pressure in experimental animal models also reduces heart enlargement, a leading cause of heart failure. Similar drugs developed at UC Davis are now being tested in humans to treat high blood pressure.
Nearly one in three U.S. adults have uncontrolled high blood pressure, according to the American Heart Association. The heart swells in response to chronic high blood pressure, which weakens its ability to pump blood throughout the body. The resulting condition, called heart failure, affects 5 million people and contributes to 300,000 deaths in the U.S. each year.
Initial research from the lab of study author Bruce Hammock, an entomology professor at UC Davis, revealed that a key enzyme that controls insect development is involved in the hormone system that regulates blood pressure in mammals. The enzyme, called soluble epoxide hydrolase (sEH), contributes to high blood pressure caused by the hormone angiotensin.
“The angiotensin pathway represents one of the most common targets [for drug development] for the treatment of cardiac failure,” said study co-author Nipavan Chiamvimonvat, an associate professor and cardiologist at the UC Davis Medical Center.
Earlier studies with rodents showed that angiotensin causes sEH levels to increase. If left unchecked, sEH breaks down biological mediators that help relax blood vessels, lower blood pressure and prevent heart failure.
The researchers found that blocking sEH activity with a specific drug made in Hammock’s lab reverses angiotensin’s effects by leaving the beneficial mediators intact and able to do their work to lower blood pressure.
“This is a completely new concept as a drug target,” Hammock said.
The new study further revealed that the drug prevents heart enlargement caused by angiotensin in a rat model that mimics heart failure seen in patients who are pre-diabetic and obese, two medical conditions that are associated with high blood pressure in humans.
“If you are obese, you not only increase the peripheral resistance of your blood vessels, you increase the enzyme [sEH], and so your blood pressure goes up,” Hammock said.
The study also showed that sEH levels are not elevated by exercise or the stress hormone norepinephrine, and the drug does not reduce heart enlargement caused by these other factors.
The walls of an enlarged heart are very thick and strong in a trained athlete but are very thin and weak in obese diabetics, Hammock explained. The latter condition is associated with heart failure and leads to potentially fatal arrhythmia, abnormal heartbeat, if left untreated.
A compound similar to the prototype drug used in the study has passed initial safety tests and is in the next phase of human testing to determine if it will lower blood pressure. The short-term nationwide trial begins this month and involves 150 obese pre-diabetic patients.
“Diabetes and high blood pressure commonly occur together, and a new class of drugs that addresses both is very attractive,” said Bruce German, a UC Davis professor of food science, in a statement from Arete Therapeutics, a drug company that Hammock founded and enlisted to move the drug into human trials.
The data from the study indicates that the drug, in theory, should work in humans along with common drugs that target other players in the angiotensin pathway to treat high blood pressure, Hammock said.
The hope is that success in the current trial will eventually put the drug on the market and lead to interest from big pharmaceutical companies that can test its potential for treating heart failure in patients, he said.
The study was published in January in the journal Procedures of the National Academy of Sciences and was done in collaboration with researchers from UC Riverside and Peking University in China.
ELAINE HSIA can be reached at firstname.lastname@example.org.