Angiotensin converting enzyme (ACE) inhibitors — drugs prescribed to millions of patients for high blood pressure and heart failure — can weaken the immune system's ability to fight off serious bacterial infections, according to a new study of mice and seven human volunteers. The results were published in the July 28 issue of Science Translational Medicine.
The findings need further validation in more trials, but they suggest that these common drugs might leave patients more vulnerable to problematic bacterial infections such as methicillin-resistant Staphylococcus aureus (MRSA), which are persistent threats in hospital settings.
The research team also studied angiotensin receptor blockers, a separate class of drug often used to treat similar conditions. These drugs didn't have the same immune-suppressing effects on white blood cells as ACE inhibitors, but the scientists caution more work in humans is also needed to confirm this.
"Our data suggest that treatment with ACE inhibitors may increase susceptibility to bacterial infections," said Zakir Khan, assistant professor at Cedars-Sinai Medical Center in Los Angeles and senior author of the new study.
"These findings have potential clinical implications as physicians decide whether to put patients on an ACE inhibitor or angiotensin receptor blocker to treat high blood pressure, especially immunocompromised patients who are more vulnerable to infections," he added.
However, patients usually take ACE inhibitors for prolonged periods of time to control their blood pressure. The team only studied the effects of ACE inhibitors on human cells after a week of treatment, so it's still unclear whether the drug's effects might change over extended periods.
How the Drug Mechanism May Have Unintended Effects
ACE inhibitors such as benazepril (Lotensin) and lisinopril (Qbrelis, Prinivil) can lower blood pressure by relaxing blood vessels. They work by suppressing an enzyme named ACE, which normally regulates blood pressure and is found in various types of tissues.
These properties make ACE inhibitors one of the most common treatments for high blood pressure, either alone or in combination with other drugs such as statins. There were 162.8 million prescriptions for ACE inhibitors in the U.S. in 2009, according to a report in the Journal of Managed Care and Specialty Pharmacy.
Clinicians also use ACE inhibitors to treat heart failure and diabetic kidney disease, as well as to manage patients undergoing invasive heart surgery, according to the new study.
However, some studies have suggested that the ACE enzyme also supports immune cells such as neutrophils, which defend the body against bacteria and other microbial invaders. Scientists are still unsure whether ACE inhibitors might therefore have unintended effects on the immune system.
"While these drugs have been largely thought to be safe, published studies have noted an association between the use of ACE inhibitors and some forms of infection," said Khan. "We wanted to further explore this association."
Khan, study lead author Duo-Yao Cao, and colleagues treated mice with the approved ACE inhibitors ramipril (Altace) and lisinopril. They then tested whether neutrophils in the animals' blood could kill MRSA, Klebsiella pneumoniae, and Pseudomonas aeruginosa, bacteria that frequently cause pneumonia and other infections in hospital patients.
Cao, a researcher at Cedars-Sinai Medical Center, and his team found that the neutrophils killed fewer bacteria compared to neutrophils from untreated mice. Treating mice with ramipril also left them more susceptible to severe MRSA infections.
ACE inhibitors are also used in patients who might be vulnerable to heart infections, so the research team tested the effects of ACE inhibitors in mice with damaged heart valves. Like the first experiments, the scientists observed that the animals were more vulnerable to MRSA infections in the heart after they received ramipril.
The team repeated the experiments with the angiotensin receptor blocker losartan (Cozaar), one of the most common blood pressure medications. Unlike the ACE inhibitor ramipril, losartan didn't weaken neutrophil's bacteria-fighting capabilities or leave mice more susceptible to MRSA infections.
Early Implications for Use in the Clinic
In a small pilot clinical study, Cao's team gave ramipril to seven human volunteers every day for one week. The study subjects provided blood samples before, during, and after treatment, which the researchers analyzed to assess the antibacterial functions of the neutrophils in the people.
The team found that neutrophils isolated from the volunteers couldn't properly produce superoxides and reactive oxygen species, which are molecules involved in antibacterial immune responses. The neutrophils' ability to kill MRSA, K. pneumoniae, and P. aeruginosa bacteria also declined as the patients began taking ramipril.
Khan made sure to note that his team's study has several limitations. For example, the researchers didn't treat the volunteers with angiotensin receptor blockers, so they can't yet conclude whether these drugs might have similar suppressing effects on neutrophils in humans.
For future work, Khan stressed the importance of understanding the exact mechanism by which the ACE enzyme supports antibacterial immunity from neutrophils. He added that his team is planning to compare in more detail the effects of ACE inhibitors and angiotensin receptor blockers on neutrophils in a large group of patients who received treatment at their hospital.