Unexpected Side Effects of Common Blood Pressure Medications and New Insights into ACE2

High blood pressure, or hypertension, remains a leading global health concern, affecting over a billion people worldwide, especially in low- and middle-income regions. While medications like ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly prescribed to manage hypertension by targeting the renin-angiotensin system (RAS), recent research suggests these treatments may have unintended side effects.

Researchers from the University of Pennsylvania have investigated how these medications interact with ACE2, an enzyme that plays a crucial role in regulating blood pressure and heart health. ACE2 helps reduce angiotensin II levels, promoting vasodilation and lowering blood pressure, thus exerting cardioprotective effects. Despite its importance, the impact of ACEIs and ARBs on ACE2 activity had not been thoroughly explored.

In their study, published in Hypertension Research, scientists examined how these drugs influence ACE2 activity using a novel lettuce-based plant-encapsulated system to deliver oral ACE2 in pet dogs with elevated systolic blood pressure on ACEIs and/or ARBs. The findings revealed surprising interactions: ACE inhibitors, particularly lisinopril, inhibited ACE2 activity, potentially undermining its beneficial effects. Conversely, ARBs were found to increase the angiotensin II pool, which could counteract blood pressure reduction.

These observations are critical because inhibiting ACE2 or increasing angiotensin II levels could potentially worsen cardiovascular conditions. Notably, the study highlighted that not all ACE inhibitors affect ACE2 equally; for example, lisinopril exhibited minimal inhibition, suggesting it might be a safer option regarding ACE2 activity.

Furthermore, the research uncovered links between ACE2 inhibition and increased susceptibility to SARS-CoV-2, the virus responsible for COVID-19, which also uses ACE2 as an entry point into cells. Given this connection, exploring ways to modulate ACE2 activity remains an essential area of ongoing research.

The team aims to extend this work by testing other ACE inhibitors like lisinopril in animal models. Additionally, they are developing plant-based delivery systems for ACE2 as a biologic drug for humans. The FDA has recently approved an investigational new drug (IND) application for this technology, marking a significant step toward affordable and effective treatments for cardiovascular diseases. The ultimate goal is to use these innovative approaches to improve management strategies for hypertension and related conditions while reducing treatment costs.

This research underscores the importance of understanding the complex interactions between hypertension medications and enzymes like ACE2. As new therapies evolve, personalized treatment plans considering these dynamics could enhance patient outcomes and minimize adverse effects.