Unexpected Side Effects of Common High Blood Pressure Medications

High blood pressure, known medically as hypertension, affects over a billion people worldwide, particularly in low- and middle-income nations. It is a leading factor in cardiovascular diseases, which are the primary cause of mortality globally. Conventional treatment typically involves medications such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), which target the renin-angiotensin system (RAS) to help manage blood pressure levels. However, many patients continue to experience uncontrolled hypertension, signaling a need for new and affordable treatment options.

A recent study published in Hypertension Research by researchers from the University of Pennsylvania explored the potential benefits of incorporating oral ACE2 alongside standard hypertension medications. Previous research has demonstrated that ACE2, particularly in injectable forms, can yield positive outcomes for metabolic diseases linked to the RAS.

ACE2 plays a crucial role in regulating blood pressure and heart health. Despite this, its relationship with commonly prescribed hypertension medications had not been previously examined. The RAS pathway is critical for maintaining blood pressure, triggering the release of renin when blood pressure decreases. Renin initiates a cascade that ultimately results in the production of angiotensin II, a potent vasoconstrictor. ACEIs and ARBs lower blood pressure via distinct mechanisms: ACEIs inhibit angiotensin II formation, while ARBs prevent it from binding to its receptors. Conversely, ACE2 decreases angiotensin II levels, promoting vasodilation and reducing blood pressure.

This research builds on earlier work where ACE2 was delivered orally to dogs suffering from myxomatous mitral valve disease, many of whom were also undergoing treatment with ACEIs and ARBs. The objective was to assess whether adding ACE2 would enhance treatment outcomes without altering existing medication regimens.

The researchers uncovered two unexpected findings during their investigation. Firstly, they observed that ACEIs inhibited the activity of ACE2, which was being administered to the dogs. Secondly, ARBs were found to increase levels of angiotensin II. According to the study, these outcomes are counterproductive to the goal of lowering blood pressure. However, not all ACEIs similarly affected ACE2; for instance, lisinopril, a commonly prescribed ACEI in the U.S., exhibited a lesser inhibitory effect on ACE2 than other ACEIs.

These findings bear significant clinical implications, especially considering the high prevalence of ACEI and ARB prescriptions among patients with hypertension. ACE2 has been associated with cardioprotective effects, indicating potential therapeutic applications. There is also a noted connection between ACE2 inhibition and the SARS-CoV-2 virus, which highlights the enzyme's importance in metabolic processes.

Future research will involve conducting similar studies using lisinopril to evaluate ACE2's benefits more accurately. The ultimate aim is to leverage a plant-based encapsulation system for ACE2 treatment in humans, following recent FDA approval for this delivery method. This represents a pioneering advancement as it marks the first engineered human blood protein produced in plant cells to receive FDA clearance for human clinical trials.

Developing biologic drugs typically incurs costs around $2.5 billion, underscoring the necessity for affordable treatments for prevalent conditions such as hypertension and diabetes. The research team is committed to making these therapies accessible.