A New Way to Control High Blood Pressure

Fruit flies are annoying and I hate them. It’s frustrating because I love fruit, want to have fresh fruit out all the time, and love having the windows and doors open in nice weather. In the past, however, the combination has made the occasional fruit fly outbreak seemingly inevitable. I’ve tried every solution imaginable: fly paper, traps filled with wine, juice, or vinegar, boiling water in the drains, washing all the fruits and veggies, and so on. To deal with this, I built a fruit box, a small, wooden, screened-in box where we store fruit and root vegetables. This interferes with the ability of fruit flies to get into the box, or for flies that were inadvertently on the fruit to get out. It’s not foolproof and needs to be emptied and cleaned regularly, but the difference has been overwhelming. This paradigm shift, from treating established flies to interfering with their ability to become established, is oddly similar to a paradigm shift happening now in blood pressure medications.

High blood pressure is as ubiquitous as fruit flies. Around ½ of American adults have high blood pressure and it is the leading preventable risk factor for death from heart disease and stroke.^[1.2] High blood pressure is implicated in over 660,000 deaths per year - about the same number of people who live in Boston.Nearly three-quarters of people with a diagnosis of high blood pressure do not have it under control, despite myriad medications available to treat the condition.^[2,3] Unfortunately, for many people the current medications are little more effective than a vinegar fly trap. Many of these medications target the renin-angiotensin-aldosterone system, abbreviated RAAS.

RAAS is a system of hormones in the body that helps regulate blood pressure, fluid balance, and electrolyte levels in the blood. The pathway has a few key molecules and steps, but there are many more pieces doing minor tasks:^[3,4]

• Angiotensinogen is the precursor molecule that is ultimately converted into the active hormone below
• Renin is the rate-limiting enzyme that determines how quickly angiotensinogen is converted to angiotensin I.
  • When the body detects low blood pressure, more renin is made; this system can also be corrupted by conditions like type II diabetes, which may increase blood pressure.
• Angiotensin converting enzyme (ACE) converts angiotensin I into angiotensin II, which is biochemically active and raises blood pressure.

High levels of angiotensin II constrict blood vessels, cause the kidneys to reabsorb more salt and water, and increase levels of other blood-pressure-increasing hormones.^[3,4]

• Renin inhibitors like Aliskiren target the enzyme renin to slow the conversion of angiotensinogen into angiotensin I
• Angiotensin receptor blockers (ARBs) like losartan block the receptors that angiotensin II would normally use to raise blood pressure
• Angiotensin converting enzyme inhibitors (ACE inhibitors) block the conversion from angiotensin I to angiotensin II and include lisinopril and other medications ending -pril

These medications have been effective in clinical trials, but in real-world use they face challenges as daily oral medications; doses can be missed, forgotten, burdensome, or come with side effects that may impact consistency. At a more fundamental level, however, these solutions are like trying to hunt down each fruit fly individually.

Most medications target a protein.^[5] This is great, because proteins do things in the body. Proteins include signaling hormones, receptors, structural elements, defense and inflammatory tools, and much more, so targeting them is the most common way to fight a disease. Unfortunately, proteins are relatively large, three-dimensional objects that can be hard for medicine to target.^[5] This can lead to medicines that do not “find” the protein if it’s rotated the wrong way, and medicines that accidentally bind to accidental proteins that happen to have the “correct” shape.^[5] It’s like fly paper; you have to just kinda hope the flies happen to run into the paper for it to work, and if you accidentally get your hair in the sticky part, you suffer a pretty aggravating “side effect.”

RNA interference changes the game. While most medications hunt individual proteins like they are fruit flies, RNA interference is like building a fruit box. For those of us who haven’t reviewed genetics in the last decade or so, RNA is the intermediary step between DNA and proteins. DNA gets transcribed into messenger RNA, which travels to ribosomes to be translated into a protein. This is a necessary step because DNA is “long-term storage” while a protein is functional, and the two are made of different molecules (nucleic acids for DNA and RNA and amino acids for proteins). Interfering with messenger RNA means the intended protein does not get created, stopping the problem earlier in the “life cycle.”

New medications being developed in clinical trials target this messenger RNA. RNA interference offers real potential benefits over traditional medicines: problem proteins can be stopped more effectively at earlier stages, and specific pieces of messenger RNA code can be targeted, avoiding off-target effects.^[5] Another big benefit is that RNA-interfering medications may last much longer than traditional ones, meaning that a daily pill can be replaced with a few injections per year. For a condition like high blood pressure, this would mean much easier adherence and may lead to fewer side effects. With the help of clinical trial specialists and volunteers, we may be able to bring blood pressure under control for hundreds of millions of people, and that doesn’t bug me one bit!

Creative Director Benton Lowey-Ball, MWC, BS, BFA

References

[1] Desai AS, Webb DJ, Taubel J, Casey S, Cheng Y, Robbie GJ, Foster D, Huang SA, Rhyee S, Sweetser MT, Bakris GL. Zilebesiran, an RNA interference therapeutic agent for hypertension. New England Journal of Medicine. 2023 Jul 20;389(3):228-38. https://doi.org/10.1056/NEJMoa2208391

[2] Centers for Disease Control and Prevention (CDC).Hypertension Cascade: Hypertension Prevalence, Treatment and Control Estimates Among US Adults Aged 18 Years and Older Applying the Criteria From the American College of Cardiology and American Heart Association’s 2017 Hypertension Guideline—NHANES 2017–2020. 2021 Mar 22. Updated 2023 May 12. Accessed 2026 Mar 19. https://millionhearts.hhs.gov/data-reports/hypertension-prevalence.html

[5] Hu B, Zhong L, Weng Y, Peng L, Huang Y, Zhao Y, Liang XJ. Therapeutic siRNA: state of the art. Signal transduction and targeted therapy. 2020 Jun 19;5(1):101. https://www.nature.com/articles/s41392-020-0207-x

[4] Betts JG, Young KA, Wise JA, Johnson E, Poe B, Kruse DH, et al. The adrenal glands. In: Anatomy and Physiology. OpenStax; 2013. Available from: https://openstax.org/books/anatomy-and-physiology/pages/17-6-the-adrenal-glands

[3] Romero CA, Orias M, Weir MR. Novel RAAS agonists and antagonists: clinical applications and controversies. Nature Reviews Endocrinology. 2015 Apr;11(4):242-52. http://www.nature.com/doifinder/10.1038/nrendo.2015.6