ACE inhibitors are a class of prescription drugs that lower blood pressure by blocking an enzyme called angiotensin-converting enzyme, which normally produces a powerful blood-vessel-constricting substance in your body. They are among the most widely prescribed cardiovascular medications in the world, used not just for high blood pressure but also for heart failure, kidney protection, and recovery after heart attacks. The way they work turns out to involve two complementary pathways rather than one, which explains both their broad benefits and their most recognizable side effect.
How the Enzyme Works in Your Body
To understand ACE inhibitors, you need a basic picture of the system they interrupt. Your body has a built-in mechanism for regulating blood pressure and fluid balance called the renin-angiotensin-aldosterone system, or RAAS. It is one of the most important systems governing blood pressure and the balance of water and electrolytes in the body.1PubMed Central. A New Perspective on the Renin-Angiotensin System When your blood pressure drops or your kidneys sense reduced blood flow, your kidneys release an enzyme called renin. Renin converts a protein circulating in your blood into angiotensin I, which is inactive on its own. Angiotensin-converting enzyme then steps in and converts that inactive angiotensin I into angiotensin II, a substance that constricts blood vessels and raises blood pressure.
But ACE does more than just create angiotensin II. It is also responsible for breaking down bradykinin, a substance that relaxes blood vessels and promotes fluid excretion.2PubMed Central. Inhibitor and substrate binding by angiotensin-converting enzyme: quantum mechanical/molecular mechanical molecular dynamics studies So ACE sits at a crossroads: it simultaneously builds up a constrictor and tears down a dilator. That dual role is the key to understanding why blocking it is so effective.
What Happens When You Block ACE
When you take an ACE inhibitor, the drug binds to the enzyme and prevents it from doing both of its jobs. Less angiotensin II gets produced, so your blood vessels relax and widen. At the same time, less bradykinin gets broken down, so more of this natural vasodilator stays active in your bloodstream. The combined effect is a drop in the resistance your heart has to pump against, without the increase in heart rate that some other blood pressure drugs cause.3PubMed. Angiotensin-converting enzyme inhibitors ACE inhibitors also promote the excretion of sodium and water, which reduces blood volume and further lowers pressure.
The bradykinin side of the equation turns out to be more than a bonus. Research has shown that the preserved bradykinin triggers a chain of events involving nitric oxide, a molecule that relaxes blood vessels and has protective effects on the heart. In studies of cardiac enlargement, an ACE inhibitor slowed the progression of heart thickening through this bradykinin-nitric oxide pathway, and the benefit disappeared when bradykinin receptors were blocked.4PubMed Central. Angiotensin converting enzyme inhibitor prevents left ventricular remodelling after myocardial infarction in angiotensin II type 1 receptor knockout mice This suggests ACE inhibitors protect the heart through routes that go beyond simply lowering angiotensin II.
What ACE Inhibitors Are Prescribed For
High blood pressure is the most common reason people end up on an ACE inhibitor, but the list of conditions these drugs treat is long. A 2024 expert consensus recommended ACE inhibitors as a first choice over the related drug class (ARBs) for reducing the risk of heart attack, for preventing heart failure in at-risk patients, and for secondary prevention of stroke.5PubMed Central. ACE Inhibitors and Angiotensin Receptor Blockers for the Primary and Secondary Prevention of Cardiovascular Outcomes: Recommendations from the 2024 Egyptian Cardiology Expert Consensus in Collaboration with the CVREP Foundation The same consensus favored ACE inhibitors for blood pressure control in people with type 2 diabetes and for preventing diabetic kidney disease.
After a heart attack, ACE inhibitors help prevent a process called ventricular remodeling, where the damaged heart gradually enlarges and weakens. Animal studies have shown that even when treatment is started late, after significant heart dysfunction has already developed, ACE inhibitors can still reverse some of the structural damage. In one experiment, survival at nine months went from about 28% with placebo to 90% with early treatment and 61% with delayed treatment.6PubMed. Early versus delayed angiotensin-converting enzyme inhibition in experimental chronic heart failure. Effects on survival, hemodynamics, and cardiovascular remodeling While these are animal data, the principle that it is rarely too late to start carries through to clinical practice.
For kidney protection, ACE inhibitors reduce the amount of protein leaking into the urine in people with diabetic kidney disease. A meta-analysis found that ACE inhibitors and ARBs significantly decreased albuminuria (a marker of kidney damage), and this effect was independent of any blood pressure change.7Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. Effects of ACE Inhibitors and Angiotensin Receptor Blockers in Normotensive Patients with Diabetic Kidney Disease In other words, the kidney benefit is not just a side effect of lowering blood pressure; there seems to be a direct protective effect on the kidney’s filtering units.
The Cough That Gives ACE Inhibitors Away
If you have ever been on an ACE inhibitor, you may know the cough. A persistent, dry, tickling cough is the most common reason people stop taking these drugs. The culprit is the same bradykinin buildup that provides cardiovascular benefits. Because ACE normally degrades bradykinin and a related molecule called substance P, blocking the enzyme lets both accumulate in the airways. Bradykinin sensitizes the nerve fibers in your throat and lungs, triggering a cough reflex that can persist for as long as you take the medication.8PubMed Central. ACEI-induced cough: A review of current evidence and its practical implications for optimal CV risk reduction
The good news is that the cough resolves after stopping the drug. In a study tracking patients who discontinued enalapril (a common ACE inhibitor), the skin response to bradykinin dropped significantly within just three days, and the cough itself faded over the first couple of weeks.9PubMed Central. Resolution of ACE inhibitor cough: changes in subjective cough and responses to inhaled capsaicin, intradermal bradykinin and substance-P If the cough is intolerable, switching to an ARB (which blocks angiotensin II through a different route and does not affect bradykinin) usually solves the problem.
Angioedema and Other Serious Side Effects
A rarer but more dangerous side effect is angioedema, a sudden swelling of the deeper layers of the skin that usually affects the face, lips, tongue, or throat. Like the cough, angioedema is driven by bradykinin buildup. The excess bradykinin increases blood vessel permeability and stimulates the release of substance P, causing fluid to leak into tissues.10PubMed Central. Angiotensin-converting enzyme inhibitor-induced angioedema: A review of the literature When swelling involves the airway, it can become a medical emergency. Risk factors that have been identified include Black race, female sex, being a smoker, age over 65, and a history of drug rashes or seasonal allergies. Anyone who experiences swelling of the face or throat while taking an ACE inhibitor should seek emergency care and typically should not be restarted on any drug in the class.
ACE inhibitors can also raise potassium levels. Because angiotensin II normally stimulates the release of aldosterone (a hormone that promotes potassium excretion), blocking that signal means your body retains more potassium. This is usually mild in people with healthy kidneys, but it becomes a real concern if your kidney function is reduced. In people with lower kidney filtration rates, the ACE inhibitor lisinopril raised potassium levels meaningfully, accompanied by a drop in aldosterone.11Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. ACE inhibition or angiotensin receptor blockade: Impact on potassium in renal failure Periodic blood tests to check potassium and kidney function are standard when you are on these medications.
Who Should Not Take ACE Inhibitors
Pregnancy is an absolute contraindication. ACE inhibitors can cause severe birth defects and kidney failure in a developing fetus, particularly in the second and third trimesters. Women who become pregnant while taking an ACE inhibitor should contact their prescriber immediately to switch to a safer alternative.
People with significant narrowing of the arteries supplying both kidneys (bilateral renal artery stenosis) are also at high risk. In this situation, the kidneys depend heavily on angiotensin II to maintain filtration pressure. Blocking angiotensin II with an ACE inhibitor can cause a sharp drop in kidney function.12PubMed. Safety of angiotensin-converting enzyme inhibitors in patients with bilateral renal artery stenosis following successful renal artery stent revascularization If someone has had stenting to open those arteries, ACE inhibitors may be reconsidered, but only with careful monitoring.
A history of angioedema from any ACE inhibitor is another hard stop. The reaction can recur with any drug in the class, and sometimes even with an ARB, though the risk is much lower with ARBs.
ACE Inhibitors Versus ARBs
Angiotensin receptor blockers (ARBs) are the closest relatives of ACE inhibitors. Instead of blocking the enzyme that produces angiotensin II, ARBs block the receptor that angiotensin II binds to. The endpoint is similar: less vasoconstriction, lower blood pressure. But the mechanisms diverge in a meaningful way. ARBs do not prevent bradykinin breakdown, which means they lack the bradykinin-related benefits and, importantly, they cause far less cough and angioedema.
Head-to-head comparisons in large reviews have found no significant difference between the two classes for overall mortality, cardiovascular events, or cardiovascular death.13PubMed Central. Angiotensin converting enzyme (ACE) inhibitors versus angiotensin receptor blockers for primary hypertension Where they do differ is tolerability: ARBs have a slightly lower rate of treatment discontinuation due to side effects, with an absolute difference of about two percentage points over four years, driven mostly by the cough issue. Some researchers believe that ACE inhibitors may offer modest extra cardiovascular protection in certain high-risk groups (like people recovering from a heart attack) because of the bradykinin pathway, but the evidence is not settled.14PubMed Central. Differences in the clinical effects of angiotensin-converting enzyme inhibitors and Angiotensin receptor blockers: a critical review of the evidence In practice, many prescribers start with an ACE inhibitor and switch to an ARB if side effects become a problem.
Not All ACE Inhibitors Are the Same
There are over a dozen ACE inhibitors on the market, and while they all block the same enzyme, they differ in how your body handles them. Captopril, the first one developed, is active as soon as you swallow it. Enalapril, on the other hand, is a prodrug: it has to be processed in the liver into its active form (enalaprilat) before it can do anything, which means it takes longer to kick in.15PubMed. Angiotensin-converting enzyme inhibitors: a comparative review Lisinopril is another one that does not need liver activation, making it a better choice for people with severe liver disease.16Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. Pharmacologic, Pharmacokinetic, and Therapeutic Differences among ACE Inhibitors Enalaprilat also happens to be the only ACE inhibitor available in an intravenous form, which matters in hospital settings when a patient cannot take pills.
How often you take the drug matters too. Captopril is typically dosed two or three times a day, while lisinopril and most newer ACE inhibitors are once-daily pills. A meta-regression of cardiovascular medication adherence found that people taking once-daily medications had adjusted adherence rates roughly 14% better than those on twice-daily regimens.17PubMed. Impact of once- or twice-daily dosing frequency on adherence to chronic cardiovascular disease medications: A meta-regression analysis That gap can be clinically meaningful over years of treatment. If you are struggling to remember multiple daily doses, it is worth asking your prescriber about once-daily options.
Watch Out for the NSAID Combination
One of the most underappreciated risks with ACE inhibitors involves a drug interaction that millions of people could stumble into. Over-the-counter anti-inflammatory painkillers like ibuprofen and naproxen (NSAIDs) affect the kidney through a pathway that overlaps with ACE inhibitors. ACE inhibitors dilate the outflow vessel of the kidney’s filtering unit, while NSAIDs constrict the inflow vessel. Used together, they squeeze kidney blood flow from both ends. Combining both with a diuretic creates what researchers have called a “triple whammy” that can trigger acute kidney injury.18PubMed Central. Drug Interactions Affecting Kidney Function: Beware of Health Threats from Triple Whammy
Clinical reports have documented reversible kidney failure in patients taking both an ACE inhibitor and an NSAID, even when neither drug alone caused any kidney trouble.19PubMed. Nephrotoxicity associated with concomitant ACE inhibitor and NSAID therapy The risk climbs in older adults and people who are already on a diuretic for fluid management. If you take an ACE inhibitor and need pain relief, acetaminophen (Tylenol) is generally safer for the kidneys. If you do need an NSAID, keeping the dose low and the duration short, with your prescriber’s knowledge, is the prudent approach.
Racial Differences in Response
ACE inhibitors do not work equally well in everyone, and race is one factor that has received significant clinical attention. Multiple monotherapy trials have found that Black patients tend to have a smaller blood pressure reduction from ACE inhibitors used alone compared with white patients.20PubMed. A Review of ACE Inhibitors and ARBs in Black Patients With Hypertension The reasons are not fully settled but likely involve differences in the activity of the renin-angiotensin system: Black patients as a group tend to have lower circulating renin levels, which means the system that ACE inhibitors target is less active to begin with.
A large observational study comparing cardiovascular outcomes in hypertensive patients found that ACE inhibitor use in Black patients was associated with higher rates of heart attack, stroke, and heart failure compared with Black patients not on ACE inhibitors, while no such pattern appeared in white patients.21PubMed Central. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitor-Based Treatment on Cardiovascular Outcomes in Hypertensive Blacks versus Whites This does not mean ACE inhibitors are harmful to Black patients in all contexts. When combined with a second drug, particularly a thiazide diuretic or a calcium channel blocker, the gap in blood pressure response largely disappears. Current guidelines generally recommend that if an ACE inhibitor is used in Black patients for hypertension, it should be part of a combination regimen rather than used alone.
The Snake Venom Connection
The origin story of ACE inhibitors is one of the stranger tales in pharmacology. In the 1960s, a Brazilian researcher studying the venom of a pit viper noticed that certain peptides in the venom caused a dramatic drop in blood pressure. These peptides, called bradykinin-potentiating peptides, turned out to work by inhibiting ACE. That discovery led to the development of captopril, the first oral ACE inhibitor, approved in 1981. Scientists continue to find new ACE-inhibiting peptides in snake venoms to this day, including peptides from rattlesnake and horned viper species that show strong inhibitory activity.22SpringerOpen. Rapid screening and identification of ACE inhibitors in snake venoms using at-line nanofractionation LC-MS These are not being developed as drugs themselves, but they remain useful tools for understanding how the enzyme works and for designing the next generation of inhibitors.
The fact that a lethal snake venom led to one of the most beneficial drug classes in cardiovascular medicine is a reminder that drug discovery often comes from unexpected places. It also illustrates a broader point about ACE inhibitors: they work because they mimic something nature already figured out. The peptides in snake venom that drop a prey animal’s blood pressure exploit the same enzymatic target that captopril and its descendants were designed to hit, just with far less precision and far more collateral damage.