Bradykinin and ACE Inhibitors: What the Research Reports

The short version, in plain language

Bradykinin is a small signalling peptide made of nine amino acids. It is produced in tissue and blood when enzymes called kallikreins cut larger precursor proteins called kininogens. Once released, bradykinin widens blood vessels, makes small vessels leakier, and sensitises certain nerve endings. It is cleared quickly because several enzymes chew it apart within seconds to minutes.

One of those clearing enzymes is angiotensin converting enzyme, usually shortened to ACE. ACE has two well described jobs: it converts angiotensin I into angiotensin II, and it degrades bradykinin, which is why older literature also calls it kininase II. A 2015 review of the chemistry and pharmacology of the ACE inhibitor class described both of those enzymatic roles and the pharmacological consequences of inhibiting the enzyme (PMID 25388457).

Because one enzyme does both jobs, a drug that blocks ACE does two things at once: it lowers angiotensin II production and it slows bradykinin breakdown. The second effect is the reason bradykinin appears in discussions of the dry cough and the angioedema described with this drug class. For deeper background on the peptide itself, see the bradykinin physiology page, and for the opposing hormonal system see the angiotensin overview.

This page is for educational purposes only and is not medical advice; consult a licensed physician about any symptom, any prescription medicine and any personal health question. Nothing here is guidance to start, stop, change or avoid any medicine, and decisions about prescription therapy belong with a prescribing clinician.

The biochemistry: one enzyme, two substrates

ACE is a zinc dependent dipeptidyl carboxypeptidase anchored mostly on the surface of endothelial cells, including the dense vascular bed of the lungs, and it also circulates in a soluble form. It removes two amino acid residues from the carboxyl end of its substrates. Applied to angiotensin I, that cleavage yields the eight residue pressor peptide angiotensin II. Applied to bradykinin, the same cleavage strips the terminal dipeptide and then cuts again, producing inactive fragments.

The sequence of bradykinin is Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg. Its proline rich backbone makes it resistant to many ordinary proteases but a good substrate for ACE, neprilysin and aminopeptidase P. Bradykinin signals mainly through the B2 receptor, which is expressed constitutively, while the B1 receptor is induced during inflammation and responds to the des-Arg metabolite of bradykinin rather than the parent peptide.

The 2015 pharmacology review set out how inhibitors of the enzyme interact with the active site and how the class differs in chemistry and tissue handling (PMID 25388457). The practical point for this page is structural rather than clinical: the binding site that the drug class occupies is the same site that would otherwise degrade bradykinin, so inhibition of angiotensin II formation and preservation of bradykinin are not separable effects.

Why the angiotensin receptor blocker class is discussed alongside it

Drugs that block the angiotensin II type 1 receptor act downstream of the enzyme rather than on it, so they do not occupy the catalytic site that degrades bradykinin. A 2003 review examined the role of AT1 receptor blockers in the treatment of arterial hypertension and discussed their pharmacological profile relative to enzyme inhibition (PMID 14624277). Mechanistic context on the hormone itself is collected on the angiotensin II page.

How the literature links bradykinin to a dry cough

The cough associated with the ACE inhibitor class is characteristically dry, persistent and tickling rather than productive. The mechanistic account that appears across reviews is that reduced degradation allows bradykinin, and related mediators such as substance P and prostaglandins, to accumulate in airway tissue, where they sensitise sensory C fibres and rapidly adapting receptors and lower the threshold for the cough reflex.

A 2023 paper in the European Journal of Internal Medicine examined the pathophysiology of cough with ACE inhibitors and asked specifically how within class differences might be explained, discussing differences in tissue binding and in the handling of kinins among members of the class (PMID 36628825). That framing matters because it treats the cough as a mechanism linked phenomenon rather than an idiosyncratic one.

A 2020 review in the Indian Heart Journal surveyed the current evidence on ACE inhibitor induced cough and discussed its practical implications for cardiovascular risk reduction, noting that the symptom is one of the more common reasons the class is discontinued (PMID 33189192). An earlier evidence based clinical practice guideline published in Chest in 2006 addressed ACE inhibitor induced cough within the broader diagnostic approach to chronic cough and treated it as a class effect that should be considered when a patient on these agents presents with an unexplained persistent cough (PMID 16428706).

Beyond cough: other upper airway symptoms

A 2014 BMJ Case Reports article described upper respiratory symptoms occurring in association with ACE inhibitor therapy, illustrating that the respiratory picture reported in the literature is not limited to cough alone (PMID 25035451). Case reports describe single situations and cannot establish how often something happens, but they are part of how the clinical pattern was first characterised.

A 2005 study in Physiological Research examined co-administration of an ACE inhibitor with a calcium channel blocker and the respiratory side effects attributed to the enzyme inhibitor, an experimental approach to the question of whether a second agent alters the respiratory response (PMID 15641937). Researchers in that work treated the airway response as the measured outcome rather than as an incidental observation.

Why some people cough and others do not

If bradykinin accumulation were the whole story, everyone taking an enzyme inhibitor would cough, and that is not what the literature describes. Genetic variation is one proposed explanation. A 2011 pharmacogenetics study evaluated predictors of ACE inhibitor induced cough and examined the role of the ACE, ABO and BDKRB2 genes, the last of which encodes the bradykinin B2 receptor (PMID 21832968). The study design places receptor level variation, not only peptide level accumulation, inside the proposed mechanism.

Cough and Angioedema with ACE Inhibitors: What Studies Report

Angioedema is swelling of the deeper layers of skin and mucosa, typically of the lips, tongue, face, floor of the mouth or larynx. It is the adverse event most often discussed alongside bradykinin because the swelling is attributed to increased vascular permeability driven by kinin signalling rather than to histamine release.

A 2015 review in The American Journal of Medicine addressed angiotensin converting enzyme inhibitor induced angioedema and set out its bradykinin mediated pathophysiology, its typical head and neck distribution, and the airway risk that gives it clinical weight (PMID 25058867). Researchers in that review described the condition as distinct from allergic, histamine driven swelling, which is why the two are discussed as different entities in the literature.

Timing is not always straightforward. A 2021 case report in Cureus described a first occurrence of angioedema arising after discontinuation of an ACE inhibitor, a presentation that complicates any simple assumption that symptoms track exposure minute by minute (PMID 34917435). As a single case, it describes what happened in one situation and does not establish frequency.

Angioedema has also been described with the angiotensin receptor blocker class. A 2015 case series in The Laryngoscope reported on the treatment of angiotensin receptor blocker induced angioedema, indicating that the event is not confined to enzyme inhibition alone (PMID 25646708).

On the cough side, the reviews cited above characterise it as persistent, non productive and capable of appearing at variable intervals after therapy begins (PMID 33189192, PMID 36628825). The Chest guideline positioned it as a diagnosis to consider in evaluating chronic cough in people taking the class (PMID 16428706). Any individual symptom, including swelling of the face, tongue or throat or a new persistent cough, is a matter for a licensed clinician and not for interpretation from a web page.

Targeting the bradykinin pathway directly

Because bradykinin acts through the B2 receptor, blocking that receptor is a separate pharmacological strategy from blocking the enzyme that degrades the peptide. A 2021 study protocol published in Trials described a three armed randomised controlled trial designed to evaluate the efficacy and safety of the B2 receptor antagonist icatibant and of a C1 esterase and kallikrein inhibitor in severe COVID-19 (PMID 33472675). A protocol describes an intended design rather than results, and it is cited here only to show that the kallikrein to kinin axis has been investigated as a pharmacological target in its own right.

Summary table of the cited literature

What this literature does and does not settle

The enzymatic overlap is not in dispute: the same catalytic machinery that generates angiotensin II also degrades bradykinin, as the pharmacology review described (PMID 25388457). What remains less settled is why only a minority of people develop cough or angioedema, why onset timing varies so widely, and why members of the same class may differ, which is precisely the question the 2023 pathophysiology paper framed (PMID 36628825). Genetic work has offered candidate explanations without closing the question (PMID 21832968).

Readers should also note the difference between evidence types used above. Reviews and guidelines synthesise many sources; case reports and small case series describe individual presentations and cannot be converted into rates or probabilities. Nothing on this page describes dosing, and no study dose is reproduced as guidance of any kind.

References

• Chemistry and pharmacology of Angiotensin-converting enzyme inhibitors (Current Pharmaceutical Design, 2015)
• Pathophysiology of cough with angiotensin-converting enzyme inhibitors: How to explain within-class differences? (European Journal of Internal Medicine, 2023)
• ACEI-induced cough: A review of current evidence and its practical implications for optimal CV risk reduction (Indian Heart Journal, 2020)
• Angiotensin-converting enzyme inhibitor-induced cough: ACCP evidence-based clinical practice guidelines (Chest, 2006)
• ACE inhibitors: upper respiratory symptoms (BMJ Case Reports, 2014)
• Enalapril and diltiazem co-administration and respiratory side effects of enalapril (Physiological Research, 2005)
• Pharmacogenetic predictors of angiotensin-converting enzyme inhibitor-induced cough: the role of ACE, ABO, and BDKRB2 genes (Pharmacogenetics and Genomics, 2011)
• Angiotensin-converting enzyme inhibitor-induced angioedema (The American Journal of Medicine, 2015)
• The First Occurrence of Angioedema After Discontinuation of Angiotensin-Converting Enzyme Inhibitor (Cureus, 2021)
• Treatment of angiotensin receptor blocker-induced angioedema: A case series (The Laryngoscope, 2015)
• Role of angiotensin II AT1 receptor blockers in the treatment of arterial hypertension (American Journal of Therapeutics, 2003)
• Evaluation of the efficacy and safety of icatibant and C1 esterase/kallikrein inhibitor in severe COVID-19: study protocol for a three-armed randomized controlled trial (Trials, 2021)