Bradykinin: The Peptide Behind ACE Inhibitor Cough

Cardiovascular Peptides

5-35% of ACE inhibitor patients develop cough

Bradykinin, a 9-amino-acid peptide normally degraded by ACE, accumulates when ACE inhibitors block its breakdown. The result: sensitized airway nerves and the persistent dry cough that leads millions of patients to switch medications.

Fox et al., Chest, 1996

Fox et al., Chest, 1996

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If you have ever taken lisinopril, enalapril, ramipril, or any other ACE inhibitor for blood pressure and developed an annoying dry cough that would not go away, you have experienced bradykinin in action. The cough affects 5-35% of patients on ACE inhibitors (with higher rates in certain populations, particularly East Asian patients), and it is the most common reason people discontinue these otherwise effective blood pressure medications. The cause is a nine-amino-acid peptide called bradykinin that accumulates when ACE, the enzyme that normally degrades it, is pharmacologically blocked. Among the cardiovascular peptides that regulate blood vessel function, bradykinin occupies a unique position: it is simultaneously a beneficial vasodilator and a problematic inflammatory mediator.

But the ACE inhibitor cough is only one chapter of bradykinin's story. This peptide also drives hereditary angioedema, contributes to inflammatory pain, played a role in COVID-19 lung injury, and has spawned an FDA-approved drug (icatibant) designed specifically to block its receptor.

What Bradykinin Is

Bradykinin is a nonapeptide (nine amino acids: Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) produced by the kallikrein-kinin system. It is generated when the enzyme kallikrein cleaves high-molecular-weight kininogen (HMWK) in the blood, or when tissue kallikrein cleaves low-molecular-weight kininogen to produce kallidin (Lys-bradykinin), which is then converted to bradykinin by aminopeptidases.

Once released, bradykinin has a half-life of approximately 15-30 seconds in the bloodstream. It is rapidly degraded by two main enzymes: angiotensin-converting enzyme (ACE, also called kininase II), which cleaves bradykinin at the Pro7-Phe8 bond, and carboxypeptidase N (kininase I), which removes the C-terminal arginine to produce des-Arg9-bradykinin. ACE2, the enzyme that gained fame during the COVID-19 pandemic, also degrades bradykinin's active metabolite des-Arg9-bradykinin.^[1]

The extremely short half-life means bradykinin acts as a local hormone (autacoid) rather than a circulating hormone. Its effects are concentrated at the site of production, where it activates two receptors: B1 and B2.

The Two Bradykinin Receptors

B2 receptor: the constitutive mediator

The B2 receptor is expressed on most cell types under normal conditions. It is a G-protein coupled receptor that responds to intact bradykinin and kallidin. When activated, it triggers vasodilation (through endothelial nitric oxide and prostacyclin release), increased vascular permeability, smooth muscle contraction (in the gut and airways), and pain signaling through sensory nerve activation.

The B2 receptor mediates most of bradykinin's acute physiological effects, including the cardiovascular benefits that make ACE inhibitors effective: vasodilation and reduced blood pressure. It also mediates the unwanted cough and the acute attacks of hereditary angioedema. Understanding how peptides activate G-protein coupled receptors is central to understanding bradykinin's signaling.

B1 receptor: the inducible inflammatory receptor

The B1 receptor is normally expressed at low levels but is dramatically upregulated by tissue injury, infection, and inflammatory cytokines (IL-1beta, TNF-alpha). Its primary ligand is des-Arg9-bradykinin, the metabolite produced when carboxypeptidase N removes bradykinin's C-terminal arginine.

The B1 receptor drives chronic inflammatory pain, neutrophil recruitment, and sustained vascular permeability in damaged tissue. Because it is induced only under pathological conditions, it has attracted interest as a drug target that could be blocked without disrupting bradykinin's normal physiological functions.

How Bradykinin Causes ACE Inhibitor Cough

The mechanism connecting ACE inhibitors to cough involves a cascade of peptide signaling in the airways.

Step 1: ACE inhibition blocks bradykinin degradation. ACE (kininase II) is the primary enzyme that breaks down bradykinin in the lungs. When patients take ACE inhibitors (enalapril, lisinopril, ramipril, etc.), bradykinin accumulates in the airway tissue because its primary degradation pathway is blocked.

Step 2: Bradykinin sensitizes airway sensory nerves. Accumulated bradykinin activates B2 receptors on vagal C-fiber afferents and rapidly adapting stretch receptors in the airway epithelium. Fox et al. (1996) demonstrated in electrophysiology studies that responses of single vagal C fibers to capsaicin were markedly increased after perfusion with bradykinin. The nerve fibers become hypersensitive to stimuli that would not normally trigger coughing.

Step 3: Neuropeptide release amplifies the response. Sensitized C-fibers release substance P and neurokinin A, which cause airway smooth muscle contraction, mucus secretion, and further sensitization of the cough reflex.^[2] Bradykinin also induces cyclooxygenase-2 (COX-2) in airway cells, increasing prostaglandin and thromboxane production, which further sensitizes cough receptors.

Step 4: The cough reflex threshold drops. The combined effect of direct nerve sensitization, neuropeptide release, and prostaglandin production lowers the cough reflex threshold. Stimuli that a patient would normally not notice, minor airway irritation, temperature changes, talking, become sufficient to trigger coughing.

This is why the ACE inhibitor cough is characteristically dry, persistent, and worse at night or when lying down. It is also why the cough resolves within 1-4 weeks of stopping the ACE inhibitor: bradykinin levels return to normal once ACE activity is restored.

Why ARBs don't cause cough

Angiotensin II receptor blockers (ARBs) like losartan and valsartan lower blood pressure by blocking the angiotensin II receptor instead of inhibiting ACE. Because ACE remains active, bradykinin degradation continues normally, and bradykinin does not accumulate. This is the primary reason ARBs are prescribed as alternatives for patients who develop ACE inhibitor cough.

Bradykinin and Pain

Beyond the cough, bradykinin is one of the most potent endogenous pain-producing substances. It directly activates sensory neurons and amplifies pain signaling through multiple mechanisms.

Mathivanan et al. (2016) demonstrated that bradykinin induces rapid exocytotic recruitment of TRPV1 (transient receptor potential vanilloid 1) receptors to the surface of peptidergic nociceptors.^[3] TRPV1 is the receptor that detects capsaicin (the active component of chili peppers) and heat. By increasing the number of TRPV1 receptors on the cell surface, bradykinin makes neurons more sensitive to thermal and chemical stimuli, a process called peripheral sensitization.

This mechanism explains why inflamed tissue is hypersensitive to touch and temperature: bradykinin released at the site of injury literally installs more pain receptors on nearby nerve cells. It also connects bradykinin to the broader neuropeptide pain system, where substance P and CGRP (calcitonin gene-related peptide) work alongside kinins to drive inflammatory pain.

Manivong et al. (2025) developed peptide-grafted nanogels designed to deliver sustained endothelin and bradykinin blockade directly to osteoarthritic joints, targeting both the vascular and pain components of joint inflammation with a single peptide-based delivery system.^[4]

Hereditary Angioedema: When Bradykinin Goes Unchecked

Hereditary angioedema (HAE) is a rare genetic condition (affecting approximately 1 in 50,000 people) that demonstrates what happens when bradykinin signaling is chronically dysregulated. Most HAE cases result from mutations in the C1-inhibitor gene, which produces a protein that normally restrains kallikrein activity. Without functional C1-inhibitor, kallikrein is overactive, producing excessive bradykinin, which causes episodic swelling of the face, extremities, airways, and gastrointestinal tract.

Icatibant (Firazyr) is a synthetic 10-amino-acid peptide that acts as a selective B2 receptor antagonist. In the landmark FAST-1 and FAST-2 clinical trials published in the New England Journal of Medicine (Cicardi et al., 2010), icatibant resolved HAE attack symptoms in a median of 2.0-2.5 hours, compared to 4.6 hours for placebo and 12.0 hours for tranexamic acid. The drug is self-administered by subcutaneous injection.

Icatibant's success in HAE validated the bradykinin pathway as a druggable target and demonstrated that peptide-based therapeutics can effectively modulate peptide signaling in clinical practice.

The COVID-19 Bradykinin Storm

During the COVID-19 pandemic, bradykinin gained renewed attention through the "bradykinin storm" hypothesis. SARS-CoV-2 enters cells via ACE2, and viral infection depletes ACE2 from cell surfaces. Since ACE2 degrades des-Arg9-bradykinin (the B1 receptor ligand), ACE2 depletion was hypothesized to cause des-Arg9-bradykinin accumulation, driving the vascular permeability and lung edema seen in severe COVID-19.

Zinn et al. (2023) published evidence from fatal COVID-19 cases supporting the hypothesis that targeting bradykinin metabolism could be therapeutically relevant, finding altered kinin pathway markers in lung tissue from patients who died of COVID-19.^[5] This connected the ACE2 biology, initially described when Donoghue et al. (2000) first cloned the ACE2 gene,^[1] to clinical disease through bradykinin dysregulation.

Clinical trials of icatibant in COVID-19 showed mixed results, with some studies reporting reduced oxygen requirements and others showing no significant benefit. The bradykinin storm hypothesis remains an active area of investigation.

From Snake Venom to ACE Inhibitors

One of the most remarkable chapters in bradykinin's history is its connection to ACE inhibitor development. In the 1960s, Brazilian scientist Sergio Ferreira discovered that venom from the pit viper Bothrops jararaca contained peptides that potentiated bradykinin's effects by inhibiting the enzyme that degrades it. These bradykinin-potentiating peptides (BPPs) led directly to the development of captopril, the first ACE inhibitor, by David Cushman and Miguel Ondetti at Squibb in the 1970s.

Gouda et al. (2021) reviewed the pharmacology of snake venom-derived bradykinin-potentiating peptides, noting that these peptides continue to be studied for their potential therapeutic applications beyond blood pressure control, including as possible COVID-19 interventions.^[6]

The irony is complete: snake venom peptides that enhance bradykinin led to the most prescribed class of blood pressure medications, which work partly by accumulating the same bradykinin, which causes the side effect that drives patients to switch to a different drug class.

Bradykinin in the Broader Peptide Signaling Network

Bradykinin does not operate in isolation. It intersects with several other peptide signaling systems:

Angiotensin II. ACE converts angiotensin I to angiotensin II (a vasoconstrictor) and simultaneously degrades bradykinin (a vasodilator). ACE inhibitors shift this balance by reducing angiotensin II production while increasing bradykinin levels. Fournie-Zaluski et al. (1994) developed dual inhibitors of neutral endopeptidase and ACE, targeting both peptide degradation pathways simultaneously.^[7]

Apelin. The apelin-ACE2 axis intersects with bradykinin metabolism. Kalea et al. (2010) described the interplay between apelin and ACE2 in cardiovascular disease, with ACE2 serving as the degradation enzyme for both apelin and des-Arg9-bradykinin.^[8]

Substance P. Bradykinin triggers substance P release from sensory nerve endings, and substance P amplifies the inflammatory response. Choi et al. (2023) demonstrated that ACE inhibition increases PKC-beta-I isoform expression via activation of the substance P pathway, providing a molecular link between ACE inhibitor use and substance P signaling.^[2]

Microbial interactions. Jarocki et al. (2019) showed that Mycoplasma hyopneumoniae produces surface proteases that cleave bradykinin, substance P, and neurokinin A, demonstrating that bacteria can directly modulate the kinin system to evade immune responses.^[9]

Schreiber et al. (2020) developed validated assays for measuring bradykinin and substance P protease activity using capillary blood samples, enabling more accessible research on kinin metabolism in clinical settings.^[10]

The Bottom Line

Bradykinin is a nine-amino-acid inflammatory peptide that causes the dry cough associated with ACE inhibitors by sensitizing airway sensory nerves and triggering neuropeptide release. It acts through two GPCRs: the constitutive B2 receptor and the injury-induced B1 receptor. Beyond the cough, bradykinin drives hereditary angioedema (treated by the peptide drug icatibant), amplifies inflammatory pain through TRPV1 receptor recruitment, and was implicated in COVID-19 lung injury through the bradykinin storm hypothesis. The peptide's history connects snake venom research to the development of ACE inhibitors, one of the most important drug classes in cardiovascular medicine.

Frequently Asked Questions

Why do ACE inhibitors cause a cough?

ACE inhibitors block the enzyme (ACE/kininase II) that normally degrades bradykinin in the lungs. When bradykinin accumulates, it sensitizes airway C-fiber nerve endings through B2 receptor activation, triggers release of substance P and neurokinin A, and induces COX-2 production of prostaglandins. These combined effects lower the cough reflex threshold, causing a persistent dry cough in 5-35% of patients. The cough typically resolves 1-4 weeks after stopping the medication.

What is bradykinin and what does it do?

Bradykinin is a nine-amino-acid peptide (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) produced by the kallikrein-kinin system during inflammation. It causes vasodilation, increases vascular permeability, contracts smooth muscle, and activates pain-sensing nerve fibers. Its half-life is only 15-30 seconds because it is rapidly degraded by ACE and other enzymes. Bradykinin plays roles in blood pressure regulation, inflammatory pain, wound healing, and immune responses.

What is icatibant and how does it work?

Icatibant (brand name Firazyr) is a synthetic 10-amino-acid peptide that blocks the bradykinin B2 receptor. It is FDA-approved for treating acute attacks of hereditary angioedema, a rare condition caused by excessive bradykinin production. In clinical trials, icatibant resolved angioedema symptoms in a median of 2.0-2.5 hours versus 4.6-12.0 hours for comparators (Cicardi et al., NEJM, 2010). It is administered by subcutaneous self-injection.

What is the bradykinin storm in COVID-19?

The "bradykinin storm" hypothesis proposed that SARS-CoV-2 depletes ACE2 from cells, reducing degradation of des-Arg9-bradykinin (a bradykinin metabolite). The resulting accumulation activates B1 receptors on blood vessels, causing the vascular leakage and lung edema seen in severe COVID-19. Evidence from fatal COVID-19 cases showed altered kinin pathway markers in lung tissue (Zinn et al., 2023). Clinical trials of icatibant in COVID-19 showed mixed results.

Why do ARBs not cause cough like ACE inhibitors?

ARBs (angiotensin receptor blockers) like losartan and valsartan lower blood pressure by blocking angiotensin II receptors, not by inhibiting ACE. Because ACE remains active when taking ARBs, bradykinin is still degraded normally and does not accumulate in the lungs. Without bradykinin buildup, there is no airway nerve sensitization and no cough. This is why ARBs are the standard alternative for patients who cannot tolerate ACE inhibitor cough.

How did snake venom lead to ACE inhibitors?

In the 1960s, Brazilian researcher Sergio Ferreira discovered that pit viper (Bothrops jararaca) venom contained bradykinin-potentiating peptides that inhibited the enzyme degrading bradykinin. These peptides directly inspired the development of captopril, the first ACE inhibitor, by Cushman and Ondetti at Squibb in the 1970s (Gouda et al., Biomed Pharmacother, 2021). ACE inhibitors became one of the most prescribed drug classes worldwide.