Understanding the Enzymes: What Destroys Bradykinin?

October 5, 2025 •

4 min read

With a plasma half-life of only 15–30 seconds, bradykinin is a potent peptide whose biological effects are tightly controlled by rapid enzymatic destruction. The primary enzyme responsible for this rapid inactivation is angiotensin-converting enzyme (ACE), but it is not the only one. This article explores the specific enzymes involved and the medical implications when the system that naturally destroys bradykinin is inhibited.

Quick Summary

This article details the complex network of enzymes responsible for the rapid degradation of the peptide bradykinin. It examines the central role of angiotensin-converting enzyme (ACE) and highlights other crucial peptidases like neprilysin and carboxypeptidase N. The text explains the pharmacological and clinical consequences of inhibiting this natural process, including the development of drugs for cardiovascular health and the potential for side effects like angioedema.

Key Points

Angiotensin-Converting Enzyme (ACE) is the Primary Degrader: ACE, also known as kininase II, is the main enzyme responsible for destroying bradykinin, especially as it passes through the lungs.
ACE has Dual Roles: In the body's renin-angiotensin system, ACE both converts angiotensin I into vasoconstricting angiotensin II and destroys the vasodilator bradykinin.
ACE Inhibitors Cause Bradykinin Buildup: Medications like lisinopril and captopril inhibit ACE, preventing bradykinin's breakdown and leading to its accumulation, which contributes to their blood pressure-lowering effect.
Other Enzymes Contribute to Degradation: Neprilysin, carboxypeptidase N, and aminopeptidase P are other key peptidases that help inactivate bradykinin, particularly when ACE activity is reduced.
Bradykinin Accumulation has Side Effects: Increased bradykinin levels due to enzyme inhibition can cause side effects, most notably a persistent dry cough and the more serious condition of angioedema.
Drug Interactions Involve Multiple Pathways: Combining drugs like ACE inhibitors and neprilysin inhibitors can significantly increase bradykinin levels, highlighting the importance of understanding the full metabolic cascade.

The Importance of Bradykinin in the Body

Bradykinin is a naturally occurring peptide that plays a crucial role in various physiological processes, most notably as a potent vasodilator and inflammatory mediator. It causes the relaxation of smooth muscles in blood vessel walls, leading to the enlargement of arteries and a decrease in blood pressure. Bradykinin also increases vascular permeability, a key aspect of the inflammatory response that allows fluid to leak from blood vessels into tissues, and it can stimulate pain receptors. Due to these powerful effects, the body has a robust system of enzymes to rapidly break down and inactivate bradykinin, preventing its uncontrolled buildup. A malfunction in this system, or its inhibition by medication, can lead to serious consequences, such as angioedema, a severe and potentially life-threatening form of tissue swelling.

Angiotensin-Converting Enzyme (ACE) and Bradykinin Degradation

Angiotensin-converting enzyme (ACE), also known as kininase II, is the single most important enzyme responsible for destroying bradykinin in the body. Located primarily in the endothelial cells of blood vessels, especially in the lungs, ACE rapidly inactivates bradykinin during its passage through the pulmonary circulation. This process is crucial for preventing excessive vasodilation and regulating blood pressure.

ACE has a dual function in the renin-angiotensin-aldosterone system (RAAS), a hormonal system that regulates blood pressure. While it breaks down bradykinin, it also converts angiotensin I into the powerful vasoconstrictor, angiotensin II. This makes ACE a central point of control in the body's cardiovascular regulation.

The Impact of ACE Inhibitors

This dual function is the basis for a major class of cardiovascular drugs: ACE inhibitors, which include medications like lisinopril and captopril. By inhibiting ACE, these drugs prevent the production of angiotensin II, a potent vasoconstrictor, and simultaneously prevent the breakdown of bradykinin. The resulting accumulation of bradykinin leads to prolonged vasodilation, which contributes to the therapeutic blood pressure-lowering effect of the medication.

However, this increase in bradykinin is also responsible for some of the medication's adverse effects.

Dry Cough: An increase in bradykinin levels in the lungs can lead to a persistent, dry cough, a common side effect of ACE inhibitors.
Angioedema: In rare but serious cases, high bradykinin levels can cause angioedema, a rapid and potentially fatal swelling of the face, tongue, and airways. Patients of African descent have a higher risk of developing this side effect.

The Supporting Cast of Bradykinin-Degrading Enzymes

While ACE is the primary player, bradykinin is a peptide susceptible to degradation by a wide variety of other peptidases found throughout the body. These enzymes provide alternative or redundant pathways for inactivation, and their relative importance can vary depending on the tissue and physiological conditions.

Key secondary bradykinin-degrading enzymes include:

Neprilysin (NEP): Also known as neutral endopeptidase 24.11, neprilysin is another important peptidase involved in bradykinin degradation. It is widely distributed, with significant activity in the kidneys and heart. Neprilysin inhibitors can also increase bradykinin levels, and when combined with ACE inhibitors, they have shown a higher risk of angioedema.
Carboxypeptidase N (CPN): Also referred to as kininase I, CPN cleaves the last amino acid from bradykinin, converting it into a metabolite called des-Arg9-bradykinin. While CPN primarily acts on high levels of bradykinin, its role becomes more significant when ACE is inhibited.
Aminopeptidase P (APP): This enzyme is another player in kinin metabolism, responsible for degrading certain bradykinin metabolites. Genetic polymorphisms affecting APP activity have been linked to an increased risk of ACE inhibitor-induced angioedema, particularly in African Americans.
Endothelin-Converting Enzyme-1 (ECE-1) and others: A range of other enzymes contribute to the overall process, highlighting the redundancy of the body's system for regulating bradykinin levels.

The Clinical Implications of Enzyme Activity

The balance of these enzymes and their activity is crucial for maintaining physiological homeostasis. Medications that interfere with this balance can have profound therapeutic and adverse effects. For instance, the use of sacubitril/valsartan, a combination drug that inhibits neprilysin, led to concerns about increased angioedema risk due to the simultaneous increase in bradykinin. Understanding the specific enzymatic pathways helps physicians predict and manage the potential side effects of these important medications. The existence of multiple, redundant degrading enzymes is a testament to how essential the precise control of bradykinin levels is to the body.

Comparison of Major Bradykinin-Degrading Enzymes


Enzyme	Alias	Primary Site of Action	Inhibiting Medication Class	Clinical Relevance
Angiotensin-Converting Enzyme (ACE)	Kininase II	Lungs and Kidneys	ACE Inhibitors (e.g., Lisinopril, Captopril)	Primary bradykinin destruction; inhibition leads to increased bradykinin, causing vasodilation, cough, and angioedema.
Neprilysin (NEP)	Neutral Endopeptidase 24.11	Kidneys, Heart, Lungs	Neprilysin Inhibitors (e.g., Sacubitril)	Significant role in heart and kidney; inhibition increases bradykinin and natriuretic peptides. Used in heart failure treatment, but combined with ACE inhibitors, increases angioedema risk.
Carboxypeptidase N (CPN)	Kininase I	Plasma	N/A	Degrades high concentrations of bradykinin and its metabolites. Takes on a more significant role in bradykinin degradation when ACE is inhibited.
Aminopeptidase P (APP)	X-Pro aminopeptidase	Plasma, Endothelial Cells	N/A	Contributes to the breakdown of bradykinin and its metabolites. Genetic variations in APP can predispose individuals to angioedema with ACE inhibitor use.

Conclusion

To fully answer the question of what destroys bradykinin, one must look beyond a single enzyme and recognize a multi-layered enzymatic defense system. While angiotensin-converting enzyme (ACE) is the most prominent and clinically significant player, other enzymes like neprilysin and carboxypeptidase N provide crucial, often redundant, metabolic pathways. The delicate balance maintained by these enzymes is essential for regulating blood pressure and inflammation. When this process is intentionally altered by medications, such as ACE inhibitors or neprilysin inhibitors, the therapeutic benefits must be weighed against the risks of increased bradykinin levels, which can lead to side effects like persistent cough and, in rare cases, life-threatening angioedema. This complex pharmacological landscape underscores the importance of a comprehensive understanding of bradykinin metabolism for effective and safe medical treatment.

Frequently Asked Questions

The primary enzyme that destroys bradykinin is Angiotensin-Converting Enzyme (ACE), which is also known as kininase II. It is responsible for a significant portion of bradykinin inactivation, particularly in the lungs.

ACE inhibitors cause a dry cough by preventing the breakdown of bradykinin. The resulting accumulation of bradykinin in the lungs can lead to irritation and cause the characteristic persistent, dry cough experienced by some patients.

Yes, other drugs can affect bradykinin levels. For example, neprilysin inhibitors, used in heart failure, block another enzyme that degrades bradykinin, which can lead to increased bradykinin levels. Additionally, certain anti-diabetic medications (DPP-4 inhibitors) and thrombolytic agents can also interfere with bradykinin breakdown.

Angioedema is a medical condition characterized by rapid, localized swelling, often affecting the face, tongue, and airways. It can be caused by excessive bradykinin, which increases vascular permeability. This can occur with ACE inhibitor use or in hereditary conditions.

Some natural substances have been investigated for their potential to influence bradykinin, though this is not a substitute for medical treatment. Examples mentioned in studies include bromelain from pineapple, aloe, and polyphenols found in green tea and red wine, but these should be discussed with a healthcare provider.

ACE inhibitors are effective for treating high blood pressure because they inhibit ACE, which has two beneficial effects. They block the formation of the vasoconstrictor angiotensin II and prevent the degradation of the vasodilator bradykinin. The combined effect of these actions is a reduction in blood pressure.

If bradykinin is not destroyed properly, it can accumulate and cause excessive vasodilation and increased vascular permeability. This can lead to persistent low blood pressure, a dry cough, and potentially life-threatening angioedema.

Kininase II is another name for Angiotensin-Converting Enzyme (ACE), the main enzyme that degrades bradykinin. Kininase I is another name for Carboxypeptidase N (CPN), which also plays a role in bradykinin metabolism by cleaving off its last amino acid.