Bradykinin Function: Its Role in Health and Disease

Bradykinin is a potent signaling peptide involved in a wide array of bodily processes. This substance acts locally near its site of release to regulate physiological events. Its actions are fundamental to maintaining normal bodily function, but it also plays a significant part in the development of various disease states.

Bradykinin Synthesis and Degradation

Bradykinin is not stored within cells for later use; instead, it is produced on demand when specific triggers are present. Its formation is a direct result of the kallikrein-kinin system, a cascade of proteins in the blood. The process begins when an enzyme called plasma kallikrein cleaves a larger precursor molecule known as high-molecular-weight kininogen (HMWK). This enzymatic action liberates the small, nine-amino-acid peptide, bradykinin.

The body maintains tight control over bradykinin levels through rapid degradation, giving it a very short half-life in the bloodstream. The primary enzyme in this process is angiotensin-converting enzyme (ACE), which is abundant in the lungs and kidneys. ACE, also known as kininase II, efficiently breaks down bradykinin, terminating its signaling activity. Other enzymes, such as aminopeptidase P and carboxypeptidase N, also contribute to its degradation.

Physiological Effects of Bradykinin

Bradykinin carries out its functions by binding to specific receptors on the surface of various cells. The two main types are known as B1 and B2 G protein-coupled receptors. The interaction between bradykinin and these receptors initiates a cascade of signals inside the cells, leading to physiological responses involving inflammation, blood pressure regulation, and pain.

One effect of bradykinin is vasodilation, the widening of blood vessels. By acting on the endothelial cells that line blood vessels, it stimulates the release of other vasodilator substances, including nitric oxide and prostacyclin. This relaxation of the smooth muscle in artery walls leads to increased blood flow and a decrease in blood pressure, contributing to the body’s regulation of cardiovascular function.

Bradykinin also increases vascular permeability, making the walls of small blood vessels leakier. This allows fluid, proteins, and immune cells to move from the bloodstream into surrounding tissues. While this is a feature of the normal inflammatory response to deliver healing factors to an injury site, it is also the reason bradykinin contributes to swelling, or edema. The combination of increased blood flow and permeability causes the classic signs of inflammation: redness, heat, and swelling.

Bradykinin is a pain-producing substance that directly stimulates sensory nerve endings, a process called nociception, to send pain signals to the brain. This action serves as a protective alarm, alerting the body to injury or damage. Its role in inflammation contributes to the discomfort associated with such conditions. The peptide can also cause smooth muscles in organs like the bronchi and gut to contract.

Bradykinin in Disease States

Dysregulation of the bradykinin system is a feature of several medical conditions. One example is hereditary angioedema (HAE), a genetic disorder characterized by recurrent and severe swelling of the face, limbs, and airways. In many cases of HAE, a deficiency in the C1 esterase inhibitor protein leads to unchecked activation of the kallikrein-kinin system and excessive bradykinin production. This overabundance of bradykinin increases vascular permeability, causing angioedema attacks.

The clinical relevance of bradykinin pathways is also highlighted by the side effects of a common class of blood pressure medications. Angiotensin-converting enzyme (ACE) inhibitors, such as lisinopril and ramipril, work by blocking the ACE enzyme to lower blood pressure. However, because ACE is also the primary enzyme for breaking down bradykinin, these drugs lead to its accumulation. For many patients, this results in a persistent, dry cough, and in some, it can cause a form of angioedema similar to HAE.

Bradykinin also contributes to other inflammatory and allergic conditions. It is one of several mediators released during severe allergic reactions and anaphylaxis, contributing to the sharp drop in blood pressure and swelling. Its pro-inflammatory actions mean it is also involved in conditions like asthma and rhinitis. Research has explored the “bradykinin storm” hypothesis in severe inflammatory responses like those in COVID-19, suggesting its overproduction could be a factor in vascular complications.

Therapeutic Interventions Targeting Bradykinin

The understanding of bradykinin’s role in disease has led to the development of targeted therapies. These treatments are designed to interfere with the bradykinin pathway by either preventing its production or by blocking its effects. This approach has been useful in the management of hereditary angioedema (HAE).

One strategy involves the use of bradykinin receptor antagonists. These drugs work by binding to bradykinin receptors, preventing the peptide from activating them. Icatibant is an example of a B2 receptor antagonist used to treat acute attacks of HAE. It blocks bradykinin’s ability to increase vascular permeability, thereby reducing swelling.

Another therapeutic approach is to inhibit the enzymes that produce bradykinin. Kallikrein inhibitors, such as lanadelumab and ecallantide, are designed to block the action of plasma kallikrein. By preventing this enzyme from cleaving HMWK, these drugs reduce the overall production of bradykinin. This strategy is used as a prophylactic treatment to prevent HAE attacks.

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