Bradykinin is a small, nine-amino-acid peptide that acts as a powerful regulator of various bodily functions. It belongs to a class of compounds called kinins, which are short-lived, biologically active substances. Bradykinin is primarily known for its effects on the cardiovascular system, where it helps control blood vessel diameter and blood pressure. Its presence is fundamentally tied to the body’s localized response to injury, acting as a potent mediator of inflammation and pain signaling.
The Kinin-Kallikrein System
The production and destruction of bradykinin are tightly regulated by a complex enzymatic pathway known as the kinin-kallikrein system. This system ensures that the potent effects of bradykinin are localized and temporary, preventing systemic over-activation. Bradykinin is synthesized on demand from a larger, inactive precursor protein called kininogen, which circulates in the blood and is present in tissues.
The synthesis begins when an enzyme called kallikrein cleaves the kininogen, releasing the active bradykinin peptide. This reaction is often triggered by contact with negatively charged surfaces, such as those exposed during tissue injury or inflammation. Once released, bradykinin is short-lived.
The rapid deactivation of bradykinin is primarily accomplished by a group of enzymes called kininases. The most significant of these is Kininase II, which is identical to the Angiotensin-Converting Enzyme (ACE). ACE quickly breaks down bradykinin into inactive fragments, ensuring that its effects are tightly controlled and localized.
Core Physiological Actions
Once produced, bradykinin acts by binding to specific receptors, primarily the B2 receptors, which are widely expressed on the surface of endothelial cells lining blood vessels. This binding triggers a cascade of effects designed to increase blood flow and initiate the inflammatory response. Bradykinin is a potent vasodilator, causing the smooth muscle cells in arterial walls to relax.
This relaxation leads to a widening of the blood vessels, resulting in increased blood flow to the local tissue and a reduction in overall blood pressure. Simultaneously, bradykinin increases vascular permeability by causing the endothelial cells to slightly separate. This makes the vessels “leaky,” allowing fluid and immune cells to move from the bloodstream into the surrounding tissue, which is a hallmark of swelling and inflammation.
Bradykinin also plays a direct role in the sensation of pain, acting on nearby sensory nerve endings. It stimulates these nerve fibers and sensitizes them to other painful stimuli like heat and pressure. This contributes to the localized tenderness and discomfort experienced at a site of injury or infection.
Interaction with Common Medications
The dual function of Angiotensin-Converting Enzyme (ACE) as both an angiotensin-converting enzyme and the primary bradykinin-degrading enzyme (Kininase II) has clinical implications. Angiotensin-Converting Enzyme Inhibitors (ACEIs) are a class of medications prescribed to treat high blood pressure and heart failure. The intended therapeutic effect of these drugs is to block ACE, which prevents the formation of the potent vasoconstrictor Angiotensin II, thereby lowering blood pressure.
However, blocking ACE also prevents the breakdown of bradykinin, leading to its accumulation in the body, particularly in the lungs and airways. This unintended increase in bradykinin levels is responsible for the most common side effect of ACE inhibitor therapy: a persistent, non-productive dry cough. The accumulated bradykinin sensitizes the sensory nerve fibers in the respiratory tract, triggering the chronic cough reflex.
This dry cough can affect up to 20% of patients taking ACE inhibitors and typically resolves within a few weeks to months after the medication is discontinued. Understanding this bradykinin-mediated side effect is why physicians may switch patients to an alternative class of blood pressure medication, such as an Angiotensin II Receptor Blocker, if the cough is intolerable.
Role in Acute Swelling Conditions
Dysregulation of the bradykinin pathway causes a specific, severe form of swelling known as bradykinin-mediated angioedema. This condition involves rapid, localized swelling beneath the skin or mucous membranes, often affecting the face, lips, tongue, larynx, or gastrointestinal tract. Unlike common allergic swelling (hives/urticaria), this form of angioedema does not respond to standard treatments like antihistamines or corticosteroids because it is not mediated by histamine.
One well-known type is hereditary angioedema (HAE), a genetic disorder often caused by a deficiency or dysfunction of the C1 inhibitor protein. The C1 inhibitor normally helps regulate the kinin-kallikrein system; without it, the system becomes overactive, leading to the uncontrolled production of bradykinin. This surge in bradykinin causes excessive vascular permeability and fluid leakage into the tissues, resulting in painful swelling episodes.
Acquired forms of bradykinin-mediated angioedema also exist, most notably the angioedema induced by ACE inhibitors. In both hereditary and drug-induced cases, the severe swelling is a direct result of bradykinin overwhelming the local control mechanisms. Targeted treatments for these conditions, such as B2 receptor antagonists, work by blocking bradykinin’s action at the receptor site, directly addressing the underlying mechanism of the swelling attack.