Bradykinins, Analogs and Sequences

Especially in processes connected to inflammation, vascular tone, pain regulation, and immunological responses, bradykinin is a peptide that is essential for many physiological and pathological mechanisms. Made from kininogen, it is a fundamental modulator in both acute and chronic inflammatory diseases. It is part of the kinin system.

What is Bradykinin?

The enzymes known as kallikreins work to convert high-molecular-weight kininogen (HMWK) into bradykinin, a nonapeptide (a peptide made up of nine amino acids). The body uses bradykinin primarily to control immunological responses, blood pressure, vascular tone, and pain perception. It functions as a local mediator that influences several bodily systems and is generated in response to certain physiological circumstances.

Bradykinin has a major impact on blood vessel permeability and is one of the body's strongest vasodilators. It contributes to a variety of acute inflammatory reactions and is essential for injury-related pain, edema, and hypotension. Bradykinin's therapeutic uses, especially in models of inflammation and vascular dysfunction, depend on our ability to comprehend how it interacts with various tissues and receptors.

Bradykinin Function

Bradykinin is a strong vasodilator that affects many biological processes, including those in the neurological and vascular systems. Among the primary roles of bradykinin are:

Vasodilation: Bradykinin acts on the endothelial cells lining blood vessels to drive prostacyclin and nitric oxide (NO) generation. Especially in cases of inflammation or damage, these substances promote the relaxation of smooth muscles and induce vasodilation, hence lowering blood pressure and improving blood flow to tissues. Bradykinin-induced vasodilation is necessary to maintain an appropriate blood supply to tissues and organs, particularly in demanding conditions.

Increased Vascular Permeability: Bradykinin drives vascular endothelial cells to become more permeable, therefore allowing proteins, fluid, and immune cells to move from the circulation into the surrounding tissues. By allowing immune cells—such as neutrophils and macrophages—to be attracted to the site of injury or infection, this stimulates inflammation and healing.

Pain Sensitization: Bradykinin is essential for how pain is perceived, particularly when inflammation is present. It attaches itself to nociceptors' receptors, which are sensory nerve fibers that sense pain. Bradykinin increases the perception of pain in inflammatory regions by directly activating these pain receptors and making them more sensitive to other unpleasant stimuli. Conditions including neuropathic pain, musculoskeletal injury, and arthritis are impacted by this process.

Control of Smooth Muscle Contraction: Bradykinin also affects the tone of smooth muscles in the airways and gastrointestinal system, among other tissues. Depending on the kind of tissue, bradykinin may either elicit contraction or relaxation via activating B2 receptors on smooth muscle cells.

Immune Modulation: By stimulating immune cells like neutrophils and macrophages, bradykinin alters immunological responses. It causes the production of inflammatory mediators, such as prostaglandins, chemokines, and cytokines, which support the body's defenses against tissue damage and infection. The immune-modulatory function of bradykinin is crucial for wound healing, inflammatory illness, and infection response.

What does Bradykinin Do?

Bradykinin is involved in several physiological processes, such as:

Vasodilation: Bradykinin relaxes and widens blood vessels, which lowers blood pressure and increases blood flow.

Inflammation and Pain: Bradykinin increases the perception of pain in inflammatory tissues by triggering pain receptors and enhancing sensitivity to other stimuli.

Tissue Healing and Repair: Bradykinin promotes tissue vascularization and immune cell recruitment throughout the healing process, which helps with tissue repair.

Immune System Modulation: It helps to build a successful immune response by inducing the production of pro-inflammatory chemicals.

Bradykinin's function as a double-edged sword is shown by its involvement in these activities. As shown in many types of inflammatory illnesses, excessive or unchecked bradykinin production may result in persistent inflammation, discomfort, and edema, even if it is helpful for healing damage and inflammation.

Bradykinin Pathway

Bradykinin is produced from its precursor, kininogen, via a closely controlled series of processes known as the kinin system. The bradykinin pathway's primary stages are:

Kininogen Cleavage: When kallikrein enzymes break down the kininogen precursor protein, bradykinin peptides are produced. Stress, inflammation, and tissue damage all cause kallikrein to become active.

Bradykinin Receptor Activation: Bradykinin binds to G-protein-coupled receptors (GPCRs) B1 and B2 once it is released. While the B1 receptor is activated after inflammation or injury and plays a role in chronic inflammatory responses, the B2 receptor mediates the majority of bradykinin's effects under normal circumstances.

Intracellular Signaling: A number of intracellular pathways are triggered when target cells' B2 receptors are activated. This involves the synthesis of IP3 and DAG as well as the activation of phospholipase C (PLC), which raises intracellular calcium levels. These molecules start downstream signaling cascades that encourage a number of physiological reactions, including pain induction, vasodilation, and smooth muscle relaxation.

Regulation and Degradation: Enzymes such as kininase I and kininase II (ACE) break down bradykinin enzymatically, ending its actions. This makes sure that bradykinin levels don't stay high enough to have negative consequences like severe edema or chronic discomfort.

Bradykinin Mechanism of Action

To exert its physiological effects, bradykinin primarily binds to B2 receptors, which are widely expressed on endothelium, smooth muscle, and immune cells.

Vasodilation and Blood Pressure Regulation: By binding to the B2 receptor on endothelial cells, bradykinin promotes the production of prostacyclin (PGI2) and nitric oxide (NO). Both of these substances promote the relaxation of smooth muscle cells in blood arteries, which results in vasodilation, which reduces blood pressure and enhances blood flow to tissues.

Increased Vascular Permeability: Bradykinin makes endothelial cells more permeable, allowing proteins, immune cells, and nutrients to pass from the circulation into the surrounding tissue. This encourages inflammation and immunological responses, but if untreated, it may also lead to severe edema.

Pain Sensitization: Bradykinin attaches to nociceptors, or pain receptors, increasing their sensitivity to external stimuli like mechanical pressure or temperature changes, therefore generating an enhanced pain response (hyperalgesia).

Immunological Activation: Bradykinin stimulates neutrophils and macrophages among other immune cells by interacting with B2 receptors. Different pro-inflammatory cytokines and chemokines therefore are produced, which promotes the recruitment of additional immune cells to injury or infection regions.

Smooth Muscle Contraction: Bradykinin causes certain tissues, such the gastrointestinal system or airways, to contract their smooth muscles. This could affect gastrointestinal motility or lead to bronchoconstriction, the lung airways' narrowing.