Pharmacology of Bradykinin and Kallidin

Bradykinin and Kallidin

• Bradykinin is a nonapeptide (9 amino acids) produced in the body as a result of tissue damage, allergic reactions, viral infections, and other inflammatory events.
• Kallidin is a similar peptide with an additional lysine residue at the amino-terminal position and is sometimes referred to as lysyl-bradykinin.

Sources and Metabolism

• Bradykinin and kallidin are cleaved from α2 globulins termed kininogens, with two types: high-molecular-weight (HMW) and low-molecular-weight (LMW) kininogen.
• Kallikreins, specific serine proteases, release bradykinin and kallidin from the kininogens.
• The kinins have a short half-life in plasma (approximately 15 seconds) and are rapidly destroyed in the pulmonary vascular bed.
• Dipeptidyl carboxypeptidase (kininase II, also known as angiotensin-converting enzyme) is the primary catabolizing enzyme in the lung and other vascular beds.
• Neutral endopeptidase also inactivates kinins by removing the carboxyl-terminal dipeptide.

Receptors

• There are at least two distinct receptors for kinins: B1 and B2.
• The B2 receptor is a G protein-coupled receptor that selectively binds bradykinin and kallidin and is constitutively present in most normal tissues.
• B1 receptors selectively bind to the carboxy-terminal des-Arg metabolites of bradykinin and kallidin and are less prevalent than the B2 receptor in most tissues.

Physiological Effects

• Bradykinin and kallidin are powerful algesic agents, causing an intense, burning pain when applied to the exposed base of a blister.
• Kinins increase permeability in the microcirculation, leading to edema and a "wheal-and-flare" response.
• Kinins have been implicated in the pathophysiology of allergic airway disorders, such as asthma and rhinitis.
• Bradykinin causes vasodilation and lowers blood pressure through B2-receptor-dependent effects on endothelial nitric oxide and prostacyclin.
• Kinins have cardioprotective effects, contributing to the protective effect of preconditioning the heart against ischemia and reperfusion injury.

Renal Effects

• Renal kinins act as paracrine hormones to regulate urine volume and composition.
• Kallikrein is synthesized and secreted by the connecting cells of the distal nephron.
• Bradykinin increases renal blood flow and causes natriuresis by inhibiting sodium reabsorption at the cortical collecting duct.

Clinical Applications

• Kinin agonists have potential value in increasing the delivery of chemotherapeutic agents beyond the blood-brain barrier.
• Kinin antagonists are being tested in several inflammatory conditions.
• Bradykinin contributes to many of the effects of ACE inhibitors.