Pharmacology of Bradykinin and Kallidin

Study Notes

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.

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.

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.

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 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.

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.