In addition to histamine and serotonin; allergic reactions, tissue damage, viral infections, and other inflammatory events elicit the release of bradykinin and kallidin, both of which mediate pain, vasodilatation, increased vascular permeability, and increased synthesis of prostaglandins.  Several potential agents are currently being investigated (in both the laboratory and in clinical trials) for use in inflammatory diseases.

There have been two receptors positively identified with these autocoids: B1 and B2 (whose effects are mediated by the G_q/11 protein).  Bradykinin preferentially acts at the B2 receptor while the affinity of kallidin for both receptors is approximately equal.

Actions and Potential Uses:
Pain -- Activation of B2 receptors will produce pain both directly and through the increased release of substance P, neurokinin A, and other autocoids.  An antagonist of B2 receptors could have value as an analgesic.

Inflammation/Increased Vascular Permeability -- this is primarily a B1 effect.  Bradykinin has been positively correlated to the inflammatory responses to rhinitis, rhinoviral infection, gout, disseminated intravascular coagulation, irritable bowel syndrome, rheumatoid arthritis, and asthma.  A B1 antagonist would obviously decrease the oedema and associated inflammation in these disorders.

Bronchoconstriction -- These autocoids produce bronchoconstriction, especially in asthmatics.  Antagonists would be of benefit in these patients.

Vasodilatation -- These compounds produce vasodilatation except in injured vessels where vasoconstriction occurs.  Additionally, they may increase central sympathetic outflow, which may increase blood pressure.

Regulation of urine volume and composition -- Bradykinin and kallidin affect chloride transport in the kidney and may be related to the effect of aldosterone.  NOTE: the ability of these agents to alter sympathetic tone (as describe above) and blood volume suggests they may play a role in the regulation of blood pressure.

Reproduction -- These agents will stimulate uterine contraction, stimulate spermatogenesis, and increase sperm motility.  An agonist could be useful in the treatment of male infertility due to aspermia or decreased motility.

Parturition -- These agents dilate the foetal pulmonary artery, close the ductus arteriosus, and constrict the umbilical vessels prior to birth.  An agonist could be used to counteract birth defects such as a patent ductus arteriosus.
 

Possible Drugs -- Aprotinin inhibits the kallikreins, thereby inhibiting the entire cascade.  This agent has limited usefullness which will be discussed later.  Numerous peptide antagonists, selective for either receptor, exist for laboratory research.  However, their structures preclude effective oral administration.  WIN 64338 is a non-peptide B2 antagonist that could be orally effective.  Additionally, certain plant-derived steroid glycols show promise as kinin antagonists.

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