There is evidence that bradykinin may play a beneficial, protective role in certain cardiovascular diseases and ischemic stroke-induced brain injury. On the other hand, it has been implicated in cancer and some central nervous system diseases.
The biologic actions of kinins are mediated by specific receptors located on the membranes of the target tissues. Two types of kinin receptors, termed B1 and B2, have been defined based on the rank orders of agonist potencies; both are G protein-coupled receptors. (Note that B here stands for bradykinin, not for β adrenoceptor.) Bradykinin displays the highest affinity in most B2 receptor systems, followed by Lys-bradykinin. One exception is the B2 receptor that mediates contraction of venous smooth muscle; this appears to be more sensitive to Lys-bradykinin. Recent evidence suggests the existence of two B2-receptor subtypes, which have been termed B2A and B2B.
B1 receptors appear to have a very limited distribution in mammalian tissues and have few known functional roles. Studies with knockout mice that lack functional B1 receptors suggest that these receptors participate in the inflammatory response and may also be important in long-lasting kinin effects such as collagen synthesis and cell multiplication. By contrast, B2 receptors have a widespread distribution that is consistent with the multitude of biologic effects that are mediated by this receptor type. Agonist binding to B2 receptors sets in motion multiple signal transduction events, including calcium mobilization, chloride transport, formation of nitric oxide, and activation of phospholipase C, phospholipase A2, and adenylyl cyclase.
Drugs that modify the activity of the kallikrein-kinin system are available. Considerable effort has been directed toward developing kinin receptor antagonists, since such drugs have considerable therapeutic potential as anti-inflammatory and antinociceptive agents. Competitive antagonists of both B1 and B2 receptors are available for research use. Examples of B1 receptor antagonists are the peptides [Leu8-des-Arg9]bradykinin and Lys[Leu8-des-Arg9] bradykinin. The first B2 receptor antagonists to be discovered were also peptide derivatives of bradykinin. These first-generation antagonists were used extensively in animal studies of kinin receptor pharmacology. However, their half-life is short, and they are almost inactive on the human B2 receptor.
Icatibant is a second-generation B2 receptor antagonist. It is a decapeptide with an affinity for the B2 receptor similar to that of bradykinin and is absorbed rapidly after subcutaneous administration. Icatibant has been shown to be effective in the treatment of hereditary angioedema. It may also be useful in other conditions including drug-induced angioedema, airway disease, thermal injury, ascites, and pancreatitis.
A third generation of B2-receptor antagonists has been developed; examples are FR 173657, FR 172357, and NPC 18884. These antagonists block both human and animal B2 receptors and are orally active. They have been reported to inhibit bradykinininduced bronchoconstriction in guinea pigs, carrageenan-induced inflammation in rats, and capsaicin-induced nociception in mice. These antagonists have promise for the treatment of inflammatory pain in humans.
SSR240612 is a new, potent, and orally active selective antagonist of B1 receptors in humans and several animal species. It reduces obesity in diabetic rats, has analgesic and anti-inflammatory activities in mice and rats, and is currently in preclinical development for the treatment of inflammatory and neurogenic pain.