Plasma Kinins (Bradykinin and Kallidin)

PLASMA KININS

(Bradykinin and Kallidin)

Plasma kinins are polypeptides split off from a plasma globulin Kininogen by the action of specific enzymes Kallikreins. The two important plasma kinins, Kallidin (decapeptide) and Bradykinin (nonapeptide) were discovered around 1950 by two independent lines of investigation into the hypotensive activity of urine and certain snake venoms. These and other biological fluids were found to act indirectly: they contained enzymes which generated active substances in the plasma.

Generation and Metabolism

Kininogens are α2 globulins present in plasma which also contains inactive kininogenase prekallikrein.

Prekallikrein is activated by Hageman factor (factor XII) which itself is activated by tissue injury and contact with surfaces having negative charge, e.g. collagen, basement membrane, bacterial liposaccharides, urate crystals, etc. Plasmin facilitates contact activation of Hageman factor. Kinins are also generated by trypsin, proteolytic enzymes in snake and wasp venoms and by kallikrein present in kidney, pancreas and other tissues. Bradykinin is generated from high molecular weight (HMW) kininogen by the action of plasma kallikrein, because HMW-kininogen does not cross the capillaries. On the other hand, kallidin can be produced from both low molecular weight (LMW) kininogen as well as HMW-kininogen by the action of tissue kallikreins. Bradykinin can also be generated from kallidin on the removal of lysine residue by an aminopeptidase.

Plasma and tissues also contain kininogenase inhibitory factors of which complement (C1) esterase inhibitor is the most important. Moreover, kallikreins are normally present in their inactive forms. Thus, physiologically only small amounts of kinins are generated in plasma and tissues.

Kinins are very rapidly degraded, primarily in lungs, but also in other tissues and have a t½ of < 1 min. The principal degrading enzyme is Kininase II, also known as ‘angiotensinII converting enzyme’ (ACE) which splits off 2 amino acids from the carboxyterminal of the peptide chain. Another carboxypeptidase Kininase I removes only one amino acid (arginine) producing selective B1 receptor agonistic metabolites (desArg bradykinin and desArg kallidin) which are further degraded by other peptidases.

Actions

Bradykinin and kallidin have similar actions.

CVS

Kinins are more potent vasodilators than ACh and histamine. The dilatation is mediated through endothelial NO and PGI2 generation, and involves mainly the arterioles. Larger arteries, most veins and vessels with damaged endothelium are constricted through direct action on the smooth muscle. In addition, they can release histamine and other mediators from mast cells. Injected i.v. kinins cause flushing, throbbing headache and fall in BP. They markedly increase capillary permeability due to separation of endothelial cells → exudation and inflammation occurs if they are injected in a tissue. Intradermal injection produces wheal and flare (similar to histamine).

Kinins have no direct action on heart; reflex stimulation occurs due to fall in BP.

Smooth Muscle

Kinin induced contraction of intestine is slow (bradys—slow, kinein—to move). They cause marked bronchoconstriction in guineapigs and in asthmatic patients. Action on other smooth muscles is not prominent, some may be relaxed also.

Neurones

Kinins strongly stimulate nerve endings that transmit pain and produce a burning sensation. Applied to blister base/injected intraperitoneally or in the brachial artery, bradykinin produces intense, transient pain and has been used in analgesic testing.

Kinins release CAs from adrenal medulla. Injected directly in brain they produce a variety of effects including enhanced sympathetic discharge. They increase permeability of the blood-brain barrier.

Kidney

Kinins increase renal blood flow as well as facilitate salt and water excretion by action on tubules. The diuretic effect of furosemide is reduced by kinin B2 receptor antagonists, indicating participation of locally generated kinins in this response.

Kinin receptors Existance of two types of kinin receptors (B1, B2) has been established. Most kinin actions in noninflamed tissues are mediated by B2 receptors which are constitutively present on:

Visceral smooth muscle—contraction of intestine, uterus, airway.

Vascular endothelium—NO release, vasodilatation, increased permeability.

Sensory nerves—acute pain.

The B2 receptor is a G-protein coupled receptor which utilizes the phospholipase-C—IP3/DAG—intracellular Ca²⁺ mobilization transducer mechanism. Certain responses to kinins, e.g. bronchoconstriction and renal vasodilatation are attenuated by pretreatment with PG synthesis inhibitors (aspirin). Aspirin injected i.p. before bradykinin through the same cannula blocks its algesic action. These responses are mediated by phospholipase A activation—release of arachidonic acid and generation of PGs.

The B1 receptor is located on the smooth muscle of large arteries and veins—mediates contraction of these vessels, but is expressed minimally in normal tissues. Inflammation induces synthesis of B1 receptors, so that they might play a major role at inflamed sites.

Bradykinin has higher affinity for B2 than for B1 receptors, while Kallidin is equipotent on both. The des-Arg metabolites of bradykinin and kallidin are the natural selective agonists of B1 receptor.

Pathophysiological Roles

1. Mediation Of Inflammation Kinins produce all the signs of inflammation—redness, exudation, pain and leukocyte mobilization. Tissue injury can cause local kinin production which then sets in motion the above defensive and reparative processes. Activation of B1 receptors on macrophages induces production of IL1, TNFα and other inflammatory mediators.

2. Mediation Of Pain By directly stimulating nerve endings and by increasing PG production kinins appear to serve as mediators of pain. The B2 antagonists block acute pain produced by bradykinin, but induced B1 receptors appear to mediate pain of chronic inflammation.

3. Functional Hyperemia (In Glands During Secretion) And Regulation Of Microcirculation—especially in kidney may be occurring through local kinin production.

4. Production of kinins is integrated with clotting, fibrinolysin and complement systems. Kallikreins may have roles in these systems which are independent of kinin production.

5. Kinins appear to play no significant role in regulation of normal BP. However, they may serve to oppose overactive RAS and exert antiproliferative influence on vascular smooth muscle in hypertensive states.

6. Kinins cause closure of ductus arteriosus, dilatation of foetal pulmonary artery and constriction of umbilical vessels—they may be involved in adjusting from foetal to neonatal circulation.

7. Kinins play a major role in the development of angioedema. They also appear to be involved in shock, rhinitis, asthma, ACE inhibitor induced cough, carcinoid, postgastrectomy dumping syndrome, fluid secretion in diarrhoea, acute pancreatitis and certain immunological reactions.

Because of evanescent and unpleasant actions, kinins have no clinical use.

Bradykinin Antagonists

After characterization of B₁ and B₂ kinin receptors, several peptide and nonpeptide kinin antagonists have been produced. The synthetic peptide HOE 140 is a selective B₂ antagonist resistant to kinin degrading enzymes and having longer t½, while Icatibant, FR 173657 and some others are orally active nonpeptide B₂ antagonists that have helped in defining the pathophysiological roles of kinins and have undergone limited trials as analgesic, anti-inflammatory drugs and in pancreatitis, head injury, etc.