Bradykinin

Bradykinin pharmacology

1. Bradykinin Mr. Mangesh Bansod Asst. Prof., SDDVCPRC, Panvel

2. PLASMA KININS ( Bradykinin and Kallidin) Trypsin and certain snake venoms acted on plasma globulin to produce a substance that lowered blood pressure and caused a slowly developing contraction of the gut . Because of this slow response, they named the substance bradykinin . A term derived from the greek words bradys , meaning "slow," and kinein , meaning "to move."

3. The two important plasma kinins , Kallidin ( decapeptide ) and Bradykinin ( nonapeptide ) were discovered around 1950. These and other biological fluids were found to act indirectly: they contained enzymes which generated active substances in the plasma. Kinins are generated by proteolytic reactions triggered by tissue injury, inflammation, allergic reaction , etc., and play important mediator roles.

4. Generation and metabolism Kininogens are α 2 globulins present in plasma which also contains inactive kininogenase prekallikrein . Generation and degradation of plasma kinins HMW—High molecular weight; LMW—Low molecular weight

5. ACTIONS 1. CVS Kinins are more potent vasodilators than ACh and histamine. The dilatation is mediated through endothelial NO and PGI2 generatio n, 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.

6. 2. Smooth muscle - Kinin -induced contraction of intestine is slow ( bradys —slow, kinein —to move ). They cause marked bronchoconstriction in guineapigs and in asthmatic patients. 3. Neurones - Kinins strongly stimulate nerve endings that transmit pain and produce a burning sensation . 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 . 4. Kidney- Kinins increase renal blood flow as well as facilitate salt and water excretion by action on tubules.

7. Kinin receptors Existence of two types bradykinin receptor has been established : B1 and B2 Both are GPCR & mediate similar effects. B 1 normally expressed at very low levels but are strongly induced in inflamed or damaged tissues by cytokines such as IL-1. respond to des-Arg9-bradykinin &des-Arg9-kallidin but not to bradykinin itself. likely that B1 receptors play a significant role in inflammation and hyperalgesia B 2 Constitutively expressed in most normal tissues, selectively binds bradykinin and kallidin and mediates the majority of their effects. The B2 receptor activates PLA2 and PLC via interaction with distinct G proteins

8. Receptors Mechanism B Gq PLC PI P 2 IP 3 D A G Calcium mobil i z ation Vascular endot h e l ium NO Generation & Release Smo o th Muscle Vasodilation Increased permeability Contraction G PLA 2 Arachidonic acid PG I

9. 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 IL-1, TNF- α and other inflammatory mediators. Kinins appear to play important role in allergic inflammation manifesting as angioedema , rhinitis and asthma .

10. PATHOPHYSIOLOGICAL ROLES 2. Mediation of pain- By directly stimulating nerve endings and by increasing PG production, kinins appear to serve as mediators of pain. 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.

11. Kinins cause closure of ductus arteriosus , dilatation of foetal pulmonary artery and constriction of umbilical vessels. 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.

12. Icatibant Second generation B2 receptor antagonist. It is orally active, potent, and selective. Has a long duration of action (> 60 minutes). And displays high B2 receptor affinity in humans and all other species in which it has been tested. Has been used extensively in animal studies to block exogenous and endogenous bradykinin and in human studies to evaluate the role of kinins in inflammation, Pain and hyperalgesia . Icatibant has been recently approved in Europe for symptomatic treatment of hereditary angioedema .