The document discusses the history, generation, receptors, actions, and roles of bradykinin and the kallikrein-kinin system. Bradykinin is a nonapeptide generated from kininogen by the enzyme kallikrein. It acts on B1 and B2 receptors to produce effects like vasodilation, increased permeability, smooth muscle contraction, and pain. Bradykinin has roles in inflammation, pain sensation, and microcirculation regulation. Drugs can target different parts of the kallikrein-kinin system including B1/B2 receptor antagonists and kallikrein inhibitors.

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History.
Generation and metabolism.
Receptors ( B1 and B2).
Pharmacological actions.
Pathophysiological roles.
Drugs affecting the bradykinin system.

4. In the 1920s and 1930s, frey, kraut, and werle characterized a
hypotensive substance in urine and found a similar material in saliva,
plasma, and a variety of tissues.
The pancreas also was a rich source, so they named this material
kallikrein after a greek synonym for that organ, kallikreas.
By 1937, werle, gotze, and keppler had established that kallikreins
generate a pharmacologically active substance from an inactive
precursor present in plasma.
In 1948, werle and berek named the active substance kallidin and
showed it to be a polypeptide cleaved from a plasma globulin that
they termed kallidinogen.

5. History.
 Interest in the field intensified when rocha e silva and associates
reported that 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."

6. History.
 In 1960, the nonapeptide bradykinin was isolated by Elliott and
coworkers and synthesized by Boissonnas and associates.
Shortly thereafter, kallidin was found to be a decapeptidebradykinin with an additional lysine residue at the amino terminus.
kallidin and bradykinin are referred to as plasma kinins.

7. Generation and metabolism.
Plasma kinins are polypeptides split off from a plasma globulin
kininogen by the action of specific enzymes kallikreins.
Two important plasma kinins are kallidin (decapeptide) and
bradykinin(nonapeptide).

8.  Kininogens.
Two kininogens are known to be present in plasma:
A low-molecular-weight form (LMW kininogen) and a highmolecular-weight form (HMW kininogen).
Bradykinin is generated from high molecular weight (hmw)
kininogen by the action of plasma kallikrein.
 On the other hand, kallidin can be produced from both (lmw)
kininogen as well as hmw-kininogen by action of tissue kallikreins.
Bradykinin can also be generated from kallidin on the removal of
lysine residue by amino peptidase.

9.  Kallikreins.
Kallikreins are glycoprotein enzymes produced in the liver as
prekallikreins and present in plasma and in several tissues, including the
kidneys, pancreas, intestine etc.
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 hagemen factor.
Kinins are also generated by trypsin, proteolytic enzymes in snake and
wasp venoms.

10. Hageman factor, prekallikrein and the kininogens leak out of the vessels during inflammation
because of increased vascular permeability, and exposure to negatively charged surfaces
promotes the interaction of Hageman factor with prekallikrein. The activated enzyme then
'clips' bradykinin from its kininogen precursor.

11.  Metabolized rapidly (half-life < 15 seconds).
 By peptidases, commonly referred to as kininases.
Two plasma kininases have been well characterized.
I. Kininase I:- apparently synthesized in the liver, is a carboxypeptidase that releases the
carboxyl terminal arginine residue.
II. Kininase II :- present in plasma and vascular endothelial cell throughout the Body. It is
identical to angiotensin-converting enzyme (ace-peptidyl dipeptidase), inactivates kinins
by cleaving the carboxyl terminal dipeptide,Phenylalanyl-arginine.
Kininase II
bradykinin

12. Des-arg bradykinin
Des-arg kallidin
Kininase II
Inactive fragments

13. Kinin receptors.
 Existence of two types bradykinin receptor has been established : B1 and B2
 Both are GPCR & mediate similar effects.
B1
B2
normally expressed at very low levels but are
strongly induced in inflamed or damaged tissues by
cytokines such as IL-1.
Constitutively expressed in most normal tissues,
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
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

14. B
G
PLA2
PLC
Gq
Arachidonic acid
PG I
Calcium
mobilization
Vascular
endothelium
PIP2
NO
Generation &
Release
 Vasodilation
 Increased permeability
IP3
Smooth
Muscle
 Contraction
DAG

15. ACTIONS OF KININS
Cardiovascular system
 Kinins are more potent vasodilators than ACh and histamine.
 Dilatation is mediated through endothelial NO & PGI2 generation
and involves mainly arterioles.
 They markedly increase capillary permeability due to separation of
endothelial cell exudation and inflammation occurs.
 Larger arteries and most veins are constricted through direct action
on smooth muscle.
 Can release histamine and other mediators from mast cells.
 Injected I.V kinins cause flushing, throbbing headache and fall in
Bp.
 Kinins have no direct action on heart, reflex stimulation occur due
to fall in BP.

16.  Smooth muscle.
 Kinin induced contraction of intestine is slow.
 Cause marked bronchoconstriction in guineapig and in asthmatic
patients.
 Neurones.
 potent pain-producing agent, and its action is potentiated by the
prostaglandins.
 elicit pain by stimulating nociceptive afferents in the skin and
viscera.
 Kidney.
 Kinins increase renal blood flow.
 facilitate salt and water excretion by action on tubules.

17. PAT H O P H Y S I O L O G I C A L R O L E S
1.Mediation of inflammation
Kinins produce all 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 process.
Activation of B2 receptors on macrophages induces production of IL-1 and
TNF-α 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.
B2 antagonist block the acute pain produced by bradykinin.
But induced B1 receptors appear to mediate pain of chronic inflammation.

18. PAT H O P H Y S I O L O G I C A L R O L E S
3.Fuctional hypermia
 Functional hypermia in glands during secretion
 Regulation of microcirculation –especially in kidney may be occurring
through local kinin production.
4. Other roles
 Kinins cause closure of ductus arteriosus, dilation of foetal pulmonary artery
and constriction of umblical vessels-they may be involved in adjusting from
foetal to neonatal circulation.

19. D r u g s a ff e c t i n g k a l l i k r i e n - k i n i n s y s t e m
Drugs that modify the activity of the kallikrein-kinin system are available, though
none are in wide clinical use.
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-desArg9]bradykinin.
Non-peptide B1 receptor antagonists are not yet available.
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.

20. 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.

21. Recently, a 3rd generation of B2 receptor antagonists was 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 bradykinin-induced bronchoconstriction in
guinea pigs, carrageenan-induced inflammatory responses in rats, and capsaicininduced nociception in mice.

22.  The synthesis of kinins can be inhibited with the kallikrein inhibitor
Aprotinin
 Actions of kinins mediated by prostaglandin generation can be blocked nonspecifically with inhibitors of prostaglandin synthesis such as aspirin.
 Conversely, the actions of kinins can be enhanced with ace inhibitors,Which
block the degradation of the peptides.
 Inhibition of bradykinin metabolism by ace-inhibitors contributes
significantly to their antihypertensive action.

24. Reference
Goodman & Gilman's The Pharmacological Basis of Therapeutics
Essentials of Medical Pharmacology byK.D.Tripathi
Bertram G Katzung -Basic and Clinical Pharmacology 9th ED