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Bradykinin by sid
Bradykinin by sid
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History.
Generation and metabolism.
Receptors ( B1 and B2).
Pharmacological actions.
Pathophysiological roles.
Drugs affecting the bradykinin system.
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.
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."
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.
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).
 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.
 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.
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.
 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
Des-arg bradykinin
Des-arg kallidin

Kininase II
Inactive fragments
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
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
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.
 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.
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.
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.
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.
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.
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.
 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.
Bradykinin by sid
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

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Bradykinin by sid

  • 3. 1. 2. 3. 4. 5. 6. 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
  • 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

Hinweis der Redaktion

  1. A number of factors, including tissue damage, allergic reactions, viral infections, and other inflammatory events, activate a series of proteolytic reactions that generate bradykinin and kallidin in the tissues. These peptides contribute to inflammatory responses as autacoids.This term is derived from greek:autos-self , akos-healing substance or remedy.These are diverse(widely varied) substances produced by a wide variety of cells in the body, having intensebiological activity, but generally act locally (e.g.within inflammatory pockets) at the site ofsynthesis and release.They have also been called&apos;local hormones&apos;.However, they differ from &apos;hormones&apos; in two important ways-hormones are produced byspecific cells, and are transported through circulation to act on distant target tissues.Autacoids are involved in a number of physiological and pathological processes( especialiyreaction to injury and immunological insult) and even serve as transmitters or modulators in thenervous system, but their role at many sites is not precisely known. A number of useful drugs actby modifying their action or metabolism. The classical autacoids are-Amine autacoids Histamine, S-Hydroxytryptamine(Serotonin)Lipid derived autacoids Prostaglandins,Leukotrienes,Platelet activating factorPeptide autacoids Plasma kinins (Bradykinin,Kallidin), AngiotensinIn addition, cytokines (interleukins, TNFU,GM-CSF etc.) and several peptides like gastrin,somatostatin, vasoactive intestinal peptideand many others may be considered as autacoids.
  2. A number of interesting discoveries have contributed to the elucidation of the functions of kinins
  3. Kininogens—the precursors of kinins and substrates of kallikreins—are present in plasma, lymph, and interstitial fluid.
  4. Specific enzymes that inactivate bradykinin and related kinins are called kininases.One of these, kininase II, is a peptidyldipeptidase that inactivates kinins by removing the two C-terminal amino acids. This enzyme, which is bound to the luminal surface of endothelial cells, is identical to angiotensin-converting enzyme which cleaves the two C-terminal residues from the inactive peptide angiotensin I, converting it to the active vasoconstrictor peptide angiotensin II. Thus kininase II inactivates a vasodilator and activates a vasoconstrictor. bradykinin actions by ACE inhibitors may Kinins are also metabolised by various less specific peptidases, including a serum carboxypeptidase that removes the C-terminal arginine, generating des-Arg9-bradykinin, a specific agonist at one of the two main classes of bradykinin receptor
  5. Kinin metabolites released by basic carboxypeptidases that were formally considered inactive degradation products are agonists of a receptor (B1) that differs from that of intact kinins (B2), whose expression is induced by tissue injury. Kinins and their des-Arg metabolites also release vasoactive agents and may be mediators of inflammation and pain. These findings may open novel avenues for therapeutic intervention in chronic inflammatory conditions.
  6. 2.Considerable effort has been directed toward developing kinin receptor antagonists,since such drugs have considerable therapeutic potential as anti-inflammatory and antinociceptiveagents.