The document details the history, generation, metabolism, and physiological roles of bradykinin and angiotensin, two key peptides involved in blood pressure regulation and inflammation. Bradykinin is a potent vasodilator derived from kininogens acted on by kallikreins, while angiotensin II, generated from angiotensin I, plays a critical role in blood pressure homeostasis and fluid balance. It also discusses the pharmacological implications of these peptides, including their antagonists and inhibitors in clinical contexts.

2. History.
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. History.
 In 1960, the nonapeptide bradykinin was isolated.
Shortly thereafter, kallidin was found to be a decapeptide-
bradykinin with an additional lysine residue at the amino terminus.
kallidin and bradykinin are referred to as plasma kinins.

4. 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).

5. Two kininogens are known to be present in plasma:
A low-molecular-weight form (LMW kininogen) and a high-
molecular-weight form (HMW kininogen).
Bradykinin is generated from high molecular weight (HMW)
kininogen by the action of plasma kallikrein.
 Kininogens.

6. Kallikreins are glycoprotein enzymes produced in the liver as
prekallikreins and present in plasma, kidneys, pancreas, intestine etc.
Prekallikrein is activated by hageman factor (factor xii) which itself is
activated by tissue injury.
Kinins are also generated by trypsin, proteolytic enzymes in snake and
wasp venoms.
 Kallikreins.

7. 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.

8.  Metabolized rapidly (half-life < 15 seconds).
 By peptidases ( 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).
arg pro pro Gly phe Ser Pro Phe arg
Kininase II
bradykinin

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

10. Kinin receptors.
B1
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
 Existence of two types bradykinin receptor has been established : B1 and B2
 Both are GPCR & mediate similar effects.
B2
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

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

12. 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.
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.

13.  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.

14. PATHOPHYSIOLOGICAL ROLES
1.Mediation of inflammation
Kinins produce all signs of inflammation-redness, exudation, pain and
leukocyte mobilization.
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.

15. PATHOPHYSIOLOGICAL ROLES
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.

16. 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.

17.  The synthesis of kinins can be inhibited with the kallikrein inhibitor
Aprotinin
 Actions of kinins mediated by prostaglandin generation can be blocked non-
specifically 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.

33.  Angiotensin II is a an Octapeptide generated in plasma from a precursor
plasma alpha globulin
 Involved in the electrolyte, blood volume and pressure homeostasis.
 Active material was termed Renin, in the 1940 renin was shown to be an
enzyme which acted indirectly by producing a pressor principle from plasma
protein
 Angiotensin-I to Angiotensin II by ACE to Angiotensin III to Anigotensin IV by
aminopeptidases

35.  Amount on renin acts as a limiting factor for Ang II generation
 Plasma t half is 15 min, biological potency of Ang I is only 1/100 of Ang II,
biological potency of Ang III is 1/10 times of Ang II
 Circulating Ang II has a half life of 1 minute
 Ang I is rapidly converted into latter by ACE which is a dipeptidyl
carboxypeptidase , an ectoenzyme located primiraly on liminal surface of
vascular endothelial cells (especially lungs)
 Ang III is converted to Ang IV by aminopeptidases has very different central
actions through AT4 receptors

36. Activation of prorenin and renin is by two ways
1. Ang II independent pathway
2. Ang II dependent pathway
 Alternative ACE independent pathway of Ang II
production
 Along with cathepsin, moreover chymase can
convert Ang I to Ang II particulary in heart and
kidney
 Angiotensin IV -AT4 Receptor, binding prevents
degradation of neuropeptides involved in
congnitive function and memory in animals
 Thus Ang IV improves Memory and also have
vascular, peripheral, renal effects

37. ACTIONS OF ANGIOTENSION
1. CVS: prominent action of Ang II is vasoconstriction, directly by releasing
Adrenaline, noradrenaline from adrenal medulla , adrenergic nerve endings.
• Ang II injected I.V is much more potent than NA as a pressor agent.
• Long term infusion of low concentration of Ang II produces progressive and
sustained rise in BP ,by its renal effects promoting salt and water
reabsorption
2. Smooth muscle: Ang II contracts many visceral smooth in vitro, but in vivo
effects are insignificant
3. Adrenal cortex: Ang II and Ang III are trophic to zona glomerulosa, they
enhance synthesis and release of aldosterone to promote Na reabsorption and
K+/H+ excretion.
There acquire in concentration lower then required for vasoconstriction

38. 4. Kidney : Inaddition to indirect effect on kidney through aldosterone, it promotes
Na+/H+ and HCO-3 reabsorption
Further Ang II reduces renal blood flow and GFR, normally results in Na+
and water retention.
5. CNS: Systemically administered Ang II can gain access to certain perivascular
space of brain to induce drinking behavior and ADH release- both of these
are conductive to plasma volume expansion
Note: Brain has its own RAS and generates its own Ang II
6.Peripheral sympathetic structure: it enhances adrenaline action by peripheral
stimulation also , it releases Adr from adrenal medulla, stimulates autonomic
ganglia and increases the amount of NA from adrenergic nerve endings

39. PATHOPHYSIOLOGICALACTIONS
1. Mineralocorticoids secretion: Ang II and also Ang III are the physiological
stimulus for aldosterone secretion from adrenal cortex.
2. Electrolyte, blood volume and pressure homeostasis: changes that lower
blood volume or blood pressure or decrease Na+ content induce renin release
by three mechanism
a. Intrarenal baroreceptor pathway-increase PGs and stretch sensitive ion
channel
b. Macula densa pathway: COX-2 and nNOS are induced in macula densa
cells by Na+ depletion leads to release of PGE2 and PGI2 and acts on
juxtoglomerular cells to promote renin
c. Beta adrenoceptor pathway: baroreceptor and other reflexes which
increase sympathetic impulses to JG cell activate B2 leads to cAMP triggers
renin release

40. 3. Development of hypertension : RAS is directly involved in renovascular
hypertension, plasma renin activity is rised in most of the patients, positive
correlation is between circulating angiotensinogen levels and essential
hypertension, also may cause pregnancy induced hypertension
4. Secondary hyperaldosteronism: Instrumental in development of secondary
hyperaldosteronism
5. CNS: Ang II can be formed locally in brain and may function as transmitter or
modulator, regulation of thirst, hormone release and sympathetic outflow

41. Inhibition of RAS
1. Sympathetic blocker ( Beta blockers, adrenergic neurone blockers, central
sympatholytics)
2. Direct renin inhibitors (DRIs)
3. Angiotensin converting enzyme inhibitors (ACE inhibitors)
4. Angiotensin receptor blockers (ARBs)
5. Aldosterone antagonists