pharmacology of bradykinin , pentagastrin, cholecystokinin and angiotensin

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."

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.

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).

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.

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.

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 ( KININASES).

Two plasma kininases have been well characterized.

I. Kininase I:- apparently synthesized in the liver, is a carboxypeptidase that releasesthe carboxyl terminal arginine residue.

II. Kininase II :- present in plasma and vascular endothelial cell throughout the Body. Itis identical to angiotensin-converting enzyme (ace-peptidyl dipeptidase).

arg pro pro Gly phe Ser Pro Phe arg

Kininase II

bradykinin

Des-arg bradykinin

Des-arg kallidin

Kininase II

Inactive fragments

Kinin receptors.

B1

normally expressed at very low levels but arestrongly induced in inflamed or damaged tissues bycytokines 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

B

Gq

PLC PIP2

IP3 DAGCalcium

mobilization

Vascular

endothelium

NO

Generation &

Release SmoothMuscle

Vasodilation

Increased permeability Contraction

G

PLA2 Arachidonic acid PG I

ACTIONS OF KININS

Cardiovascular system

Kinins are more potent vasodilators than ACh and histamine.

Dilatation is mediated through endothelial NO & PGI2 generationand involves mainly arterioles.

They markedly increase capillary permeability due to separation ofendothelial cellexudation and inflammation occurs.

Injected I.V kinins cause flushing, throbbing headache and fall inBp.

Kinins have no direct action on heart, reflex stimulation occur dueto 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.

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.

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.

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 endogenousbradykinin and in human studies to evaluate the role of kinins in inflammation,Pain and hyperalgesia.

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.

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

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

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

ACTIONS OF ANGIOTENSION1. 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

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

PATHOPHYSIOLOGICAL ACTIONS1. 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

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

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