KININS

.
 Examples

• Bradykinin
• Lysyl-bradykinin (kallidin)
• Methionyllysylbradykinin

• Each contains bradykinin in its structure

• Bradykinin & kallidin are peptides
produced in response to
– Tissue damage
– Allergic reactions
– Viral infections
– Other inflammatory conditions
Synthesis & metabolism
High molecular weight kininogens

plasma & tissue kallikrein

Bradykinin + kallidin

Kininase I & II

Inactive compounds
• Kininase II = angiotensin converting
enzyme

• It is the principal catabolizing enzyme in

the lung & other vascular beds
 Synthesis- 2
Low molecular weight kininogens

tissue kallikrein
Kallidin

Bradykinin
• Kallidin is almost as active as bradykinin
• t½ = 15 seconds
• 80-90 % destroyed in the pulmonary
vascular bed
 Bradykinin receptors
• B1
– Less prevalent than B2
– Upregulated by inflammation, cytokines,
endotoxins and growth factors

• B2
– Subtypes B2A & B2B
– Mediate most of the effects of bradykinin &
kallidin in the absence of inflammation
 Bradykinin receptors
– Activate phospholipase C to produce
• Inositol triphosphate ( Ca   nitric
oxide synthesis & release), &

• Diacyl glycerol (protein kinase C activation)

 Bradykinin receptors
– Activates phospholipase A2

• Liberates arachidonic acid from membrane

bound lipids

• Arachidonic acid is metabolized to potent

inflammatory mediators & the vasodilator
prostacyclin
 Kinin effects
• Powerful algesic agents
– Bradykinin acts on sensory neurons to cause
release of neuropeptides such as substance P

– Mediated through B2 receptors

 Kinin effects
• Produce inflammation
–  permeability in small venules

– Cause edema

– B1 receptors on inflammatory cells eg

macrophages are stimulated to produce
interleukin 1 & TNF- α
 Kinin effects
• Bone
– Stimulate bone resorption

• Respiratory system
– Bronchospasm in asthmatic patients but not
normal individuals

– Sneezing & secretions in allergic rhinitis

 Kinin effects
• CVS
– Vasodilatation & low BP
 Kinin effects
• Renal system
–  Renal blood flow
 Kallikrein inhibitors
• Aprotinin

– It inhibits kallikrein & plasmin

• Ecallantide
– Used in hereditary angioedema
• Icatibant
– a second generation B2 receptor antagonist

• Non steroidal anti-inflammatory drugs

(NSAID)
– Oppose bradykinin actions mediated through
prostaglandin production
 Interaction between Angiotensin converting enzyme
inhibitors (ACE-I) & Bradykinin

• Prevent conversion of
Angiotensin I to
Angiotensin II

• Bradykinin contributes to
the effects of these drugs
– Vasodilatation
– Angioedema
– Anaphylaxis
– Chronic nonproductive
cough which reverses
when the drug is
stopped
.

OTHER EICOSANOIDS
LEUKOTRIENES &
THROMBOXANE
.
 Introduction
• Leukotrienes, prostaglandins & other
related compounds are derived from 20
carbon (eicosa) fatty acids.

• Thus called Eicosanoids.

 Eicosanoids
• Are produced in response to immunological & non
immunological stimuli.

• Comprise:
– prostaglandins
prostanoids
– thromboxanes
– leukotrienes
– lipoxins
– hydroxyeicosatetraenoic acids (HETEs)
– hepoxilins
• Eicosanoids, like hormones, display profound
effects at extremely low concentrations

• They have a very short half-life, thus act

locally

• Leukotrienes are four times more potent than

histamine & have a longer duration of action
(LTC4, LTD4, and LTE4 = the slow-reacting
substance of anaphylaxis)
 Main sites of eicosanoid biosynthesis
• Endothelial cells
• Leukocytes
• Platelets
• Kidney

• Unlike histamine, eicosanoids are NOT synthesized

in advance and stored in granules – when needed,
they can be produced very quickly from
arachidonate released from cell membranes.
 Eicosanoid biosynthesis

• 3 pathways:
A) Cyclooxygenase (COX) – produces prostaglandins and
thromboxanes

B) Lipoxygenase (LO) – produces leukotrienes, lipoxins, 12-

and 15-HETEs, and hepoxilins

C) Cytochrome P450s (monooxygenases) – produce the

other HETEs (20-HETE); principal pathway in the renal
proximal tubules
 Leukotriene synthesis pathway
• Stimulation of leukotriene producing cells leads to
arachidonic acid release by Phospholipases.

• 5 Lipoxygenase then metabolizes arachidonic acid

into hydroperoxyeicosatetraenoic acid (HPETE).

• A nuclear membrane protein FLAP (5-

lipoxygenase activating protein) is needed along
with oxygen to convert A.A into HPETE.
• 5 lipoxygenase catalyzes conversion of
.

HPETE into HETE

(hydroxyeicosatetraenoic acid), then to
LTA4.

• LTA4 is an intermediate compound and

either converts into dihydroxyleukotrienes
(LTB4) or conjugates with glutathione to
yield cysteinyl leukotrienes (LTC4).
Summary..
 Metabolism
• The limited amounts of leukotrienes that
are available in the body at the same time
allows for a large degree of control.

• They are metabolized rapidly, allowing the

body to increase or decrease their
amounts very quickly.

• Their half life is less than 5 minutes.

 Mechanism of Leukotriene
Action
• Is via Leukotriene receptors:
1) Leukotriene B4 receptors (BLT
Receptors)

2) Cysteinyl Leukotriene Receptors

(CYSLTR Receptors)
 a. BLT Receptors

• Include:
1) BLTR1 2) BLTR2

• Signaling pathway :
Are G Protein coupled receptors associated
with Gq → activate Gq protein → Gq
stimulates membrane bound phospholipase
C which cleaves PIP2 into two second
messengers, IP3 & DAG.
 .

• DAG remains bound to the membrane

• IP3 is released as a soluble structure into

cytosol & binds calcium channels, causing
an increase in Ca and release of pro
inflammatory mediators.
 Effects
• LTB4 primarily acts as a potent chemo
attractant for granulocytes

• Causes adhesion of granulocytes to the

vascular endothelium

• Increases vascular permeability

 b. CYSLTR Receptors
• Cysteinyl Leukotrienes include LTC4, LTD4 &
LTE4

• Work via:
i. CYSLTR1 Receptors- activated by LTD4.
ii. CYSLTR2 Receptors- activated by LTC4,
LTD4 & LTE4.

• Their signaling pathway is similar to that of

BLT receptors (Gq associated).
 Effects
• Constriction of airway smooth muscles
• Increased mucus secretion
• Decreased mucociliary clearance
• Increased vascular permeability
• Edema
 .

• The cysteinyl leukotriene receptors are

involved in the pathophysiology of
bronchial asthma, rhinitis & atopic
dermatitis.
.

THROMBOXANES
.
 Mechanism of action
• Mediated via Thromboxane receptors

• Are G protein coupled receptors (coupled

to Gq protein)
 Biological role of thromboxanes

• Thromboxanes are synthesized by platelets and, in

general, cause vasoconstriction and platelet
aggregation

• TXA2 is also produced in the kidney (by podocytes

and other cells) where it causes vasoconstriction and
mediates the response to angiotensin II.
 Thromboxane Inhibitors
• Aspirin- inhibits COX, thus inhibiting
synthesis of thromboxane precursors
within platelets

• Ifetroban- Thromboxane receptor

antagonist
.

THE END