Prostaglandins and leukotrienes are biologically active derivatives of essential fatty acids that act as autacoids. Leukotrienes are produced locally at sites of injury and inflammation where they cause plasma exudation and attract inflammatory cells. They are potent bronchoconstrictors and mediators of asthma. Separate receptors have been identified for leukotrienes. Angiotensin causes vasoconstriction and increases blood pressure by stimulating aldosterone release. Bradykinin causes vasodilation and increased capillary permeability, leading to inflammation. Substance P is a neurotransmitter and neuromodulator that acts as a vasodilator and regulates various biological processes.

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PROSTAGLANDINS AND LEUKOTRIENES (Eicosanoids)
• Prostaglandins (PGs) and Leukotrienes (LTs) are biologically active
derivatives of 20 carbon atom polyunsaturated essential fatty acids that
are released from cell membrane phospholipids. They are the major lipid
derived autacoids.
Leukotrienes
The straight chain lipoxygenase products of arachidonic acid are produced by
a more limited number of tissues (LTB4 mainly by neutrophils; LTC4 and
LTD4—the cysteinyl LTs—mainly by macrophages), but probably they are
pathophysiologically as important as PGs.
1. CVS and blood
• LTC4 and LTD4 injected IV. evoke a brief rise in BP followed by a more
prolonged fall.
• The fall in BP is not due to vasodilatation because no relaxant action has
been seen on blood vessels.

2. 2 RISHITA PATEL_PHARMACOLOGY-II_ IICP
• It is probably a result of coronary constriction induced decrease in
cardiac output and reduction in circulating volume due to increased
capillary permeability.
• These LTs markedly increase capillary permeability and are more
potent than histamine in causing local edema formation.
• LTB4 is highly chemotactic for neutrophils and monocytes.
• Migration of neutrophils through capillaries and their clumping at
sites of inflammation in tissues is also promoted by LTB4.
• The cysteinyl LTs (C4, D4) are chemotactic for eosinophils.
Role:
• LTs are important mediators of inflammation.
• They are produced (along with PGs) locally at the site of injury.
While LTC4 and D4 cause exudation of plasma, LTB4 attracts the
inflammatory cells which reinforce the reaction.
• 5-HPETE (5-hydroperoxyeicosatetraenoic acid, 5-HPETE) and 5-
HETE (5-hydroxyeicosatetraenoic acid) may facilitate local release
of histamine from mast cells.
2. Smooth muscle
• LTC4 and D4 contract most smooth muscles.
• They are potent broncho-constrictors and induce spastic contraction of
g.i.t. at low concentrations. They also increase mucus secretion in the
airways.
Role

3. 3 RISHITA PATEL_PHARMACOLOGY-II_ IICP
• The cysteinyl LTs (C4 and D4) are the most important mediators of
human allergic asthma.
• They are released along with PGs and other autacoids during AG: AB
reaction in the lungs.
• In comparison to other mediators, they are more potent and are
metabolized slowly in the lungs, exert a long-lasting action. LTs may
also be responsible for abdominal colics during systemic anaphylaxis.
3. Afferent nerves
The LTB4 also sensitizes afferents carrying pain impulses—contributes to
pain and tenderness of inflammation.
LEUKOTRIENE RECEPTORS
• Separate receptors for LTB4 (BLT1 and BLT2) and for the cysteinyl LTs
(LTC4, LTD4) have been defined.
• Two subtypes, cysLT1 and cysLT2 of the cysteinyl LT receptor have been
cloned.
• All LT receptors couple with Gq protein and function through the
IP3/DAG transducer mechanism.
• The BLT receptors are chemotactic and primarily expressed in
leucocytes and spleen.
• BLT1 receptor has high, while BLT2 receptor has lower affinity for
LTB4.
• The cysLT1 receptor is mainly expressed in bronchial and intestinal
muscle and has higher affinity for LTD4 than for LTC4.
• The primary location of cysLT2 receptor is leucocytes and spleen, and it
shows no preference for LTD4 over LTC4.

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• The cysLT1 receptor antagonists, viz. Montelukast, Zafirlukast, etc. are
now valuable drugs for bronchial asthma.
Angiotensin
is a peptide hormone that causes vasoconstriction and an increase in blood
pressure. It is part of the renin–angiotensin system, which regulates blood
pressure.
Angiotensin also stimulates the release of
aldosterone from the adrenal cortex to promote
sodium retention by the kidneys.

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Bradykinin (BK)
• (Greek brady-, slow; -kinin, kīn(eîn) to move) is a peptide that promotes
inflammation.
• It causes arterioles to dilate (enlarge) via the release of prostacyclin,
nitric oxide, and endothelium-derived hyperpolarizing factor and
makes veins constrict, via prostaglandin F2, thereby leading to leakage
into capillary beds, due to the increased pressure in the capillaries.
• Bradykinin consists of nine amino acids, and is a physiologically and
pharmacologically active peptide of the kinin group of proteins.
• A class of drugs called angiotensin-converting-enzyme inhibitors (ACE
inhibitors) increase bradykinin levels by inhibiting its degradation,
thereby increasing its blood pressure lowering effect.
• ACE inhibitors are FDA approved for the treatment of hypertension and
heart failure.
Substance P (SP)
• SP is an undecapeptide (a peptide composed of a chain of 11 amino acid
residues) and a type of neuropeptide, belongings to the tachykinin family
of neuropeptides.
• It is acts as a neurotransmitter and a neuromodulator.
• Substance P and its closely related neurokinin A(NKA) are produced from
a polyprotein precursor after alternative splicing of the
preprotachykinin A gene.
• Substance P is a potent vasodilator. Substance P-induced vasodilation is
dependent on nitric oxide release.
• SP initiates expression of almost all known immunological chemical
messengers (cytokines).

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• Substance P has been associated with the regulation of mood
disorders, anxiety, stress, reinforcement, neurogenesis.
• substance P has been known to stimulate cell growth in normal and
cancer cell line cultures, and it was shown that substance P could promote
wound healing of non-healing ulcers in humans.