What are prostaglandins / What does prostaglandin do in females? Prostaglandins, Leukotrienes (Eicosanoids) and Platelet Activating Factor /
Prostaglandins, Leukotrienes (Eicosanoids) and Platelet Activating Factor :
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.
In the 1930s human semen was found to contract
isolated uterine and other smooth muscle strips and to
cause fall in BP in animals. The active principle was
termed ‘prostaglandin’, thinking that it was derived
from prostate. Only in the 1960s it was shown to be
a mixture of closely related compounds, the chemical
structures were elucidated and widespread distribution in
the body was revealed. In 1970s it became clear that
aspirin like drugs act by inhibiting PG synthesis, and
that in addition to the classical PGs (PGEs and PGFs),
thromboxane (TX), prostacyclin (PGI) and leukotrienes
(LTs) were of great biological importance. Bergstrom,
Samuelsson and Vane got the Nobel prize in 1982 for
their work on PGs and LTs. Over the past 40 years
PGs and LTs have been among the most intensely
investigated substances.
CHEMISTRY, BIOSYNTHESIS AND DEGRADATION :
Chemically, PGs may be considered to be derivatives of prostanoic acid, though prostanoic
acid does not naturally occur in the body. It
has a five membered ring and two side chains
projecting in opposite directions at right angle
to the plane of the ring. There are many series
of PGs and thromboxanes (TXs) designated A,
B, C....I, depending on the ring structure and
the substituents on it. Each series has members
with subscript 1, 2, 3 indicating the number
of double bonds in the side chains.
Leukotrienes are so named because they were
first obtained from leukocytes (leuko) and have 3 conjugated double bonds (triene). They have
also been similarly designated A, B, C.....F and
given subscripts 1, 2, 3, 4.
Eicosanoids are the most universally distributed autacoids in the body. Practically every
cell and tissue is capable of synthesizing one
or more types of PGs or LTs. As such, they
have potent and a very wide range of biological activity. The pathways of biosynthesis
of eicosanoids are summarized in Fig. 13.1.
There are no preformed stores of PGs and
LTs. They are synthesized locally and the rate
of synthesis is governed by the rate of release
of arachidonic acid from membrane lipids in response to appropriate stimuli. These stimuli
activate hydrolases, including phospholipase A,
probably through increased intracellular Ca2+.
Cyclooxygenase (COX) pathway :
It generates
eicosanoids with a ring structure (PGs, TXs,
prostacyclin) while lipoxygenase (LOX) produces open chain compounds (LTs). All tissues have
COX—can form cyclic endoperoxides PGG2
and
PGH2
which are unstable compounds. Further
course in a particular tissue depends on the type
of isomerases or other enzymes present in
it. PGE2
and PGF2α are the primary prostaglandins (name based on the separation
procedure: PGE partitioned into Ether while
PGF into phosphate [Fosfat in Swedish]
buffer; α in PGF2α refers to orientation of
OH group on the ring). PGs A, B and C
are not found in the body: they are artifacts
formed during extraction procedures. Lung
and spleen can synthesize the whole range of
COX products. Platelets primarily synthesize
TXA2
which is—chemically unstable, spontaneously changes to TXB2
. Endothelium mainly generates prostacyclin (PGI2
) which is also
chemically unstable and rapidly converts to
6-keto PGF1α.
Cyclooxygenase is known to exist in two
isoforms COX-1 and COX-2. While both
isoforms catalyse the same reactions, COX-1
is a constitutive enzyme in most cells—it is
synthesized and is active in the basal state; the
level of COX-1 activity is not much changed
once the cell is fully grown. On the other
hand, COX-2 normally present in insignificant
amounts, is inducible by cytokines, growth factors and other stimuli during the inflammatory
response. It is believed that eicosanoids produced
by COX-1 participate in physiological (house
keeping) functions such as secretion of mucus
for protection of gastric mucosa, haemostasis
and maintenance of renal function, while those
produced by COX-2 lead to inflammatory and
other pathological changes. However, certain
sites in kidney, brain and the foetus constitutively express COX-2 which may play
physiological role.
A splice variant of COX-1 (designated COX-3) has
been found in the dog brain. This isoenzyme is inhibited
by paracetamol and is implicated in the genesis of fever,
but the exact role in humans is not known.
Lipoxygenase pathway :
This pathway
appears to operate mainly in the lung, WBC
and platelets. Its most important products are
the LTs, (generated by 5-LOX) particularly
LTB4
(potent chemotactic) and LTC4
, LTD4
which together constitute the ‘slow reacting
substance of anaphylaxis’ (SRS-A) described
in 1938 to be released during anaphylaxis. A
membrane associated transfer protein called
FLAP (five lipoxygenase activating protein)
carrys arachidonic acid to 5-LOX, and is essential for the synthesis of LTs. Platelets have
only 12-LOX.
\
Apart from PGs and LTs, a number of other active products
can be generated from arachidonic acid at certain sites.
HPETEs produced by LOX can also be converted to hepoxilins, trioxilins and lipoxins. A third enzymatic pathway
involving cytochrome P450 can metabolize arachidonic
acid into 19- and 20-HETEs and epoxyeicosatrienoic acids.
Free radicals can attack arachidonic acid to produce isoprostanes nonenzymatically. Brain cells couple arachidonic
acid with ethanolamine to produce anandamide and a few
other related eicosanoids which are now recognized to
be the endogenous cannabinoid receptor ligands. Accordingly, they produce cannabis like effects. Like the other
eicosanoids, they are synthesized only when needed at
the site of action.
Inhibition of synthesis :
Synthesis of COX
products can be inhibited by nonsteroidal antiinflammatory drugs (NSAIDs). Aspirin acetylates
COX at a serine residue and causes irreversible
inhibition, while other NSAIDs are competitive
and reversible inhibitors. Most NSAIDs are
nonselective COX-1 and COX-2 inhibitors, but
some later ones like celecoxib, etoricoxib are
selective for COX-2.
The sensitivity of COX in different tissues
to inhibition by these drugs varies; selective
inhibition of formation of certain products
may be possible at lower doses. NSAIDs do
not inhibit the production of LTs. Rather, LT
production may be increased since all the
arachidonic acid becomes available to the
LOX pathway.
Zileuton inhibits LOX and decreases the production
of LTs. It was used briefly in asthma, but has been
withdrawn.
Glucocorticosteroids inhibit the release of
arachidonic acid from membrane lipids (by
enhancing production of proteins called annexins
which inhibit phospholipase A2
). Production
of all eicosanoids—PGs, TXs and LTs is
indirectly curtaited. Moreover, steroids inhibit
the induction of COX-2 by cytokines at the
site of inflammation.
Degradation :
Biotransformation of arachidonates
occurs rapidly in most tissues, but fastest in the
lungs. Most PGs, TXA2
and prostacyclin have
plasma t½ of a few seconds to a few minutes.
First a specific carrier mediated uptake into cells
occurs, the side chains are then oxidized and double
bonds are reduced in a stepwise manner to yield
inactive metabolites. Metabolites are excreted in
urine. PGI2
is catabolized mainly in the kidney.
ACTIONS AND PATHOPHYSIOLOGICAL ROLES :
Prostaglandins, thromboxanes and prostacyclin :
The cyclic eicosanoids produce a wide variety
of actions depending upon the particular PG (or
TX or PGI), species on which tested, tissue,
hormonal status and other factors. PGs differ
in their potency to produce a given action and
different PGs sometimes have opposite effects.
Even the same PG may have opposite effects
under different circumstances. The important
actions of PGs and TXA2
are summarized in
Table 13.1. Since virtually all cells and tissues
are capable of forming one or more PGs, these
autacoids have been implicated as mediators
or modulators of a number of physiological
processes and pathological states.
1. CVS :
PGE2
causes vasodilatation in most,
but not all, vascular beds. PGF2α constricts
many larger veins including pulmonary vein
and artery. Fall in BP occurs when PGE2
is
injected i.v., but PGF2α has little effect on BP.
- PGI2 is uniformly vasodilatory and is more potent hypotensive than PGE2 .
- TXA2 consistently produces vasoconstriction.
- PGE2 and F2α stimulate heart by weak direct but more prominent reflex action due to fall in BP. The cardiac output increases.
Role :
- PGs do not circulate in blood and have no role in regulating systemic vascular resistance. However, PGI2 generated in the vascular endothelium, mainly by COX-2, appears to be involved in the regulation of local vascular tone as a dilator.
- PGE2 is continuously produced locally in the ductus arteriosus by COX-2 during foetal life and keeps it patent. At birth its synthesis stops and closure occurs. Aspirin and indomethacin induce closure when it fails to occur spontaneously.
- PGs, generated mainly by COX-2, along with LTs and other autacoids may mediate vasodilatation and exudation at the site of inflammation.
2. Platelets :
TXA2
, which can be produced
locally by platelets, is a potent inducer of aggregation and release reaction. On the other hand
PGI2
(generated by vascular endothelium) is a
potent inhibitor of platelet aggregation. PGE2
has dose dependent pro- and anti-aggregatory
effects.
Role :
TXA2
produced by platelets and PGI2
produced by vascular endothelium probably
constitute a mutually antagonistic system:
preventing aggregation of platelets while in
circulation and inducing aggregation on injury,
when plugging and thrombosis are needed.
Aspirin interferes with haemostasis by inhibiting platelet aggregation. TXA2
produced by
platelet COX-1 plays an important role in
amplifying aggregation. Before it is deacetylated
in liver, aspirin acetylates COX-1 in platelets
while they are in portal circulation. Further,
platelets are unable to regenerate fresh COX-1
(lack nucleus: do not synthesize protein), while
vessel wall is able to do so (fresh enzyme is
synthesized within hours). Thus, at low doses, aspirin selectively inhibits TXA2
production
and has antithrombotic effect lasting > 3 days.
3. Uterus :
PGE2
and PGF2α consistently
contract human uterus in vivo, both pregnant as
well as nonpregnant. The sensitivity is higher
during pregnancy and there is progressive
modest increase with the advance of pregnancy.
However, even during early stages, uterus is
quite sensitive to PGs though not to oxytocin.
PGs increase basal tone as well as amplitude
of uterine contractions.
At term, PGs soften the cervix at low doses
and make it more compliant.
Role :
- Foetal tissues produce PGs. At term PGF2α has been detected in maternal blood. It is postulated that PGs mediate initiation and progression of labour. Aspirin has been found to delay the initiation of labour and also prolong its duration.
- Dysmenorrhoea in many women is associated with increased PG synthesis by the endometrium. This apparently induces uncoordinated uterine contractions which compress blood vessels causing uterine ischaemia and pain. Aspirin group of drugs are highly effective in relieving dysmenorrhoea in most women.
4. Bronchial muscle :
PGF2α, PGD2
and TXA2
are potent bronchoconstrictors (more potent
than histamine) while PGE2
is a powerful
bronchodilator. PGI2
produces mild dilatation.
Asthmatics are more sensitive to constrictor as
well as dilator effects of PGs. PGE2
and PGI2
also inhibit histamine release and are effective
by aerosol. However, these antiasthmatic effects
of PGE2
and PGI2
cannot be exploited clinically
because they produce irritation of the respiratory tract and have brief action.
Role :
Asthma may be due to an imbalance
between constrictor PGs (F2α, PGD2
, TXA2
)
and cysteinyl LTs on one hand and dilator
ones (PGE2
, PGI2
) on the other. In few individuals aspirin-like drugs consistently induce
asthma, possibly by diverting arachidonic acid
to produce excess LTC4
and D4
. This sensitivity is not shared by selective COX-2 inhibitors,
indicating that suppression of COX-1 at the
pulmonary site is responsible for the reaction.
In allergic human asthma, LTs play a more
important role, and COX inhibitors are without
any effect in most patients.
5. GIT :
(i) In isolated preparations, the longitudinal
muscle of gut is contracted by PGE2
and PGF2α
while the circular muscle is either contracted
(usually by PGF2α) or relaxed (usually by
PGE2
). Propulsive activity is enhanced in man,
especially by PGE2
. This can cause colic and
watery diarrhoea, which are important side
effects. PGE2
acts directly on the intestinal
mucosa and increases water, electrolyte and
mucus secretion.
Role :
PGs may be involved in mediating toxin
induced increased fluid movement in secretory
diarrhoeas. In certain diarrhoeas, aspirin can
reduce stool volume, but it is not uniformly
effective. PGs appear to play a role in the
growth of colonic polyps and cancer. Association
of lower incidence of colon cancer with regular
intake of aspirin is now established. NSAIDs
afford relief in familial colonic polyposis by
reducing polyp formation.
(ii) PGE2
markedly reduces acid secretion in
the stomach. Volume of juice and pepsin content are also decreased. It inhibits fasting as
well as stimulated secretion. Release of gastrin
is suppressed (see Fig. 47.1). The gastric pH
may rise upto 7.0. PGI2
also reduces gastric
secretion, but is less potent. Secretion of mucus
and HCO3
¯ by gastric mucosal epithelial cells
is increased, as is mucosal blood flow. Thus,
PGs are antiulcerogenic.
Role :
PGs (especially PGI2
) appear to be
involved in the regulation of gastric mucosal
blood flow. They may be functioning as natural
ulcer protectives by enhancing gastric mucus
and HCO3
¯ production, as well as by improving
mucosal circulation and health. The ulcerogenic
action of NSAIDs appears to be due to loss
of this protective influence.
Normally, gastric mucosal PGs are produced by COX1.
Selective COX-2 inhibitors are less ulcerogenic. However,
COX-2 gets induced during ulcer healing, and COX-2
inhibitors have the potential to delay healing.
6. Kidney :
PGE2
and PGI2
increase water, Na+
and K+ excretion and have a diuretic effect.
PGE2
has a furosemide-like inhibitory effect
on Cl¯ reabsorption as well. They cause renal
vasodilatation and inhibit tubular reabsorption.
PGE2
attenuates ADH action, and this adds to
the diuretic effect. In contrast, TXA2
causes
renal vasoconstriction. PGI2
, PGE2
and PGD2
evoke release of renin.
Role :
- PGE2 and PGI2 produced mainly by COX2 in the kidney appear to function as intrarenal regulators of blood flow as well as tubular reabsorption in kidney. Accordingly, the NSAIDs, including selective COX-2 inhibitors, tend to retain salt and water. The diuretic action of furosemide is blunted by indomethacin—indicating a facilitatory role of PGs by increasing renal blood flow and/or augmenting inhibition of tubular reabsorption.
- Renin release in response to sympathetic stimulation, low salt intake and other influences may be facilitated by PGs.
7. CNS :
PGs injected i.v. penetrate brain
poorly, so that central actions are not prominent. However, injected intracerebroventricularly
PGE2
produces a variety of effects—sedation,
rigidity, behavioural changes and marked rise
in body temperature. PGI2
also induces fever,
but TXA2 is not pyrogenic.
Role :
- PGE2 may mediate pyrogen induced fever and malaise. Aspirin and other inhibitors of PG synthesis are antipyretic. Pyrogens, including cytokines, released during bacterial infection trigger synthesis of PGE2 in the hypothalamus which resets the thermostat to cause fever. COX-2 is the major isoenzyme involved; selective COX-2 inhibitors are equally efficacious antipyretics. A role of COX-3 has also been proposed.
- PGs may be functioning as neuromodulators in the brain by regulating neuronal excitability. A role in pain perception, sleep and some other functions has been suggested.
8. Sympathetic nerves :
Depending on the PG, species
and tissue, both inhibition as well as augmentation of NA
release from sympathetic nerve endings has been observed.
However, PGE2
mostly inhibits NA release.
Role :
PGs may modulate sympathetic neurotransmission
in the periphery.
9. Peripheral nerves :
PGs (especially E2
and I2
) sensitize afferent nerve endings to pain
inducing chemical and mechanical stimuli (Fig.
13.2). They irritate mucous membranes and
produce long lasting dull pain on intradermal
injection.
Role :
PGs serve as algesic agents during
inflammation. They cause tenderness and
amplify the action of other algesics. Inhibition
of PG synthesis is a major antiinflammatory
mechanism. Aspirin injected locally decreases
pain produced by injection of bradykinin at
the same site. Moreover, PGs released in the
dorsal horn of spinal cord by painful stimuli
sensitise the neurones to pain perception.
10. Eye :
PGF2α induces ocular inflammation
and lowers i.o.t by enhancing uveoscleral and
trabecular outflow. Nonirritating congeners like latanoprost are now first line drugs in wide
angle glaucoma (see p. 169).
Role :
Locally produced PGs appear to facilitate aqueous humor drainage. The finding that
COX-2 expression in the ciliary body is deficient in wide angle glaucoma patients supports
this contention.
11. Endocrine system :
PGE2
facilitates the release of
anterior pituitary hormones (growth hormone, prolactin,
ACTH, FSH and LH) as well as that of insulin and
adrenal steroids. It has a TSH-like effect on the thyroid.
12. Metabolism :
PGEs are antilipolytic, exert
an insulin like effect on carbohydrate metabolism and mobilize Ca2+ from bone. They may
facilitate hypercalcaemia due to bony metastasis.
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