Prostacyclin
Prostacyclin (or PGI2), also known as known as
eicosanoids, a member of the family prostaglandins as a metabolite of
arachidonic acid, inhibits platelet aggregation, and dilates blood
vessels and is released by healthy endothelial cells and performs its
function through a paracrine signaling cascade that involves G
protein-coupled receptors on nearby platelets and endothelial cells(a).
9. Prostacyclin-stimulating and/or thromboxane A2-inhibiting action in hypertensive pregnancy
complications
Several gynecologic and obstetric disorders are characterized by
abnormalities in prostacyclin and/or thromboxane A2. In primary
menorrhagia the uterine release of prostacyclin is increased, and
consequently menstrual blood loss can be reduced with various
prostaglandin synthesis inhibitors. Prostacyclin relaxes the nonpregnant
myometrium in vitro and may also do so in vivo, although intravenous
infusion of prostacyclin has no effect upon the uterine contractility in
nonpregnant or pregnant subjects. In the study to review the gynecologic and obstetric implications of the smooth
muscle-relaxing, antiaggregatory prostacyclin and its endogenous
antagonist, thromboxane A2, showed that patients with pelvic endometriosis may have increased levels of
prostacyclin and thromboxane A2 metabolites in the peritoneal fluid. The
prostacyclin/thromboxane A2 balance shifts to thromboxane A2 dominance
in patients with gynecologic cancer. During pregnancy the production of
prostacyclin and thromboxane A2 increases in the mother and
fetoplacental tissue. Preeclampsia and other chronic placental
insufficiency syndromes are accompanied by prostacyclin deficiency in
the mother and in fetomaternal tissues and by an overproduction of
thromboxane A2, at least in the placenta. These changes may account for
the vasoconstriction and platelet hyperactivity, which are pathognomonic
for hypertensive pregnancies. By directing the prostacyclin/thromboxane
A2 balance to prostacyclin dominance (by dietary manipulation,
administration of prostacyclin and/or its analogues, drugs with
prostacyclin-stimulating and/or thromboxane A2-inhibiting action), it
may be possible to prevent and/or treat hypertensive pregnancy
complications in the future(9).
10. Prostacyclin, thromboxane A2, and hypertension
Prostacyclin and thromboxane A2, products of separate branches of the
arachidonic acid cascade, can have opposing effects on kidney function
and on the vascular musculature. According to the study by the Shandong
Medical University, prostacyclin acts as a vasodilator while thromboxane
A2 has a
vasoconstrictor effect and the balance between these two compounds
appears to contribute to the homeostatic regulation of normal blood
pressure. In the hypertensive state, this balance is disrupted and, at
least in animal models of hypertension, there is excessive production of
both. The increase in prostacyclin formation may be a reaction to the
elevated blood pressure, possibly due to mechanical stimulation of the
vascular smooth muscle cells in the blood vessel wall. However, the
increase in thromboxane A2 may be more directly involved in the
development and maintenance of hypertension. Not only is thromboxane A2 a
vasoconstrictor but it can also stimulate the growth and proliferation
of vascular smooth muscle cells which may account for the vascular
hypertrophy seen in hypertension(10).
11. Interrelationships between prostacyclin and thromboxane A2
Prostacyclin is a product of arachidonic acid metabolism generated by
the vessel wall of all mammalian species studied including man.
According to the study by Moncada S, Vane JR. ,prostacyclin is a potent
vasodilator and the most potent inhibitor of
platelet aggregation. It inhibits platelet aggregationand can also be a
circulating hormone constantly released by the pulmonary circulation.
In contrast to the vessel wall, in blood platelets arachidonic acid is
converted by the enzyme thromboxane synthetase to a potent
vasoconstrictor and proaggregating substance, thromboxane A2. Therefore
arachidonic acid is metabolized in the vessel wall and the platelets to
potent substances with opposing biological activities. The balance
between the activities of these substances is important in the
homeostatic interaction of the platelets and the vessel wall. The
different ways of interfering with this balance and its impact in the
development of thrombosis and atherosclerosis(11).
12. Prostacyclin's biosynthesis, actions and clinical potential
Prostacyclin (PGI2) is the product of arachidonic acid metabolism
generated by the vessel wall of all mammalian species studies.
According to the study by Moncada S, Vane JR., indicated that
prostacyclin inhibits aggregation through stimulation of platelet adenyl
cyclase leading to an increase in platelet cyclic AMP. In the vessel
wall, the enzyme that synthesizes prostacyclin is concentrated in the
endothelial layer. Prostacyclin can also be a circulating hormone
released from the pulmonary circulation. Based on these observations we
proposed that platelet aggregability in vivo is controlled via a
prostacyclin mechanism. The discovery of prostacyclin has given a new
insight into arachidonic acid metabolism and has led to a new hypothesis
about mechanisms of haemostasis. Reductions in prostacyclin production
in several diseases, including atherosclerosis and diabetes, have been
described and implicated in the pathophysiology of these diseases.
Additionally, since prostacyclin powerfully inhibits platelet
aggregation and promotes their disaggregation, this agent could have an
important use in the therapy of conditions in which increased platelet
aggregation takes place and in which, perhaps, a prostacyclin deficiency
exists. Prostacyclin has been used beneficially in humans during
extracorporeal circulation procedures such as cardiopulmonary bypass,
charcoal haemoperfusion and haemodialysis. Its possible use in other
conditions such as peripheral vascular disease or transplant
surgery(12).
13. Prostacyclin in vascular tissue
Prostacyclin (PGI2) generated by the vascular wall is a potent
vasodilator, and the most potent endogenous inhibitor of platelet
aggregation. According to the study by Moncada S, Vane JR., prostacyclin inhibits platelet aggregation by increasing cyclic AMP
levels. Prostacyclin is a circulating hormone continually released by
the lungs into the arterial circulation. Circulating platelets are,
therefore, subjected constantly to prostacyclin stimulation and it is
via this mechanism that platelet aggregability in vivo is controlled.
Moreover, phosphodiesterase inhibitors such as dipyridamole or
theophylline exert their antithrombotic actions by potentiating
circulating prostacyclin. The prostacyclin:thromboxane A2 ratio is
important in the control of thrombus formation; manipulation of this
ratio by small doses of aspirin (which will inhibit mainly platelet
cyclooxygenase), a selective inhibitor of thromboxane formation, or the
dietary use of a fatty acid like eicosapentaenoic acid (which would be
the precursor for a delta17-prostacyclin (PGI3) but is transformed by
the platelets into nonaggregating thromboxane A3) might have beneficial
effects as antithrombotic therapies. Prostacyclin has interesting
potential for clinical application in conditions where enhanced platelet
aggregation is involved or to increase biocompatibility of
extracorporeal circulation systems(13).
14. Prostacyclin reduces cardiopulmonary bypass-induced pulmonary endothelial dysfunction
Cardiopulmonary bypass triggers a systemic inflammatory response that
alters pulmonary endothelial function, which can contribute to pulmonary
hypertension. According to the study by the Montreal Heart Institute,
prophylactic use of inhaled prostacyclin has a favorable impact on the
pulmonary endothelial dysfunction induced by cardiopulmonary bypass
associated with preservation of pulmonary intravascular cyclic adenosine
monophosphate content and the pulmonary vascular tone(14).
15. Healthy vascular endothelium
Healthy vascular endothelium is a powerful generator of nitric oxide (NO), prostacyclin (PGI2), prostaglandin E2 (PGE2), and plasminogen activator (t-PA). These endothelial products protect vascular wall against aggression from activated blood platelets
and leukocytes. According to the study by Jagiellonian University, In
particular they protect against thrombosis, promote thrombolysis,
maintain tissue perfusion, and inhibit remodeling of vascular and
cardiac walls. Endothelial dysfunction appears on one hand as
suppression in the release of the above mediators, and on the other as
deleterious discharge of prostaglandin endoperoxides (PGH2, PGG2),
superoxide anion O2-, peroxynitrite (ONOO-), and plasminogen activator
inhibitor (PAI-1)(15).
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Sources
(9) http://www.ncbi.nlm.nih.gov/pubmed/3890549
(10) http://www.ncbi.nlm.nih.gov/pubmed/2078914
(11) http://www.ncbi.nlm.nih.gov/pubmed/6258879
(12) http://www.ncbi.nlm.nih.gov/pubmed/6117893
(13) http://www.ncbi.nlm.nih.gov/pubmed/215463
(14) http://www.ncbi.nlm.nih.gov/pubmed/15224029
(15) http://www.ncbi.nlm.nih.gov/pubmed/12056503
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