Prostacyclin is a prostaglandin member of the family of lipid molecules known as eicosanoids.
It inhibits platelet activation and is also an effective vasodilator.
As a drug, it is also known as "epoprostenol". The terms are sometimes used interchangeably.
History During the 1960s, a U.K. research team, headed
by Professor John Vane, began to explore the role of prostaglandins in anaphylaxis and
respiratory diseases. Working with a team from the Royal College of Surgeons, Sir John
discovered that aspirin and other oral anti-inflammatory drugs work by inhibiting the synthesis of
prostaglandins. This critical finding opened the door to a broader understanding of the
role of prostaglandins in the body. Sir John and a team from the Wellcome Foundation,
had identified a lipid mediator they called “PG-X,” which inhibits platelet aggregation.
PG-X, which later would become known as prostacyclin, is 30 times more potent than any other then-known
anti-aggregatory agent. By 1976, Sir John and fellow researchers Salvador
Moncada, Ryszard Gryglewski and Stuart Bunting published the first paper on prostacyclin,
in the scientific journal Nature. The collaboration produced a synthesized molecule, which was
given the name epoprostenol. But, as with native prostacyclin, the structure of the
epoprostenol molecule proved to be unstable in solution, prone to rapid degradation. This
presented a challenge for both in vitro experiments and clinical applications.
To overcome this challenge, the research team that discovered prostacyclin was determined
to continue the research in an attempt to build upon the success they had seen with
the prototype molecule. The research team synthesized nearly 1,000 analogues.
Through innovative work done by researcher Lucie Clapp, treprostinil has demonstrated
a unique effect on PPAR gamma, a transcription factor important in vascular pathogenesis
as a mediator of proliferation, inflammation, and apoptosis. Through a complementary, yet
cyclic AMP-independent pathway, treprostinil activates PPARs, another mechanism that contributes
to the anti-growth benefits of the prostacyclin class.
Production
Prostacyclin is produced in endothelial cells from prostaglandin H2 by the action of the
enzyme prostacyclin synthase. Although prostacyclin is considered an independent mediator, it
is called PGI2 in eicosanoid nomenclature, and is a member of the prostanoids.
The series-3 prostaglandin PGH3 also follows the prostacyclin synthase pathway, yielding
another prostacyclin, PGI3. The unqualified term 'prostacyclin' usually refers to PGI2.
PGI2 is derived from the ω-6 arachidonic acid. PGI3 is derived from the ω-3 EPA.
Function Prostacyclin chiefly prevents formation of
the platelet plug involved in primary hemostasis. It does this by inhibiting platelet activation.
It is also an effective vasodilator. Prostacyclin's interactions in contrast to thromboxane, another
eicosanoid, strongly suggest a mechanism of cardiovascular homeostasis between the two
hormones in relation to vascular damage. Degradation
Prostacyclin, which has a half-life of 42 seconds, is broken down into 6-keto-PGF1,
which is a much weaker vasodilator. Mode of action
Prostacyclin 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. The platelet Gs protein-coupled receptor is activated when it binds to PGI2.
This activation, in turn, signals adenylyl cyclase to produce cAMP. cAMP goes on to inhibit
any undue platelet activation and also counteracts any increase in cytosolic calcium levels that
would result from thromboxane A2 binding. PGI2 also binds to endothelial prostacyclin
receptors and in the same manner raise cAMP levels in the cytosol. This cAMP then goes
on to activate protein kinase A. PKA then continues the cascade by dephosphorylating
the myosin light chain and inhibiting myosin light-chain kinase, which leads to smooth
muscle relaxation and vasodilation. It can be noted that PGI2 and TXA2 work as physiological
antagonists. Members
Pharmacology
Synthetic prostacyclin analogues are used intravenously, subcutaneously or by inhalation:
as a vasodilator in severe Raynaud's phenomenon or ischemia of a limb;
in pulmonary hypertension. in primary pulmonary hypertension
Its production is inhibited indirectly by NSAIDs, which inhibit the cyclooxygenase enzymes
COX1 and COX2. These convert arachidonic acid to prostaglandin H2, the immediate precursor
of prostacyclin. Since thromboxane is also downstream of COX enzymes, one might think
that the effect of NSAIDs would act to balance. However, prostacyclin concentrations recover
much faster than thromboxane levels, so aspirin administration initially has little to no
effect but eventually prevents platelet aggregation. This is explained by understanding the cells
that produce each molecule, TXA2 and PGI2. Since PGI2 is primarily produced in a nucleated
endothelial cell, the COX inhibition by NSAID can be overcome with time by increased COX
gene activation and subsequent production of more COX enzymes to catalyze the formation
of PGI2. In contrast, TXA2 is released primarily by anucleated platelets, which are unable
to respond to NSAID COX inhibition with additional transcription of the COX gene because they
lack DNA material necessary to perform such a task. This allows NSAIDs to result in PGI2
dominance that promotes circulation and retards thrombosis.
In patients with pulmonary hypertension, inhaled epoprostenol reduces pulmonary pressure, and
improves right ventricular stroke work in patients undergoing cardiac surgery. A dose
of 60 µg is hemodynamically safe, and its effect is completely reversed after 25 minutes.
No evidence of platelet dysfunction or an increase in surgical bleeding after administration
of inhaled epoprostenol has been found. See also
Essential fatty acid References