Prostacycline: Definition, Function, Pharmacology, Medical Uses and Relevance in Vascular Tissue Engineering

It is a member of the prostaglandin family of eicosanoid lipid molecules. It inhibits platelet activation and is also an effective vasodilator.

Prostacyclin, a member of the endogenous prostanoid family, is produced from arachidonic acid by the actions of prostacyclin synthase and cyclooxygenase.

PGI2 (Prostacyclin), the primary prostanoid produced by endothelial cells, has potent vasodilatory and antithrombotic effects that are important in vascular homeostasis.

It is functionally opposed to the effects of TXA2. The DNA complementary to the human and mouse IP receptor encodes proteins of 386 and 415 amino acids, respectively. IP is coupled to Gs, mainly, and also to Gq and Gi.

The role of Prostacyclin (PGI2) in cardiovascular homeostasis is well established. Prostacyclin (PGI2) is also an essential mediator of the edema and pain accompanying acute inflammation. As with PGE2, Prostacyclin (PGI2) can be anti-inflammatory and pro-inflammatory in the immune system.

Prostacyclin (PGI2), a product of the metabolism of arachidonic acid from endothelial cells, inhibits platelet aggregation both in vitro and in vivo by raising levels of platelet cytoplasmic adenosine monophosphate (cAMP).

When used as a medicine, it is also known as epoprostenol. The terms are sometimes used interchangeably.


Function of Prostacyclin

Prostacyclin mainly prevents the platelet plug formation involved in primary hemostasis (a part of blood clot formation). It does this by inhibiting platelet activation. It is also an effective vasodilator.

Prostacyclin in hypertension:

It is known that Prostacyclin (PGI2) causes vasorelaxation and inhibits platelet aggregation by mechanisms mediated by receptors.

Although cyclic adenosine monophosphate is known to act as a second messenger for platelet aggregation, hyperpolarization vasorelaxation has recently been described. In addition to the stimulation of cyclic adenosine monophosphate, it may explain the mechanism of action of Prostacyclin. (PGI2) blood recipients.

When Prostacyclin (PGI2) is infused into healthy volunteers, it reduces blood pressure only at infusion rates that also cause significant side effects, mainly nausea, vomiting, flushing, diaphoresis, and restlessness.

In hypertensive patients, blood pressure responses are complex and are influenced by secretion. Prostacyclin (PGI2) stimulates the secretion of renin by a direct effect on the juxtaglomerular apparatus and has an indirect effect by activating the sympathetic nervous system.

Therefore, it is useless as an antihypertensive agent, despite its debilitating side effects. Vascular Prostacyclin (PGI2) is synthesized endogenously by endothelial cells and the muscular layer of the arteries.

While endothelial cells undoubtedly synthesize more significant amounts of Prostacyclin (PGI2), the muscle comprises a much larger tissue mass. The overall synthesis is distributed approximately equally between endothelial and muscle cells.

In patients with hypertension induced by pregnancy and some patients with essential hypertension, the endogenous synthesis of Prostacyclin (PGI2) has been evaluated by measuring 2,3-or-6-keto-PGF1 alpha and is defective.

It has been shown that some drugs (cyclintanin, thiazides, propranolol) stimulate the synthesis of Prostacyclin (PGI2), and it has been demonstrated that the inhibition of cyclooxygenase suppresses its antihypertensive effects.

It is not yet known if the stimulation of prostacyclin synthesis (PGI2) affects the antihypertensive efficacy of these drugs.

The role of Prostacyclin in vascular tissue:

The vascular wall generated by Prostacyclin (PGI2) is a potent vasodilator and the most potent endogenous inhibitor of platelet aggregation.

Prostacyclin inhibits platelet aggregation by increasing levels of cyclic adenosine monophosphate. Prostacyclin is a circulating hormone released continuously by the lungs into the arterial circulation.

Therefore, circulating platelets are constantly subject to stimulation with Prostacyclin, and it is through this mechanism platelet aggregation is controlled in vivo.

In addition, phosphodiesterase inhibitors such as dipyridamole or theophylline exert their antithrombotic actions by potentiating circulating Prostacyclin.

Prostacyclin has exciting potential for clinical application in conditions in which enhanced platelet aggregation is involved or increases the biocompatibility of extracorporeal circulation systems.


Prostacyclin, which has a half-life of 42 seconds, breaks down into 6-keto-PGF1, a much weaker vasodilator.


The synthetic analogs of prostacyclin (iloprost, cisaprost) 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 (PPH).

The drug is transparent with a pH of 10. Its production is indirectly inhibited by the non-steroidal anti-inflammatory drug, which inhibits the cyclooxygenase enzymes COX1 and COX2. These convert arachidonic acid into prostaglandin H2 (PGH2), the immediate precursor of Prostacyclin.

Since thromboxane (an eicosanoid stimulator of platelet aggregation) is also found downstream of COX enzymes, one might think that the effect of the non-steroidal anti-inflammatory drug would act to maintain balance.

However, prostacyclin concentrations recover much faster than thromboxane levels, so aspirin administration has little or no effect but ultimately prevents platelet aggregation (the result of prostaglandins predominates as they regenerate).

This is explained by understanding the cells that produce each molecule, TXA2 and Prostacyclin (PGI2).

Since Prostacyclin (PGI2) is mainly produced in a nucleated endothelial cell, the inhibition of COX by the non-steroidal anti-inflammatory drug can be overcome over time by increased activation of the COX gene and the subsequent production of COX enzymes to catalyze the formation of Prostacyclin (PGI2).

In contrast, TXA2 is mainly released by anucleated platelets, which can not respond to the inhibition of COX by nonsteroidal anti-inflammatory drugs with the additional transcription of the COX gene because they lack the DNA material necessary to perform this task.

This allows the non-steroidal anti-inflammatory drug to result in the Prostacyclin (PGI2) domain that promotes circulation and retards thrombosis.

In patients with pulmonary hypertension, inhaled epoprostenol reduces pulmonary pressure and improves the work of suitable ventricular ACV in patients undergoing cardiac surgery. A dose of 60 μg is hemodynamically safe, and its effect completely reverses after 25 minutes.

After administering inhaled epoprostenol, no evidence of platelet dysfunction or increased surgical bleeding has been found. It is known that the medication causes redness, headaches, and hypotension.

Medical uses

It is used to treat pulmonary arterial hypertension.

Small studies of Prostacyclin (PGI2), iloprost, or other stable prostacyclin analogs in patients with complete stroke have not shown therapeutic efficacy.

In addition, a prospective controlled trial of level I demonstrated a significant worsening in 2 weeks among patients who received Prostacyclin (PGI2) within 24 hours after symptoms related to stroke compared with placebo.

So far, there has been no evidence of benefit with prostacyclin (PGI2) incomplete stroke, partly due to inadequate sample sizes and side effects.

In the pulmonary circulation, Prostacyclin is released by the endothelial cells of the pulmonary artery. In the target cells, it is bound by a receptor coupled to the G protein of the cell surface in the target cells.

The binding to the receptor and activation of the G protein triggers increases in intracellular cAMP, which activates protein kinase A.

This causes relaxation and vasodilation of PA-SMC, even in vasoconstrictors. In addition, Prostacyclin inhibits the proliferation of PA-SMC, mainly when administered in combination with phosphodiesterase inhibitors.

Prostacyclin analog

The prostacyclin analogs currently used to treat pulmonary arterial hypertension are epoprostenol, treprostinil, beraprost, and iloprost. They have vasodilatory and antiplatelet properties, but they also have an anti-re mobilizing effect.

Epoprostenol is an instant synthetic prostacyclin analog that must be administered continuously intravenously and has an extremely short half-life of 3 minutes. The disadvantages are serious adverse effects, such as septic complications. Interruption of intravenous therapy can be life-threatening.

In experimental studies, there has been no evidence of teratogenicity. The placental transfer is unknown. Moodley (1992) described almost 50 cases of the use of epoprostenol during the last stage of pregnancy for the treatment of severe eclampsia.

No specific fetal harm was reported; The reported complications were mainly due to prematurity or the severity of the maternal disease.

Epoprostenol for pulmonary hypertension in 10 pregnant women has been described, but only 3 of the women were exposed during the first trimester or for a more extended period.

In a case report, epoprostenol was injected and inhaled. There was a reasonable success rate in the treatment of pulmonary hypertension, and there are no indications of fetal or embryonic adverse effects.

Although the experience in the first trimester is minimal, the maternal benefit in pulmonary hypertension outweighs any possible risk to the embryo/fetus.

Treprostinil should be administered by continuous subcutaneous infusion. Local pain at the injection site is a significant side effect in approximately 85 percent of the subjects. There is no experience in human pregnancy.

Beraprost and iloprost are stable synthetic analogs of epoprostenol with similar activity. Beraprost can be administered orally, but there are no data on its use during pregnancy.

Its elimination half-life is 35-40 minutes. Iloprost can be inhaled or administered intravenously. Its half-life in plasma is 20-30 minutes. One publication describes its use in three pregnancies.

The first woman started therapy at eight weeks of gestation. At first, she inhaled iloprost, but it became iloprost iv as it deteriorated. She gave birth to a premature male baby without congenital anomalies at 26 weeks of gestation (650 g, Apgar scores of 8 to 1 minute and 9 to 5 minutes).

The second woman started treatment with iloprost at 19 weeks of gestation and gave birth to a healthy male baby at 36 weeks. The third woman started iloprost nebulized at 17 weeks of pregnancy and gave birth to a healthy girl at 35 weeks.

Relevance in vascular tissue engineering

Prostacyclin is an antiplatelet and antithrombotic mediator that plays a vital role in developing cardiovascular disease.

The activity of dysfunctional Prostacyclin has been implicated in the development of various cardiovascular diseases, including thrombosis, myocardial infarctionstroke, atherosclerosis, and hypertension.

A reduction in the binding affinity of platelets has been observed by the synthesis of Prostacyclin and cyclic adenosine monophosphate in patients with acute myocardial infarction compared to healthy subjects.

Because various cytokines positively regulate the PGIS gene, it has been reported that prostacyclin biosynthesis increases in the presence of atherosclerosis and platelet activation.

Mice deficient in the PGIS gene are hypertensive and develop vascular disorders with thickening of the vascular wall and interstitial fibrosis, particularly in the kidneys. The inhibition or deficiency of PGIS in vivo causes a marked enhancement of the formation of white platelet thrombi.

Several researchers have reported that the synthesis of abnormal metabolism of Prostacyclin may be a risk factor for myocardial and cerebral infarction. The administration of PGIS in vivo can prevent the proliferation and migration of smooth muscle cells, critical steps in the development of restenosis and atherosclerosis.

Although Prostacyclin reduces cerebral infarction in animal models, many therapeutic trials of Prostacyclin have not achieved significant clinical improvement.

A decrease in prostacyclin production has been implicated in the pathogenesis of severe pulmonary hypertension but not in essential human hypertension. However, in hypertension induced by pregnancy, it has been reported that a decrease in Prostacyclin precedes clinical manifestation.

Mice deficient in the PI receptor have been studied in several disease scenarios. They found that inactivated PI receptor mice exhibit an increased thrombotic tendency but have a reduction in inflammatory inflammation and pain responses and are not susceptible to hypertension.

Carotid artery injury leads to obstruction in mice lacking the PI receptor, and this response was abolished in mice lacking TXA2. In null IP mice, the production of TXA2 by platelets and the components of the injured vessel wall increased.

Female mice that lack the IP receptor are no longer atheroprotective when reintroducing estrogen. Estrogen, when bound to the alpha estrogen receptor, positively regulates Prostacyclin through the activation of COX-2.

The opposing actions of Prostacyclin and TXA2 on platelets and the vessel wall and their levels of concentration at the site of injury are considered critical for the formation of thrombi and in various vascular occlusive diseases, including coronary disease.

During cardiac ischemia/reperfusion, the synthesis of PGI2 and TXA2 is significantly increased. PGI2 and its analogs have been reported to attenuate cardiac ischemia/reperfusion injury when administered exogenously in animal models, possibly due to its inhibitory effect on platelets and neutrophils.

Clinical studies suggest that loss of the PI receptor may contribute to atherogenesis in patients with chronic spinal cord injury.

During spontaneous angina pectoris, severe atherosclerosis, and acute myocardial infarction, Prostacyclin binding capacity and the number of IP receptors have been reported to decrease, but not in other patients with angiographically proven coronary artery disease and stable angina.

In myocardial infarction and unstable angina, the biosynthesis of Prostacyclin increases considerably, which could lead to receptor changes induced by agonists, such as desensitization of PGI2 binding sites.

The short half-life of Prostacyclin has led to the development and practical application of various prostacyclin mimetics. The most commonly used are cicaprost, iloprost, and carb cycling, all analogs of PGI2.

Cicaprost is usually the analog of choice since iloprost is less selective and acts partially as an agonist of prostaglandin E1 receptors.

In the clinical context, the administration of prostacyclin mimetics, such as epoprostenol, has been used to limit platelet aggregation, but a significant drawback is the profound vascular dilatation they induce.

In pulmonary arterial hypertension (PAH), treatment with prostacyclin analogs, such as epoprostenol, treprostinil, iloprost, and beraprost, continues to play an important role despite the complications induced by their generally short half-lives and complicated drug delivery systems.

More recently, it was shown that epoprostenol has no effect in patients with pulmonary embolism.

It has been shown that this same medication induces headaches in healthy patients and migraine-like episodes suffer the sensitization of sensory afferents around the extracranial arteries.

However, it has been shown that epoprostenol increases the survival of patients with pulmonary arterial hypertension and improves lung function, even during thoracic transplantation.

To improve the effects of beraprost on pulmonary arterial hypertension, this medication has been used in conjunction with other medicines, such as an angiotensin blocker, or has been reformulated to last longer to improve lung pressure and quality of life.

Iloprost is also being studied for its effectiveness in pulmonary arterial hypertension, even during heart transplants. It shows, alone or in conjuncture with other drugs, the point of improving pulmonary arterial pressure and hemodynamics.

Treprostinil has been studied more extensively, particularly as a replacement for epoprostenol, because it is more durable. All studies report improved pulmonary vasodilation, exercise capacity, hemodynamics, and survival.

Iloprost has been used to treat systemic sclerosis, a connective tissue disease in which the immune system attacks body tissues, leading to collagen accumulation in these tissues.

Studies have analyzed their effects on oxidative stress that occurs due to frequent ischemia/reperfusion events during the pathogenesis of this disease. Still, there has been no agreement if this drug has a role.

However, iloprost effectively prevents pulmonary hypertension in patients with systemic sclerosis.

Two analogs of Prostacyclin have been studied to treat peripheral arterial disease (arteriosclerosis obliterans): iloprost and beraprost.

Iloprost effectively reduces inflammation and oxidative stress at the juncture with aspirin treatment; alone, it has not been effective in treating the disease.

Beraprost effectively treats peripheral artery disease by reducing renal anemia, decreasing endothelin-1 levels, and improving quality of life.

Prostacyclin analogs are also being tested in kidney diseases. People with acute renal failure who require continuous venovenous hemodiafiltration have an increased risk of thrombosis.

Treatments to prevent this cause an increase in bleeding. It was shown that a prostacyclin analog reduces the platelet aggregation induced by adenosine diphosphate and collagen in these patients.

In another study, patients with renal failure undergoing coronary intervention received iloprost prophylactically protected against contrast-induced nephropathy—finally, people on chronic peritoneal dialysis experience endothelial injury and thrombosis.

Patients treated with beraprost had a reduction in D-dimer and von Willebrand factor markers, indicative of thrombosis and endothelial damage, respectively.

Aspirin (acetylsalicylic acid) has an antithrombotic effect based on its preferential action on the blockade of COX in platelets and the endothelium by acetylating the active center of COX.

It has also been reported that aspirin increases NO production in neutrophils and the arterial wall. There are two different cyclooxygenases, COX-1 and COX-2.

COX-1 is involved in synthesizing TXA2 in platelets, while COX-2 is involved in synthesizing Prostacyclin in endothelial cells.

The aspirin, at low doses, acetylates COX-1 in platelets and, therefore, irreversibly blocks the synthesis of TXA2 during its life in circulation. In the same low doses, aspirin has little effect on the synthesis of PGI2.

Therefore, the general effect of low-dose aspirin is a reduced risk of thrombosis. The combined inhibition of both isoforms of COX, but not the selective inhibition of COX-2, attenuates atherogenesis in mice.