Enhancement of PGI2 formation by a new vasodilator, 2-nicotinamidoethyl nitrate in the coupled system of platelets and aortic microsomes

Exogenous arachidonate addition to the coupled system of platelets and aortic microsomes resulted in production of TXA₂ and PGI₂ (detected as the stable degradation products, TXB₂ and 6-keto PGF_1α, respectively). Imidazole, papaverine and dipyridamole increased PGI₂ and decreased TXA₂ in the coupled system. All of these agents inhibited TXA₂ formation by platelets from arachidonate. Nitroglycerin did not show any effect on PGI₂ and TXA₂ formation in the coupled system and on TXA₂ formation by platelets. In contrast with these compounds, in spite of showing no inhibitory effect on TXA₂ formation by platelets alone, 2-nicotinamidoethyl nitrate (SG-75) increased PGI₂ and decreased TXA₂ in the coupled system. It is suggested that SG-75 accelerated the conversion of PGH₂ to PGI₂ so that smaller amounts of TXA₂ was produced in the coupled system.     

Effects of all CIS-5, 8,11,14,17 eicosapentaenoic acid and PGH3 on platelet aggregation

In human platelet-rich plasma (PRP) eicosapentaenoic acid (EPA) inhibited platelet aggregation induced by a stable analogue of PGH₂ (U46619), arachidonic acid, collagen or ADP. EPA was more potent than oleic, linoleic, α-linolenic or γ-linolenic acids. In aspirin-treated platelets, aggregation induced by U46619 was inhibited to a similar extent by arachidonic acid or by EPA over a range of concentrations of 0.05–0.3 mM. EPA incubated with PRP did not induce the generation of a thromboxane (TXA)-like activity; indeed it prevented the formation of TXA₂ induced by arachidonic acid or by collagen. The anti-aggregatory activity of EPA was not influenced by inhibitors of cyclo-oxygenase and lipoxygenase. The anti-aggregatory action of EPA may be caused by a rapid occupancy by EPA of TXA₂/PGH₂ “receptors” on platelet membrane as well as by a slower displacement of arachidonic acid from platelet phospholipids by chemically unchanged molecules of EPA.Not all samples of PRP were irreversibly aggregated by PGH₂, but in those that were, PGH₃ also induced an immediate dose-dependent but reversible aggregation. After a 4 min incubation of non-aggregating doses of PGH₂ or PGH₃ (100–300 nM) with PRP a stable anti-aggregatory compound was detected. The inhibitory activity produced from PGH₃ was apparently more potent (ca 10 times) than that obtained from PGH₂. The anti-aggregating compounds were identified by TLC and GLC-MS as PGD₂ and PGD₃. The apparent difference of potency between PGD₂ and PGD₃ was attributed to the concurrent production of PGE₂ and PGE₃. PGE₂ prevented the inhibitory effect of PGD₂ whereas PGE₃ did not affect the activity of PGD₃.It is concluded that one of the reasons for the low incidence of myocardial infarction in Eskimos could be that the pro-aggregatory arachidonic acid is replaced in their phospholipids by the anti-aggregatory EPA.     

The use of prostacyclin in the separation from plasma and washing of human platelets

A new method for the separation from plasma and washing of human platelets is described. The use of prostacyclin (PGI₂) throughout the procedure prevents the activation of platelets. The method allows a 60–70% yield of platelets from PRP. The platelet sensitivity to ADP, collagen, adrenaline, arachidonic acid and thrombin is the same as in PRP. The platelet suspension is stable for long periods and the reactivity to aggregating agents remain unchanged for periods greater than 48 h when platelets are stored at 4°C.     

Prostacyclin and thromboxane A2 release in isolated rat lungs

The influence of platelets and platelet membranes on the generation of prostacyclin (PGI₂) and thromboxane A₂(TXA₂) by isolated rat lung and porcine aortic endothelial cell, as measured by RIA of their stable end-producs, 6-oxo-PGF_1α and TXB₂ respectively, was studied. After introduction of either aspirin-treated platelets or membranes from aspirin-treated platelets to the perfusate, 1 5-fold increase in the amount of 6-oxo-PGF_1α and TXB₂ in the perfusate was observed. Treatment of the lung with aspirin produced a 50% reduction in the platelet-stimulated release of PGI₂ and TXA₂. Treatment of the lung with the phospholipase inhibitor, mepacrine, significantly reduced the platelet-stimulated release of PGI₂ and TXA₂. Incubation of endothelial cells with untreated platelet membranes did not alter the generation of PGI₂. These results suggest that platelet-stimulated release of PGI₂ and TXA₂ occurs via mechanical stimulation of phospholipase A₂, liberating arachidonic acid.     

The effects of itnravenous ZK36-374, a stsable prostacyclin analogue, on normal volunteers

Prostacyclin (PGI₂) therapy has been evaluated in many vascular diseases. However, it is unstable and a potent vasodilator, able to lower blood pressure. Although such effects may be desirable in some situations, they are unwanted in others. ZK36-374 (Schering AG) is a carbacyclin derivatives with a similar action to PGI₂; however, it is chemically stable and has less of a hypotensive action.We evaluated the effects of a 4-hour I.V. infusion of ZK36-374 at a maximum dose of 2ng/Kg/min. in ten normal volunteers. Prior to the infusion and at 2 and 4 hours, blood was sampled for estimation of platelet aggregation in both platelet rich plasma and whole blood. β-thromboglobulin, 6-keto-PGF_1α and TXB₂ were measuerd by radioimmunoassay, as were other coagulation and rheological tests. The infusion was well tolerated with facial flushing, jaw trismus and some nausea at max dose. Blood pressure and pulse rate were not significantly altered. During infusion of ZK36-374, the rates of platelet aggregation to 2μm AdP and 2μg collagen in PRP were significantly decreased when compared to baseline, as was whole blood aggregation to 2μm ADP and 0.5 μg collagen. βTG also fell significantly, as did the levels of 6-keto-PGF_1α and TXB₂. Fibrinolysis, blood viscosity, and red cell deformability were unchanged.ZK36-374 is an effective anti-platelet agent without major toxic or hypotensive effects.     

Potentiation of anti-aggregating activity of PGI2 by 7-ethoxycarbonyl-6,8-dimethyl-4-hydroxymethyl-1(2H)-phthalazinone (EG-626) in rabbit platelets in vitro

Anti-aggregating activity of 7-ethoxycarbonyl-6,8-dimethyl-4-hydroxymethyl-1(2H)-phthalazinone (EG-626) was tested using rabbit platelets in vitro. EG-626 alone, when added before, prevented platelet aggregation induced by ADP, as did PGI₂, papaverine and dipyridamole. Spontaneous disaggregation was also accelerated when EG-626 was added after the maximal aggregation induced by ADP. EG-626 alone also inhibited platelet aggregation induced by collagen and arachidonic acid. ID₅₀s of these agents in ADP-induced aggregation were 7–9 nM for PGI₂, 223 μM for EG-626, 266 μM for papaverine and 957 μM for dipyridamole. When EG-626 was used in combination with PGI₂, a threshold dose (50 μM) of EG-626 potentiated the anti-aggregating effect of subthreshold dose (3 nM) of PGI₂ upto 100% inhibition in collagen-induced platelet aggregation. The marked potentiating effect of EG-626 was accompanied by an accumulation of cyclic AMP in the platelets. These effects might be due to inhibition of phosphodiesterase. Papaverine and dipyridamole, other phosphodiesterase inhibitors, also potentiated the anti-aggregating activity of PGI₂. The activity of papaverine, however, was one eighth of EG-626 and that of dipyridamole was much less. The most effective combination of PGI₂ and EG-626 to induce 50% inhibition was obtained with 20% of ID₅₀ of each agent, whereas that of PGI₂ and papaverine or dipyridamole was 39 or 41%, respectively.     

Comparison of umbilical vein models for measurement of relative prostacyclin and thromboxane production

There is growing evidence that blood vessels generate TXA₂ in addition to PGI₂. We examined effluents from continously perfused human umbilical vein and supernatants from umbilical vein rings for TXB₂ and 6-keto-PGF_1α measurements (stable metabolites of TXA₂ and PGI₂, respectively). TXB₂ and 6-keto-PGF_1α were identified in all samples. 6-keto-PGF_1α to TXB₂ ratio was higher in intact vein effluents than in the venous ring supernatants (112:1 and 28:1, respectively, P<0.01). Arachidonate stimulation increased 6-keto-PGF_1α and TXB₂ levels similarly in the intact vein effluent. In contrast, stimulation of the venous rings resulted in a relatively larger increase in TXB₂ than in 6-keto-PGF_1α. This caused 6-keto-PGF_1α to TXB₂ ratio to decline (p<0.01). The identity of TXB₂ was confirmed in several different ways. These data suggest that 1) human umbilical veins produce TXA₂ in addition to PGI₂, 2) TXA₂ release is more by venous rings than by the intact vein probably reflecting contribution from non-endothelial layers, and 3) arachidonate stimulation causes relatively greater release of TXA₂ than of PGI₂ from the venous rings, whereas release of PGI₂ and TXA₂ is similar from the intact vein.     

Anti-platelet aggregating and disaggregating activities of 6,9-methano PGI2

Anti-platelet aggregating and disaggregating activities of the chemically stable 6,9-methano prostaglandin I₂ (6,9-methano PGI₂) were investigated. 6,9-Methano PGI₂ inhibited ADP-induced platelet aggregation in PRP from humans, rabbits and rats. 6,9-Methano PGI₂ also inhibited rabbit platelet aggregation induced by ADP, collagen, thrombin, arachidonic acid and 11,9-epoxy-methano PGH₂. Antiaggregating activities of 6,9-methano PGI₂ were 0.3 to 2.0 times greater than those of PGE₁. 6,9-Methano PGI₂ facilitated platelet disaggregation in a dose related manner. Antiaggregating and disaggregating activities of 6,9-methano PGI₂ were markedly enhanced by incubation with the phosphodiesterase inhibitor, theophylline.     

Effect of taurine on arterial, uterine and cardiac PGI2 and TXA2 synthesis in the rat

The influence of taurine (in drinking water for 6 weeks) on PGI₂ and TXA₂ synthesis by some female rat organs was investigated using radioimmunoassay and platelet antiaggregatory bioassay. Taurine 100 and 200 mg/kg/day increased aortic PGI₂ release from 0.59 ± 0.04 (control) to 0.85 ± 0.05 and 1.01 ± 0.06 ng/mg, respectively and that by the myometrium from 0.24 ± 0.02 (control) to 0.38 ± 0.01 and 0.50 ± 0.04 ng/mg wet tissue, respectively (P < 0.05, n = 6). It did not affect PGI₂ and TXA₂ production in the heart or TXA₂ in the aorta. Taurine 200 mg/kg depressed uterine TXA₂ synthesis from 148.6 ± 9.8 (control) to 85.4 ± 6.8 pg/mg (P < 0.05, n = 6). Furthermore taurine 0.4 and 0.8 mM in vitro stimulated PGI₂ released by the myometrial and aortic tissues from pregnant rats. The stimulant effect of taurine on PGI₂ may be related to its antioxidant effect whereas its inhibitory effect on uterine TXA₂ may result from direction of synthesis towards PGI₂. It is concluded that endogenous taurine may participate in regulation of PGs synthesis and that prostanoids may contribute to its known actions. On broad basis, taurine-induced release of PGI₂ may prove of potential value in those ailments characterised by deficiency in PGI₂ release.     

Manipulation of thrombus formation in the hamster cheek pouch with drugs that interact with PGI2

A single platelet thrombus was formed in an arteriole of the hamster cheek pouch by electrical stimulation followed by topical application of ADP. The sizes of the thrombi were continuously recorded with a photocell placed on a TV monitor screen and quantified by areas on the record. Repeated application of small doses of ADP (5–15 nmol/10 μl) resulted in very reproducible formation of the thrombi, and the size of the thrombi was reduced dose-dependently by topical application of PGI₂. Three drugs were tested in this model. Cycloxygenase inhibitor (indomethacin 10 mg/kg, i.p.) increased the formatiion of thrombi, while a smaller dose (3 mg/kg) did not have any significant effect. This could be explained by inhibition of the generation of endogemous PGI₂, since aggregation of hamster platelets by ADP was not inhibited by indomethacin . EG-626 (phthalazinol, a phosphodiesterase inhibitor) (300 mg/kg, i.p.) decreased the size of thrombus. AI-122 (1.0 mg/kg, i.p.) which has been proven to enhance PGI₂ biosynthesis from isolated rat aortae, also decreased the formation. Thus, drugs such as EG-626 or AI-122 are quite promising as anti-thrombic drugs.     

Aggregation and thromboxane B2 formation in platelets and vascular prostacyclin production from genetically obese rats

Obesity, diabetes, hyperlipidaemia and age are conditions predisposing to atheroscleorosis and arterial occlusion. Recently it has been claimed that increased synthesis of thromboxane A₂ by platelets and decreased synthesis of prostacyclin (PGI₂) by blood vessels play an important role. The “Zucker” rat, a genetically obese animal with hyperlipidaemia, hyperinsulinaemia and normoglycaemia was used to study platelet aggregation, thromboxane (TXB₂) production and aortic PGI₂ synthesis. Two age groups (6–8 months and 14–16 months old) and their homozygote lean controls were used. In the obese rats no increased aggregation was found with ADP, arachidonic acid and collagen. On the contrary platelets from young fatty rats were less sensitive to ADP than platelets from lean young animals. An increase in platelet sensitivity to aggregating agents with age was observed, especially in the obese rats. TXB₂ measured in platelet rich plasma after exposure to ADP, arachidonic acid, arachidonic acid plus ADP and collagen was similar in the fatty and lean animals.Production of PGI₂ from incubated aortic rings was lowest in young lean animals. No differences existed between the other groups of rats studied. Insulin added to aortic rings had no influence on PGI₂ production. It is concluded that age rather than obesity, hyperlipidaemia or hyperinsulinaemia may cause platelet hyperresponsiveness to aggregating agents. Thromboxane and plateletaggregation do not closely correlate. PGI₂ production is not reduced by metabolic alterations, thought to predispose to atherosclerosis.     

Regulation of microvascular prostacyclin and thromboxane with inhibitors or arachidonic acid metabolism

The levels of the stable degradation products of prostacyclin (PGI₂) and thromboxane A₂ (TXA₂): 6-oxo-prostaglandin F_1α(6-oxo-PGE_1α) and thromboxane B₂ (TXB₂) respectively were determined in the effluent of the rabbit epigastric skin flap after infusion of exogenous arachidonic acid. The blood to the flap passes through the microcirculation and thus the changes in eicosanoid biosynthesis in this part of the vasculature were recorded. The aim was to use inhibitors of arachidonic acid metabolism to increase the PGI₂/TXA₂ ratio. This may be potentially beneficial to ischaemic skin flaps by reducing platelet aggregation associated with damaged microvascular endothelium, overcoming vasospasm and increasing microvascular blood flow. Increased PGI₂/TXA₂ ratios (up to 5-fold) were best achieved using TXA₂ synthetase inhibitors such as dazoxiben hydrochloride. These were significantly more potent than the phosphodiesterase inhibitor dipyridamole, and the lipoxygenase inhibitor Bay g6575. No increase in blood flow was achieved. The cyclooxygenase inhibitor indomethacin did slow the blood flow at high concentrations (above 10⁻⁵ M), and inhibited both PGI₂ and TXA₂ synthesis. Approximately 2-fold higher concentrations of dazoxiben hydrochloride and dipyridamole were required to produce the same TXA₂ synthetase inhibition in the flap microvasculature compared with platelets .     

Myocardial prostacyclin and thromboxane A2 synthetase activities during ischemia and reperfusion in isolated rabbit heart

The aim of the study was to determine the prostacyclin (PGI₂) and thromboxane A₂ (TXA₂) synthetase activities of myocardial tissue and their variation during ischemia and reperfusion. Regional ischemia was induced by 10 min occlusion of the left anterior descending coronary artery in isolated Langendorff rabbit hearts. Biosynthesis of PGI₂ and TXA₂ were carried out by using arachidonic acid as substrate and left ventricle microsomes (LVM) from ischemic and non-ischemic areas as sources of PGI₂ and TXA₂ synthetase. 6-keto-PGF_1α and TXB₂, stable metabolites of PGI₂ and TXA₂ respectively, were determined by radioimmunoassay. Experiments carried out under the adopted conditions showed that LVM were able to synthetise PGI₂ as well as TXA₂ from arachidonic acid. On the other hand, ischemia depressed both PGI₂ and TXA₂ synthetase activities of cardiac tissue: the depression was more pronounced on TXA₂ synthetase than on PGI₂ synthetase with no significant difference between ischemic and non-ischemic regions. Moreover, ischemia increased the ratio indicating therefore that it can facilitate the formation of PGI₂. The post ischemic reperfusion of the heart counteracted the decrease in PGI₂ synthetase induced by ischemia which returned to the normal level: reperfusion also slightly reversed the decrease in TXA₂ synthetase. However, the diminution in TXA₂ synthetase of non-ischemic myocardium was attenuated but it remained lower than the normal level. These results suggested that the whole left ventricle is affected by regional ischemia. Furthermore it appears that myocardial TXA₂ synthetase is more vulnerable than PGI₂ synthetase to a lack of oxygen and nutrients.     

Effects of nitrogen dioxide exposure on prostacyclin synthesis in lung and thromboxane A2 synthesis in platelets in rats

Effects of nitrogen dioxide (NO₂) exposure on prostacyclin (PGIP₂) synthesis in the rat lung and thromboxane A₂ (TXA₂) synthesis in the platelets were studied. Male Wistar rats were exposed to 10 ppm NO₂ for 1, 3, 5, 7 and 14 days. PGI₂ synthesizing activity of homogenized lung decreased. The damage of PGI₂ synthesizing activity reaches its maximum at 3 days. At 14 days, PGI₂ synthesizing activity returned to the normal level. The activity of PGI₂ synthetase decreased significantly. The formation of lipid peroxides due to NO₂ exposure may cause the depression of PGI₂ synthesizing activity of lung. On the other hand, platelet TXA₂ synthesizing activity increased. This increased TXA₂ synthesizing activity lasted at least till 3 days. Then, it returned to the normal level. The counts of platelet were decreased significantly by 1, 3, 5 and 7 days NO₂ exposure. Then the decreased counts of platelet returned to the normal level at 14 days NO₂ exposure. These results indicate that the depression of PGI₂ synthesizing activity lung by NO₂ exposure cause an increase in TXA₂ synthesizing activity of platelets. It may contribute to induce platelet aggregation and to the observed decrease in the number of platelets during NO₂ exposure.     

Prostacyclin and thromboxane formation in human umbilical arteries following stimulation with vasoactive autacoids

The formation of prostacyclin (PGI₂) and thromboxane A₂ (TXA₂) (measured as the stable metabolites 6-keto-PGF_1α and TXB₂) during stimulation with vasoactive autocoids was registered in human umbilical arteries perfused . Responses were registered within 3–4 minutes after addition of the subtances. Both angiostensin I and II were found to increase the formation of PGI₂ while depressing that of TXA₂. Serotonin increased the formation of TXA₂ but not that of PGI₂. Both PGE₂ and PGF_2α stimulated the PGI₂ formation. The TXA₂ mimetic U46619, increased PGI₂ production, whereas PGI₂ slighlty increased the formation of TXA₂. All responses were found to be completely inhibited by indomethacin.     

Circulatory and platelet actions of 6,9-thiaprostacyclin (PGI2-S) in the cat.

A new analog of prostacyclin, 6,9-Thiaprostacyclin was infused intravenously in pentobarbital anesthetized cats in order to determine its hemodynamic and anti-platelet aggregating properties. At an infusion rate of 0.01 μmoles/kg/min, PGI₂-S moderately decreased arterial blood pressure without altering heart rate of superior mesenteric artery flow or platelet aggregation responses to ADP. However, at 0.05 μmoles/kg/min, PGI₂-S significantly reduced arterial blood pressure and significantly increased heart rate, and superior mesenteric artery flow. Moreover, at 0.05 μmoles/kg/min, PGI₂-S inhibited ADP platelet aggregation by 80%. PGI₂-S may be a useful agent in circulatory shock.     

Dose-related effects of low dose aspirin on hemostasis parameters and prostacyclin/thromboxane ratios in late pregnancy

Background: The purpose of this study was to determine which low dose of low dose aspirin (LDA) optimized the urinary prostacyclin (PGI₂)/thromboxane (TXA₂) ratio and minimized evidence of platelet aggregation during normal late pregnancy.Methods: Twelve women with uncomplicated singleton pregnancies between 28 and 34 weeks gestation participated in a randomized blinded study. Blood samples for salicylate levels were obtained pretreatment, 4 hours and 7 days after administration of placebo, 20mg, 40mg or 80mg of aspirin. Twenty-four hour urine specimens collected at the same intervals were assayed for PGI₂ and TXA₂ metabolites. In addition, bleeding time and platelet aggregation studies were performed prior to and after 7 days of LDA or placebo.Results: A dose-related increase in bleeding time occurred with 40 mg and 80 mg of LDA, but not with the 20 mg dose or placebo. Platelet aggregation studies changed progressively from a normal baseline to abnormal with an increasing dose of LDA. The ratio increased with aspirin doses as low as 20mg, with a decrease in TXA₂ metabolites but not in PGI₂ metabolites. Serum salicylate was not detectable in any sample from any patient.Conclusion: There are dose-related changes in platelet aggregation and bleeding times with progressively increasing doses of LDA. A lower dose of LDA, such as 20–40 mg per day, may be as efficacious as higher doses in the prophylaxis of pre-eclampsia in high risk populations.     

The metabolism of arachidonic acid to an antiaggregatory compound in isolated lungs of fetal and neonatal rabbits

The developmental pattern of fetal and neonatal rabbit lungs to generate an antiaggregatory compound from arachidonic acid (AA) was studied in isolated rabbit lungs, which were perfused with Krebs bicarbonate buffer. The antiaggregatory effect of the nonrecirculating perfussion effluent was tested by adding a small portion of the effluent to human platelet rich plasma (PRP) in a Born-type aggregometer before the aggregation was induced by ADP. The production of an antiaggregatory compound was minimal, when exogenous AA was not infused into the pulmonary circulation. When arachidonate (40 nmol/min) was infused into the pulmonary circulation of rabbits which were 1 day or 1 week old, the perfusion effluent significantly inhibited the ADP induced aggregation of PRP. Perfused lungs from fetal rabbits (gestation age 28–31 days) formed also an antiaggregatory compound fro AA, but the antiaggregatory effect was not as great as 1 day after birth. It seems that neonatal rabbit lungs metabolize AA more to an antiaggregatory compound than late fetal lungs. The fact that the AA induced production of an antiaggregatory compound is inhibited by simultaneous infusion of indomethacin favours the hypothesis that this antiaggregatory compound could he PGI₂.     

Effect of dipyridamole of prostaglandin generation by human platelets and vessel walls

These experiments were conducted to determine the effects of dipyridemole on human platelet aggregation, platelet thromboxane A₂ (TXA₂) and human vessel wall prostacyclin (PGI₂) generation. Dipyridamole in varying concentrations (5 to 50 μg/ml) had no direct effect on ADP-induced platelet aggregation in vitro, but it potentiated PGI₂-induced platelet aggregation inhibition at these concentrations. Dipyridamole also inhibited arachidonic acid-induced platelet TXA₂ generation at these concentrations. In continuously perfused umbilical vein segments, dipyridamole treatment resulted in stimulation of PGI₂ release determined by bioassay and by measurement of its stable metabolite 6-keto-PGF_1α. Minimum concentration of dipyridamole causing PGI₂ release was 50 μg/ml. These in vitro studies suggest that anti-thrombotic effects of dipyridamole in man are mediated mainly by potentiation of PGI₂ activity and to some extent by TXA₂ suppression. Stimulation of PGI₂ release by human vessels may not be seen in usual therapeutic concentrations.     

Manipulation of thrombus formation in the hamster cheek pouch with drugs that interact with PGI2in vitro

A single platelet thrombus was formed in an arteriole of the hamster cheek pouch by electrical stimulation followed by topical application of ADP. The sizes of the thrombi were continuously recorded with a photocell placed on a TV monitor screen and quantified by areas on the record. Repeated application of small doses of ADP (5–15 nmol/10 μl) resulted in very reproducible formation of the thrombi, and the size of the thrombi was reduced dose-dependently by topical application of PGI₂. Three drugs were tested in this model. Cycloxygenase inhibitor (indomethacin 10 mg/kg, i.p.) increased the formatiion of thrombi, while a smaller dose (3 mg/kg) did not have any significant effect. This could be explained by inhibition of the generation of endogemous PGI₂, since aggregation of hamster platelets by ADP was not inhibited by indomethacin $\text{in vitro}$. EG-626 (phthalazinol, a phosphodiesterase inhibitor) (300 mg/kg, i.p.) decreased the size of thrombus. AI-122 (1.0 mg/kg, i.p.) which has been proven to enhance PGI₂ biosynthesis from isolated rat aortae, also decreased the formation. Thus, drugs such as EG-626 or AI-122 are quite promising as anti-thrombic drugs.