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PubMed1987

Platelet resistance to prostacyclin. Enhancement of the antiaggregatory effect of prostacyclin by pentoxifylline.

With regard to existence of high prostacyclin (PGI2) levels during atheromatosis and thrombus formation, resistance of platelets to prostacyclin and its analogues seems to play an important pathophysiologic key role for the clarifying of vasoocclusive phenomena. Platelet resistance to prostacyclin was studied in vitro and ex vivo in 160 atherosclerotic patients (assessed by objective diagnostic criteria) with and without thrombotic complications and in 50 controls. Prostacyclin resistance phenomena were more pronounced and frequent in patients with occlusive complications, the difference from controls being statistically significant. However, there was no significant difference between the controls and the nonthrombotic patient sample. The intraplatelet cAMP levels might be the metabolic basis of the PGI2 resistance phenomenon, because in the patient group, platelet cAMP levels were decreased by 50% after Ca2+ stimulation. Compared to controls beta-thromboglobulin and thromboxane B2 plasma levels were significantly increased (30 +/- 9 to 87 +/- 26 ng/ml and 9 +/- 5 to 54 +/- 21 pg/ml, respectively), confirming the hyperreactivity state of resistant platelets. From the therapeutic point of view, patients with resistant platelets require PGI2 doses that cause, however, increased side effects. We were able to demonstrate in vivo that IV pretreatment with pentoxifylline--a known stimulator of cAMP formation in platelets--followed by a simultaneous and continuous IV infusion of PGI2 + pentoxifylline, permitted us to reduce significantly the mean PGI2 doses needed for triggering an antiplatelet effect, without inducing side effects. In ex vivo studies, PGI2 resistant platelets of atherosclerotic patients pretreated with pentoxifylline showed normalized stimulation response, and platelet cAMP levels increased from 7.8 +/- 2.7 to 15.2 +/- 1.9 pmol/10(8) platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2004

New developments on thromboxane and prostacyclin modulators part II: prostacyclin modulators.

Prostacyclin (PGI(2)) is a potent endogenous inhibitor of platelet function and possesses a strong vasodilator effect. Furthermore, prostacyclin is currently presented as the physiologic antagonist of thromboxane A(2)(TXA(2)), which exhibits pro-aggregatory and vasoconstrictor properties. So, the balance between PGI(2) and TXA(2) production is crucial for the cardiovascular system. Indeed, an imbalance in the production or effect of these products is deleterious for the circulatory system and can lead to characterized vascular diseases such as hypertension, stroke, atherosclerosis or myocardial infarction. Although the biological effects of PGI(2) are considered to be clinically useful, its use as therapeutic agent is largely limited by both its chemical and metabolic instability. Actually, several prostacyclin agonists have been synthesized and pharmacologically evaluated. Among these, some have been clinically evaluated as therapeutic agents in several vascular diseases. This review focuses on the latest chemical and pharmacological developments in the field of the prostacyclin agonists.

Cardiovascular System↗

PubMed1982

Abnormal prostacyclin metabolism in the hemolytic uremic syndrome: equivocal effect of prostacyclin infusions.

In a child with the hemolytic uremic syndrome, plasma 6 keto-prostaglandin F1 alpha levels remained undetectable throughout the acute phase of the disease. The patient's plasma failed to stimulate prostacyclin production by "exhausted" rat aorta rings. In vitro study of the patient's vessels indicated that they retained the capacity to synthesize prostacyclin from exogenous arachidonic acid but that their endogenous arachidonic acid stores were either depleted or non-available. The response to repeated infusion of exogenous prostacyclin was equivocal, suggesting that abnormal prostacyclin metabolism in the hemolytic uremic syndrome may not be the only factor in its pathogenesis.

Child, Preschool↗

PubMed1983

Effect of 7-fluoro prostacyclin, a stable prostacyclin analogue, on cAMP accumulation and prostaglandin binding in mastocytoma P-815 cells.

The effect of 7-fluoro prostacyclin (PGI2-F), a chemically stable analogue of prostacyclin, on cAMP accumulation in and [3H]PGE binding to mastocytoma P-815 cells was compared with those of the Na salt and methyl ester of prostacyclin (PGI2-Na or PGI2-Me), which are rapidly inactivated in aqueous solution or metabolized in the tissue. PGI-F was as effective as PGI2-Me, and slightly less effective than PGI2-Na in stimulating cAMP accumulation in mastocytoma cells and rabbit platelets. PGI2-F was also more stable than PGI2-Me or PGI2-Na, and retained its original cAMP elevating activity even after incubation with or without cells for 4 h at 37 degrees C. Cells which had been exposed to PGI2-F and then washed free of unbound reagent continued to produce cAMP for more than 3 h. PGI2-F was also as effective as PGE1 or PGE2 in displacing [3H]PGE2 bound to the cells. Non-competitive inhibition by PGI2-F or PGI2-Me of [3H]PGE2 binding to the cells, with apparent Kis of 1.29 microM and 1.13 microM, respectively, indicates the presence of different receptors for PGE2 and for PGI2-F or PGI2-Me in mastocytoma P-815 cells.

Animals↗

PubMed1984

Evidence for isosorbide dinitrate (ISDN) promoting effect on prostacyclin release by the lung and prostacyclin implication in ISDN-induced inhibition of platelet aggregation in humans.

We investigated thromboxane B2 (TxB2), 6-keto-PGF1 alpha (6KPGF1 alpha reflecting prostacyclin), PGE2 and PGF2 alpha plasma levels; TxB2, PGE2 and PGF2 alpha platelet production and platelet aggregation response in ascending aorta (reflecting trans-pulmonary difference) and in venous coronary sinus (reflecting transcardiac difference) simultaneously in patients with ischemic heart disease, before and after right-atrial administration of 3 mg ISDN bolus. Transcardiac differences were scarce before as well as after ISDN administration. In aortic blood, ISDN administration into the right atria resulted in a significant increase in prostacyclin and PGF2 alpha plasma levels (472% and 242%, respectively), a decrease of both PGE2 plasma level (-173%) and PGE2 platelet production (-485%) and a marked lowering of platelet aggregation response to ADP, concomittantly. In contrast, TxB2-related features were poorly affected by ISDN. In coronary sinus blood, the aortic increase in 6KPGF1 alpha and PGF2 alpha plasma levels was detected to a lower extent whereas the characteristics of platelet aggregation had returned to control levels. By contrast, PGE2 plasma level (-191%) and PGE2 platelet production (-133%) were lower than prior ISDN administration. The results we report here, strongly support the view that ISDN promotes release of prostacyclin and PGF2 alpha from the lung and inhibit PGE2 production. These prostanoids may be responsible for the concomittant platelet reactivity lowering, thus providing a basis for understanding how ISDN might relieve myocardial ischemia favoring prostanoid mediated vasodilation and inhibition of platelet reactivity.

6-Ketoprostaglandin F1 alpha↗

PubMed2005

Role of prostacyclin versus peroxisome proliferator-activated receptor beta receptors in prostacyclin sensing by lung fibroblasts.

Prostacyclin and its mimetics are used therapeutically for the treatment of pulmonary hypertension. These drugs act via cell surface prostacyclin receptors (IP receptors); however, some of them can also activate the nuclear receptor peroxisome proliferator-activated receptor beta (PPARbeta). We examined the possibility that PPARbeta is a therapeutic target for the treatment of pulmonary hypertension. Using the newly approved (for pulmonary hypertension) prostacyclin mimetic treprostinil sodium, reporter gene assays for PPARbeta activation and measurement of lung fibroblast proliferation were analyzed. Treprostinil sodium was found to activate PPARbeta in reporter gene assays and to inhibit proliferation of human lung fibroblasts at concentrations consistent with an effect on PPARs but not on IP receptors. The effects of treprostinil sodium on human lung cell proliferation are mimicked by those of the highly selective PPARbeta ligand GW0742. There are no receptor antagonists for PPARbeta or for IP receptors, but by using lung fibroblasts cultured from mice lacking PPARbeta (PPARbeta-/-) or IP (IP-/-), we demonstrate that the antiproliferative effects of treprostinil sodium are mediated by PPARbeta and not IP in lung fibroblasts. These observations suggest that some of the local, longer-term benefits of treprostinil sodium on reducing the remodeling associated with pulmonary hypertension may be mediated by PPARbeta. This study is the first to identify PPARbeta as a potential therapeutic target for the treatment of pulmonary hypertension, which is important because orally active PPARbeta ligands have been developed for the treatment of dyslipidemia.

Animals↗

PubMed1985

Experimental endotoxemia in the rat: efficacy of prostacyclin or the prostacyclin analog iloprost.

The purpose of this study was to examine the effects of PGI2 and iloprost, a prostacyclin analog, on the sequelae of experimental endotoxic shock. Endotoxemia was produced in rats by IV injection of 20 mg/kg Salmonella enteritidis (LPS). Mean arterial blood pressure fell from 117 +/- 5 mmHg (N = 22) to 92 +/- 5 mmHg and 71 +/- 10 mmHg at 30 and 180 min post-LPS, respectively. In LPS vehicle-treated rats, blood glucose levels fell from 100 +/- 10 mg/dl to 36 +/- 8 mg/dl at 180 min. Plasma glutamate-oxaloacetate transaminase and lactate dehydrogenase (liver fraction) activities were significantly elevated above concentrations in nonshocked animals, increasing to 426 +/- 86 IU/ml and 1,019 +/- 339 IU/ml, respectively. Infusion of PGI2 or iloprost (0.5 micrograms/kg/min) did not alter the blood pressure response to LPS compared to vehicle controls. PGI2 significantly prevented the LPS-induced hypoglycemia while neither treatment significantly reduced the elevations in plasma enzymes nor prevented the lethality of LPS. Thus, the hemodynamic and biochemical indices of shock severity were not significantly improved by either prostacyclin or iloprost. It is suggested that the beneficial effects of PGI2 or prostacyclin analogs observed in other species during endotoxemia does not extend to the rat.

Animals↗

PubMed1990

Heparin and acidic fibroblast growth factor interact to decrease prostacyclin synthesis in human endothelial cells by affecting both prostaglandin H synthase and prostacyclin synthase.

Prostaglandin production by cultured human endothelial cells varies with growth conditions. We observed a marked diminution in both spontaneous and inducible production of prostacyclin (PGI2) by human umbilical vein and saphenous vein endothelial cells when they were cultured in the presence of the heparin-binding growth factor, acidic fibroblast growth factor (aFGF) and heparin, compared with PGI2 production during culture in medium lacking these factors. Decreased PGI2 production was related to duration of exposure of the cells to aFGF and heparin and depended on the concentration of both substances. Heparin (1-100 micrograms/ml) strongly potentiated the effects of aFGF but had a limited and variable effect alone. The decrease in PGI2 production correlated with a reduction in the cellular content of immunoreactive prostaglandin H synthase and prostacyclin synthase. Arachidonate deacylation was not decreased. In addition, the eicosanoid profile of endothelial cells was changed by exposure to aFGF and heparin. These studies indicate that heparin acts as a modulator of prostaglandin synthesis in endothelial cells through its interaction with aFGF, mediated by alterations in two key enzymes in the arachidonate metabolic pathway.

Arachidonic Acid↗

PubMed1986

Rapid recovery of in vivo prostacyclin formation after inhibition by aspirin. Evidence from measurements of the major urinary metabolite of prostacyclin by GC-MS.

The effect of aspirin on the in vivo formation of prostacyclin and thromboxane A2 in normal healthy individuals was studied by measuring the urinary excretion of 2,3-dinor-6-keto-PGF1 alpha and 2,3-dinor-TxB2 by gas chromatography-mass spectrometry. Administration of 500 mg aspirin twice daily caused a sustained reduction in the excretion of 2,3-dinor-TxB2 to 10-15% of the predose value, while the excretion of 2,3-dinor-6-keto-PGF1 alpha was reduced for only about 3 hours after the aspirin dose. The data demonstrate a considerable difference in the inhibitory effect of aspirin on the in vivo synthesis of thromboxane A2 and prostacyclin.

6-Ketoprostaglandin F1 alpha↗

PubMed1984

The use of a prostacyclin analogue, [3H]iloprost, for studying prostacyclin-binding sites on human platelets and neuronal hybrid cells.

The stable prostacyclin analogue [3H]iloprost has been used for labelling prostacyclin-binding sites on human platelets and NCB-20 neuronal hybrid cells. The ligand-binding properties of the sites have been determined and correlate well with stimulation of cAMP synthesis in NCB-20 cells and inhibition of aggregation in human platelets.

1-Methyl-3-isobutylxanthine↗

PubMed1995

Prostacyclin receptor in the brain and central terminals of the primary sensory neurons: an autoradiographic study using a stable prostacyclin analogue [3H]iloprost.

Presence and localization of the prostacyclin receptor in the rat brain and spinal cord were examined by in vitro autoradiography using [3H]iloprost, a highly specific and stable agonist for this receptor. Density of specific binding sites for iloprost was generally high in four regions of the lower brain stem, that is, the medial and commissural subnuclei of the nucleus tractus solitarius, the area postrema, superficial layers of the spinal trigeminal nucleus caudalis and dorsal horn. Moderate density was found in the thalamus, cerebral cortex, hippocampus, striatum and dorsal cochlear nucleus. The distribution pattern was distinct from those of other prostanoid binding sites previously studied except that prostaglandin E2 binding sites were also abundant in the nucleus tractus solitarius, spinal trigeminal nucleus caudalis and dorsal horn. Even in these regions, binding sites for iloprost had several features clearly different from those for prostaglandin E2. First, within the medial and commissural subnuclei of the nucleus tractus solitarius, iloprost binding sites were distributed preferentially in the dorsal part, while those for prostaglandin E2 were located more ventrolaterally. Second, on postnatal day 0, iloprost binding sites have already been expressed in large amounts in the nucleus tractus solitarius, spinal trigeminal nucleus caudalis and dorsal horn of rats, while prostaglandin E2 binding sites are negligible at this stage. Thirdly, the binding of 10 nM [3H]iloprost in these three regions was almost completely displaced by 10 microM unlabelled iloprost but only slightly by 10 microM unlabelled prostaglandin E2. Unilateral nodose ganglionectomy or dorsal rhizotomy decreased the density of iloprost binding sites in the nucleus tractus solitarius or dorsal horn, respectively, with a greater decrease in the operated side. Ligation of the vagus either central or peripheral to the nodose ganglion resulted in an accumulation of iloprost binding sites proximal to the ligation. These results suggest that specific binding sites for iloprost, presumably prostacyclin receptor, are present in the nervous system and, in particular, that the iloprost binding sites in the nucleus tractus solitarius, dorsal horn and possibly in the superficial layers of the spinal trigeminal nucleus caudalis are produced in their sensory ganglia and transported to central terminals of the primary sensory afferents as well as to their peripheral terminals.

Animals↗

PubMed1988

The adenylate cyclase of rheumatoid synovial fluid macrophages is more sensitive for dl-5E, 19,14-di dehydro-carbo-prostacyclin, a stable prostacyclin analogue, than for prostaglandin E2.

dl-5E, 19,14-di dehydro-carbo-prostacyclin (DDH-carbo PGI2), a stable prostacyclin (PGI2) derivative, but not prostaglandin (PG) E2, stimulated the adenylate cyclase of synovial fluid macrophages, isolated from rheumatoid patients with an active synovitis, in a dose dependent manner (10-1000 ng/ml). DDH-carbo PGI2 also stimulated synovial macrophage cAMP synthesis when injected into the knee joint. Exogenous arachidonic acid (AA) had little effect on cyclic-AMP (cAMP) formation or PGI2 release (assayed as 6ketoPGF1 alpha). It stimulated, however, the release of PGE2 and, to a lesser extent, thromboxane (Tx) A2 (measured as TxB2).

Adenylyl Cyclases↗

PubMed2004

17beta-estradiol up-regulates prostacyclin production in cultured human uterine myometrial cells via augmentation of both cyclooxygenase-1 and prostacyclin synthase expression.

OBJECTIVE: To investigate whether 17beta-estradiol elevates prostacyclin (PGI(2)) production in human myometrial cells in the middle of gestation. METHODS: The concentration of 6-keto-PGF(1alpha), a stable metabolite of PGI(2), in the culture medium was assessed using enzyme-linked immunosorbent assay (ELISA). Western blot analysis and quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) using TaqMan (Applied Biosystems, Foster City, CA) technology were performed to evaluate the expression of cytosolic phopholipase A(2) (cPLA(2)), cyclooxygenase-1 (COX-1), COX-2, and prostacyclin synthase (PGIS) in cultured human myometrial cells prepared from second trimester pregnant women (n = 3) after stimulation with 17beta-estradiol. RESULTS: Treatment with 17beta-estradiol (4-400 nM) dose-dependently elevated PGI(2) secretion from cultured human myometrial cells. Western blot analysis detected cPLA(2) and COX-1 and PGIS protein expression in the cultured human myometrial cells; however, COX-2 protein expression was below the detection sensitivity. Stimulation with 40-nM 17beta-estradiol significantly up-regulated protein and mRNA expression of both COX-1 and PGIS. CONCLUSION: 17beta-Estradiol from placenta may contribute to the augmentation of PGI(2) production in the human myometrium in the middle of gestation via up-regulation of both COX-1 and PGIS expression.

6-Ketoprostaglandin F1 alpha↗

PubMed2002

Cyclic mechanical stretch augments prostacyclin production in cultured human uterine myometrial cells from pregnant women: possible involvement of up-regulation of prostacyclin synthase expression.

Prostacyclin (PGI(2)), a potent smooth muscle relaxant, is a major prostaglandin secreted from human myometrium. The concentrations of PGI(2) metabolites in the maternal plasma were reported to be elevated during pregnancy, especially in labor. To clarify the mechanism in PGI(2) secretion from the myometrium, we first investigated the protein expression of cytosolic phospholipase A(2), cyclooxygenase (COX)-1, COX-2, and prostacyclin synthase (PGIS) in the human uterine myometrium at various gestational ages before labor. To elucidate the involvement of labor in the increase in PGI(2) production during labor, we next examined the effect of labor-like cyclic mechanical stretch on PGI(2) production by cultured human myometrial cells. Pregnancy specifically increased COX-1 and PGIS protein expression in the myometrial tissues before labor (P < 0.01 for both). Cyclic mechanical stretch augmented PGIS promoter activity, via activation of activator protein-1 site, and PGIS mRNA and protein expression in cultured human myometrial cells and resulted in a 3.5-fold increase in the concentration of 6-keto-prostaglandin F(1alpha), the stable metabolite of PGI(2), in the culture medium (P < 0.05). However, stretch did not affect the levels of prostaglandin E(2), prostaglandin F(2alpha), or thromboxane A(2) secreted into the same culture media. These results suggest that cyclic mechanical stretch during labor may contribute to the increase in the PGI(2) concentration in the maternal plasma during parturition.

Benzoquinones↗

PubMed1987

Effects of acute pressure overload on prostacyclin release and myocardial blood flow in canine hearts: inhibition of prostacyclin synthesis with 15-hydroperoxy-eicosatetraenoic acid.

This study was undertaken to evaluate the effects of acute pressure overload on prostacyclin (PGI2) release and the influences of 15-hydroperoxy-eicosatetraenoic acid (15-HPETE), an inhibitor of PGI2 synthetase, and indomethacin, an inhibitor of cyclo-oxygenase, in canine hearts. Gradual stenosis of the ascending aorta was performed in 24 anesthetized open-chest dogs. The mongrel dogs were divided into three groups, which received indomethacin, 15-HPETE, and no drug. Changes in the hemodynamics, regional myocardial blood flow (MBF) by the method of H2 gas clearance, and plasma immunoreactive 6-keto-prostaglandin (PG) F1 alpha level in the descending aorta (AO) and great cardiac vein (GCV) were measured. Five minutes after aortic stenosis, the plasma immunoreactive 6-keto-PGF1 alpha level in the GCV and MBF increased from 162 +/- 23 to 289 +/- 37 pg/ml and from 87 +/- 5 to 107 +/- 8 ml/min/100 g, respectively, and the calculated coronary vascular resistance (CVR) decreased significantly from 0.93 +/- 0.08 to 0.77 +/- 0.08 mmHg/ml/min/100 g. These significant changes persisted thereafter. Continuous infusion of 15-HPETE (66 pg/kg/min) into the coronary artery simultaneously prevented significant changes in MBF and the plasma immunoreactive 6-keto-PGF1 alpha level in the GCV and CVR. Intravenous infusion of indomethacin (5 mg/kg), on the other hand, induced a significant decrease in the plasma immunoreactive 6-keto-PGF1 alpha level in both the GCV and AO; significant changes in MBF 5 to 15 min after aortic stenosis and CVR were not affected. From these results, it is suggested that PGI2 plays an important role in the regulation of coronary blood flow in canine hearts with acute pressure overload.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗

PubMed1978

Regional differences in prostacyclin formation by the kidney. Prostacyclin is a major prostaglandin of renal cortex.

Microsomes prepared from rabbit renal cortex were found to synthesize substantial amounts of 6-ketoprostaglandin F1alpha from prostaglandin G2 or arachidonic acid during an incubation. In contrast, no 6-ketoprostaglandin F1alpha was formed by renal medullary microsomes which synthesize predominantly prostaglandin E2. Mass spectral confirmation of the structure of 6-ketoprostaglandin F1alpha from these incubations demonstrates the ability of the renal cortex to synthesize prostacyclin.

Animals↗

PubMedDate not supplied

Synergistic inhibitory effects of adrenoceptor antagonists and prostacyclin, and umbilical artery-derived prostacyclin-like activity on platelet aggregation.

Adrenoceptor antagonists are being used increasingly for the treatment of pregnancy-induced hypertension (PIH). Previous studies have shown that these drugs can inhibit platelet aggregation and thromboxane production. The aims of this study were to determine (i) whether adrenoceptor antagonists had any effect on vascular prostacyclin (PGI2) production and (ii) whether these drugs acted synergistically with PGI2 and the PGI2-like activity derived from umbilical artery to inhibit platelet aggregation in vitro. The adrenoceptor antagonists labetalol, pindolol and propranolol were found to have no effect on PGI2 production from the umbilical artery at low drug concentrations. These agents were also found to act synergistically with both pure PGI2 and PGI2-like activity derived from umbilical artery to inhibit platelet aggregation. This synergistic effect may be beneficial in the treatment of disorders which are associated with reduced PGI2 production, such as PIH where such synergy may help compensate for PGI2 deficiency.

6-Ketoprostaglandin F1 alpha↗

PubMed1982

The human placental anti-aggregating factor is neither prostacyclin, nor a prostacyclin metabolite.

Using PGH2 as substrate, we have previously demonstrated that human placenta synthesizes mainly PGE2, TxB2 and PGD2(1,2). Other reports have shown that placental tissue generates a substance which inhibits ADP-induced platelet aggregation and which was supposed to be PGI2 (3). The present study indicates that the stability of that substance is different from the stability of prostacyclin (released by umbilical artery pieces). By GC-MS and multiple ion-monitoring, we have shown the presence of 6-keto-PGF1 alpha (the stable metabolite of PGI2) in the umbilical artery incubation medium, while no trace of 6-keto-PGF1 alpha could be found in the placental medium. No conversion of AA to 6-keto-PGF1 alpha by placental microsomes was observed, even in the presence of antioxidants. The placenta possesses, in addition to the known 15-OH-PGDH and delta-13 reductase activities, a weak 9 OH PGDH which is specific for PGF2 alpha (and not PGI2 nor 6-keto-PGF1 alpha). GC-MS analysis showed that the expected metabolites of PGI2 through those three enzymes were not found in the placental medium, indicating that neither PGI2 synthesis nor metabolism could be demonstrated in the placenta.

15-Oxoprostaglandin 13-Reductase↗