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PubMed1988

The significance of prostacyclin produced by pregnant rat myometrium: the relationship between myometrial prostacyclin producing activity and passive stretch of myometrium by growing conceptus.

The present experiment was performed to elucidate the significance of prostacyclin (PGI2) produced by pregnant rat myometrium. PGI2-like substance producing activity of various portions of the uterus was measured at selected gestational stages by platelet bioassay; surface area per 1 gm of uterine wall enveloping one conceptus was calculated; and spontaneous contractility of myometrium of both conceptus and non-conceptus regions and the effects of authentic PGI2 on it were examined. PGI2-like substance producing activity increased with advancing pregnancy, but the activity varied according to area of the myometrium, being highest in the area where it was most greatly stretched by the growing conceptus and lowest where no conceptus was contained. Spontaneous contractility was reduced in regions with high PGI2 producing activity. Though authentic PGI2 generally exhibited a stimulatory effect, it had an inhibitory effect on Day 10 pregnant myometrium. From these results, it may be concluded that the producing activity of PGI2, which remarkably increases in the conceptus region with the advance of pregnancy, keeps the uterine wall relaxed, making the uterus adapt to the growth of the fetus. Passive myometrial stretch by the growing conceptus is thought to be one of factors which enhance myometrial PGI2 producing activity.

Animals↗
PubMed1991

TEI-9063, a stable and highly specific prostacyclin analogue for the prostacyclin receptor in mastocytoma P-815 cells.

The prostacyclin (PGI2) analogues, TEI-9063 and its methyl ester, TEI-1324, have been compared with another stable analogue, iloprost, with respect to binding to the PGI2 receptor, stimulation of adenylate cyclase activity and inhibition of thrombin-induced Ca2+ mobilization in mastocytoma P-815 cells. TEI-9063 displaced the [3H]iloprost binding to the membrane fraction, the IC50 value being 3 nM, but showed very low affinity for the PGE receptor. TEI-9063 dose dependently stimulated cAMP formation in the cells and GTP-dependent adenylate cyclase activity in the membrane fraction, the EC50 value being 50 and 10 nM, respectively. Furthermore, TEI-9063 prevented the thrombin-induced increase in the intracellular Ca2+ concentration, the IC50 value being 50 nM. These IC50 and EC50 values are lower than those obtained for iloprost. On the other hand, those of TEI-1324 were about two-orders higher. Although PGI2 lost its ability to stimulate cAMP formation by preincubation for 20 min at 37 degrees C, TEI-9063 completely retained its ability after 60-min preincubation. These results demonstrate that TEI-9063 is a stable and stronger agonist for the PGI2 receptor than iloprost, and that it prevents thrombin-induced Ca2+ mobilization through stimulation of the adenylate cyclase system in mastocytoma cells.

Adenylyl Cyclases↗
PubMed1990

Cellular distribution of prostacyclin synthase and specific prostacyclin binding sites in bovine corpora lutea of pregnancy.

The cellular distribution of prostacyclin (PGI2) synthase and specific PGI2 binding sites was investigated by light microscope immunocytochemistry and quantitative autoradiography. The immunostaining for the enzyme was found in small (15-18 microns) and large (18-45 microns) cells as well as in non-luteal cells, arteriole smooth muscle and endothelium. There was no consistent difference between small and large luteal cells and luteal vs. non-luteal cells in the immunostaining. Vascular smooth muscle and endothelial cells, on the other hand, contained less immunostaining than the other cells. Contrary to wide-spread distribution of PGI2 synthase, specific PGI2 binding sites were only found in the luteal cells. On a per cell basis, large luteal cells contained more sites than small luteal cells and vice versa when expressed per unit cell area. The [3H]PGI2 binding to the luteal cells was time and temperature dependent and was inhibited by excess unlabeled PGI2 but not by its metabolite, 6-keto-PGF1 alpha or other eicosanoids which bind to their own receptors. In conclusion, while PGI2 synthase is widely distributed among different cell types in bovine corpora lutea, specific binding sites which may mediate luteotropic actions of PGI2 are only present in small and large luteal cells.

Animals↗
PubMed1993

Effects of starvation on the urinary contents of primary thromboxane and prostacyclin metabolites and a possible selenium-dependent role of prostacyclin in the renal handling of ketone bodies.

The aim of this study was to investigate whether urinary prostanoids, as an index of renal synthesis of these compounds, are affected in selenium (Se) deficiency and, if so, whether such changes could add to our understanding of the high excretion of ketone bodies in Se-deficient rats (p < 0.005 vs Se-adequate rats). Male rats were fed a Se-deficient diet with less than 0.01 mg Se/kg or the same diet supplemented with 0.2 mg Se/kg. The urinary contents of prostaglandin E2 (PGE2), PGF2 alpha and 6-keto PGF1 alpha were not significantly affected by the Se status. However, there was a positive correlation between the urinary contents of ketone bodies and 6-keto PGF1 alpha in Se deficiency (with p < 0.02 for acetaoacetate and p < 0.05 for 3-hydroxybutyrate). In contrast, only negative (nonsignificant) relationships were observed between these same parameters in Se-adequate rats. No correlations between urinary contents of ketone bodies and PGE2, PGF2 alpha or thromboxane B2 (TXB2) were obtained. Compared to fed rats, starvation caused a 4-fold increase in the urinary TXB2 content in Se-adequate, as well as in Se-deficient rats (p < 0.001). Starvation had an opposite effect on the content of 6-keto PGF1 alpha, which decreased (to 64% that of fed animals p < 0.001) in Se-adequate rats and, nonsignificantly (to 93% that of fed animals) in the Se-deficient group. It is concluded that starvation profoundly affects the urinary contents (and thus, probably renal synthesis) of TX and prostacycline (PGI2).(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1999

Altered gene expression of prostacyclin synthase and prostacyclin receptor in the thoracic aorta of spontaneously hypertensive rats.

OBJECTIVE: The aim of this study was to evaluate the possible role of prostacyclin (PGI2) in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR). METHODS: Measurement of mRNA and protein levels of PGH synthase (PGHS)-1, PGI2 synthase and the PGI2 receptor, in the thoracic aorta was performed in SHR aged 5, 10, 20, and 40 weeks old and in age-matched normotensive Wistar-Kyoto (WKY) rats with a competitive polymerase chain reaction method and immunoblotting. Aortic production of 6-keto-PGF1 alpha, the main metabolite of PGI2, was also measured. RESULTS: Compared with age-matched WKY rats, PGHS-1 mRNA and protein levels in the thoracic aorta of SHR increased with age, reaching three- and twofold higher than WKY rats at 40 weeks old, respectively. PGI2 synthase mRNA and protein levels in SHR were significantly higher than in WKY rats at 20 and 40 weeks old. In contrast, PGI2 receptor mRNA levels in SHR were consistently lower than in WKY rats at all ages. CONCLUSIONS: These results provide evidence that hypertension elicits alterations in levels of arachidonic acid metabolites, including PGH2 and PGI2. They also suggest that the decreased expression of PGI2 receptor mRNA in prehypertensive SHR could be one of the causes of hypertension in SHR.

Aging↗
PubMed1999

The mechanism of thrombin-induced prostacyclin synthesis in human endothelial cells with reference to the gene transcription of prostacyclin-related enzymes and Ca2+ kinetics.

This study was designed to evaluate the effect of thrombin on prostacyclin (PGI2) production in cultured human vascular endothelial cells in association with intracellular Ca2+ and with the gene expression of prostaglandin H2 synthase (PGHS) and phospholipase A2 (PLA2) using competitive polymerase chain reaction. Thrombin enhanced the PGI2 synthesis dependent with time. Additionally, thrombin increased the intracellular Ca2+, which stimulates PLA2, resulting in arachidonic acid cleavage from membrane phospholipids and its subsequent conversion into PGI2 through the PGHS pathway. The elevation of intracellular Ca2+ was a result of Ca2+ influx and Ca2+ release from its intracellular storage sites. In this study, PGHS-1 mRNA was constitutively expressed, whereas PGHS-2 mRNA was not. With the stimulation of thrombin, cytosolic PLA2 (cPLA2) mRNA increased 9-fold at 15 min, PGHS-1 mRNA increased 3.4-fold at 180 min, and PGHS-2 mRNA increased 38-fold at 60 min. These results suggest that the elevation of intracellular Ca2+ and the expression of cPLA2, PGHS-1, and PGHS-2 mRNA cause PGI2 generation.

Calcium↗
PubMed2006

Engineering of a protein with cyclooxygenase and prostacyclin synthase activities that converts arachidonic acid to prostacyclin.

Prostacyclin (PGI2), a vascular protector with vasodilation and antithrombotic properties, is synthesized by coupling reactions of cyclooxygenase (COX, the first enzyme) with PGI2 synthase (PGIS, the second enzyme) using arachidonic acid (AA) as an initial substrate. The first COX product, prostaglandin H2 (PGH2) is also a command substrate for other prostanoid enzymes that produce distinct eicosanoids, such as thromboxane A2 (TXA2). The actions of TXA2 to cause vasoconstriction and platelet aggregation oppose the vasodilatory and anti-aggregatory effects of PGI2. Specifically upregulating PGI2 biosynthesis is an ideal model for the prevention and treatment of the TXA2-mediated thrombosis involved in strokes and myocardial infarctions. Here, we report that a single protein was constructed by linking COX-2 and PGIS together to form a new fusion enzyme through a transmembrane domain with 10 or 22 residues. The engineered protein expressed in HEK293 and COS-7 cells was able to continually convert AA to prostaglandin (PG) G2 (catalytic step 1), PGH2 (catalytic step 2), and PGI2 (catalytic step 3). The studies first demonstrate that a single protein with three catalytic functions could directly synthesize PGI2 from AA with a Km of approximately 3.2 microM. Specific upregulation of PGI2 biosynthesis through expression of the engineered single protein in the cells has shown strong activity in inhibiting platelet aggregation induced by AA in vitro, which creates a great potential for the fusion enzyme to be used as one of the new therapeutic interventions for strokes and heart attacks. The studies have also provided a model linking COX with its downstream enzymes to specifically regulate biosynthesis of eicosanoids which have potent biological functions.

Amino Acid Sequence↗
PubMed1991

Possible role of prostacyclin synthase in altered prostacyclin generation in DOCA-salt hypertensive rats.

Prostacyclin (PGI2) synthase is one of the key enzymes for vasodepressor PGI2 biosynthesis in the vascular wall. In this study, we attempted to define the alterations in PGI2 synthase and its role in the PGI2 generation in the vascular wall of deoxycorticosterone acetate (DOCA)-salt rats. The PGI2-generating capacity was enhanced significantly when DOCA-salt rats established hypertension, whereas the generation of other arachidonate metabolites, eg, PGE2, PGF2 alpha, and thromboxane, was unaltered. Moreover, the increase in PGI2 generation was associated with an increase in PGI2 synthase activity in the vascular wall. Indeed, the averaged PGI2 generating capacity was closely correlated to the averaged PGI2 synthase activity in DOCA-salt hypertensive rats and three lines of control rats. Incontrast, phospholipase C and phospholipase A2, both of which liberate arachidonate for PGI2 synthesis, were rather lowered in DOCA-salt hypertensive rats. These data clearly indicate that vascular PGI2 generation is increased in the development of DOCA-salt hypertension and that PGI2 synthase is mainly responsible for this enhancement. The increased PGI2 synthase may be relevant to the blood pressure elevation and is expected to have beneficial effects on the vascular protection in hypertension.

Animals↗
PubMed1987

Comparison of inhibitory actions of prostacyclin and a new prostacyclin analogue on the aggregation of human platelet in whole blood.

Prostacyclin (PGI2), an unstable endogenous prostanoid, is a potent vasodilator and inhibitor of platelet aggregation. The use of exogenous PGI2 as an antithrombotic agent is limited by its chemical instability and lack of dissociation between its vasodilatory and antithrombotic actions. Iloprost (ZK36374) is a recently developed, chemically stable, carbacyclin analogue of PGI2. Preliminary evaluation studies have shown a significant dissociation between vasodilatory and antithrombotic actions of Iloprost. We have compared the effects of PGI2 and Iloprost on platelet aggregation in human whole blood. Platelet aggregation was induced by ADP (4 microM), adrenaline (Adr, 0.4 microM) and arachidonic acid (AA, 0.4 mM). Aggregation was quantified as a fall in the number of single platelets counted using the Clay Adams Ultra Flo 100 whole blood platelet counter. In the absence of any PGI2 or Iloprost, each aggregating agent induced up to an 80% fall in the number of single platelets counted. When blood was pre-incubated with PGI2 (1-6 nM) or Iloprost (1-6 nM), aggregation responses to all three aggregating agents were inhibited in a dose-dependent manner. Iloprost was equipotent to PGI2 against ADP-induced aggregation but was more potent than PGI2 against Adr- and AA-induced aggregation. It is concluded that Iloprost, as a chemically stable PGI2 analogue, may be superior to PGI2 as an antithrombotic agent.

Adenosine Diphosphate↗
PubMed1990

Increased hydrolysis of cholesteryl ester with prostacyclin is potentiated by high density lipoprotein through the prostacyclin stabilization.

Prostacyclin (PGI2) has been reported to stimulate activities of acid cholesteryl ester hydrolase (ACEH; EC 3.1.1.13) and neutral cholesteryl ester hydrolase (NCEH; EC 3.1.1.13) in the smooth muscle cells leading to a decrease in intracellular cholesteryl ester. Recently, we have found that the half-life of PGI2 was prolonged through stabilization by HDL. HDL is known to have anti-atherogenic properties, although its precise mechanism has not been fully clarified. We therefore hypothesized that HDL can exert anti-atherogenic action by augmenting PGI2-stimulated increases in the activities of ACEH and NCEH. After incubation with PGI2 and HDL, a cell homogenate was made from which the activities of ACEH and NCEH were assessed. HDL significantly augmented the PGI2-induced increase in the activities of both enzymes. This effect of HDL was abolished in the absence of PGI2. Elevated intracellular levels of cyclic AMP were maintained for longer periods by HDL. The increase in both intracellular cyclic AMP levels and enzyme activities disappeared in the presence of an inhibitor of adenylate cyclase, 2'5'-dideoxyadenosine. Radiolabeled smooth muscle cells demonstrated a significant loss in total cholesterol and cholesteryl ester after treatment with PGI2 and HDL, due to the increase in cholesteryl ester hydrolytic activities. These data suggest that HDL enhanced the PGI2-stimulated hydrolysis of cholesteryl ester and augmented the PGI2-induced reduction of cellular cholesteryl ester content by stabilizing PGI2.

Animals↗
PubMed1995

Inhaled nitric oxide versus inhaled prostacyclin and intravenous versus inhaled prostacyclin in acute respiratory failure with pulmonary hypertension in piglets.

This study was a prospective, randomized design to compare oxygenation and pulmonary hemodynamics between inhaled nitric oxide (NO) and inhaled prostacyclin (PGI2), and between inhaled and i.v. PGI2 in acute respiratory failure with pulmonary hypertension. Acute respiratory failure with pulmonary hypertension was induced in 12 piglets weighing 9-12 kg by repeated lung lavages and a continuous infusion of the stable endoperoxane analogue of thromboxane. Thereafter the animals were randomly assigned either for NO or PGI2 application. All animals were treated with different concentrations of NO or different doses of PGI2 applied i.v. and inhaled in random order. Continuous monitoring included ECG, central venous pressure (CVP), mean pulmonary artery pressure (MPAP), mean arterial pressure (MAP), arterial oxygen saturation (SaO2), and mixed venous oxygen saturation (SvO2) measurements. NO inhalation of 10 ppm resulted in a significant increase in PaO2/fraction of inspired oxygen (FiO2) from 7.8 +/- 1.34 kPa to 46.1 +/- 9.7 kPa. MPAP decreased significantly from 5.1 +/- 0.26 kPa to 3.7 +/- 0.26 kPa during inhaled NO of 40 ppm; i.v. infusion of PGI2 slightly increased oxygenation parameters. A significant increase in PaO2/FiO2 up to 32.4 +/- 3.1 kPa was observed during PGI2 aerosol delivery (p < 0.01); i.v. PGI2 decreased MAP from 11.5 +/- 0.39 kPa to 9.8 +/- 0.66 kPa (p < 0.05) and MPAP from 5.8 +/- 0.53 kPa to 4.5 +/- 0.66 kPa, respectively (p < 0.05). PGI2 aerosol delivery significantly decreased the MPAP to 3.7 +/- 0.53 kPa (p < 0.05) without influencing the MAP.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed2006

Developmental regulation of prostacyclin synthase and prostacyclin receptors in the ovine uterus and conceptus during the peri-implantation period.

This study documents the expression of prostacyclin (PGI2) synthase (PTGIS) and PGI2 receptors in the trophoblast and uterus of the ewe at the time of maternal recognition of pregnancy (i.e. days 7, 9, 12, 14 and 17). The membrane receptor for PGI2 (PTGIR) and the nuclear receptors, i.e. peroxisome proliferator-activated receptors (PPAR) and their heterodimer partners the retinoid X receptors (RXR), were analysed. In the endometrium, PTGIS transcript and protein were expressed at day 9 of pregnancy and levels declined from days 12 to 17. Immunohistochemistry and in situ hybridization indicated that PTGIS was mainly located in the luminal epithelium of the endometrium. Endometrial PTGIR, PPARA, PPARG and RXRG expression was regulated during the peri-implantation period whereas PPARD, RXRA and RXRB were consistently expressed. In the trophoblast, PTGIS transcript levels rose as development progressed and peaked at day 17. PTGIR and PPARA transcripts peaked before day 12 and then declined and became nearly undetectable by day 17, whereas PPARD and PPARG transcript levels rose steadily from days 12 to 17. Because the PPARs and the RXRs display different expression profiles, we suggest that different heterodimers may form and support distinct functions as development proceeds. Our results also underline the importance of PTGIS and PPARD in the trophoblast and PTGIR in the uterus, suggesting that PGI2 is of both uterine and trophoblastic origin and is involved in a complex signalling pathway at around the time of implantation in the ewe.

Animals↗
PubMed1985

Influence of selective thromboxane synthetase blocker CGS-13080 on thromboxane and prostacyclin biosynthesis in whole blood: evidence for synthesis of prostacyclin by leukocytes from platelet-derived endoperoxides.

Increase in thromboxane A2 (TXA2) generation has been proposed as a mechanism of dynamic vaso-occlusion and in vivo platelet thrombus formation. We have examined the effects of CGS-13080, an imidazole derivative, on rabbit and human TXA2-prostacyclin (PGI2) "balance." In rabbits given CGS-13080, serum levels of TXB2 (stable metabolite of TXA2) were inhibited 81% at 2 hours and 56% at 24 hours (both P less than or equal to 0.01). Collagen-induced platelet aggregation was inhibited at 2 hours after CGS-13080 administration. In contrast, serum levels of 6-keto-PGF1 alpha (stable hydrolysis product of PGI2) increased 587% compared with control values at 2 hours (P less than or equal to 0.01). Platelet and white blood cell counts were not significantly altered. In human blood incubated in vitro with CGS-13080, serum TXB2 was completely inhibited, whereas PGI2 generation was stimulated (both P less than or equal to 0.001). In other experiments, we demonstrated uptake of platelet-generated cyclic endoperoxides by leukocytes and generation of PGI2 in the presence of CGS-13080 but not indomethacin. Thus, CGS-13080 inhibits TXA2 and stimulates PGI2 production in rabbit and human blood. Increase in PGI2 generation with TXA2 inhibition may be of potential benefit in conditions characterized by platelet hyperactivity.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Study of "prostacyclin-like" activity in the rat blood vessel: changes in prostacyclin production related to body weight.

The prostacyclin-producing capacity of various blood vessels was studied using platelet aggregation bioassay in rats of different ages. Results showed that --the PGI2 producing capacity of arteries was five to tenfold of the respective veins; --in the arteries the PGI2 production calculated for unit vascular mass declined from the centre to the periphery, despite the relative increase of endothelial surface area. This points to the importance of other vascular elements in the control of PGI2 production; --the PGI2 forming activity of some blood vessels increased with the age up to a limit (300-400 g body weight), decreasing thereafter. Based on these results we conclude that major part of PGI2 in systemic blood originates from the large arteries, whereas the low PGI2 production of the veins might play a role, among others, in the more frequent occurrence of venous thrombosis.

Aging↗
PubMed1982

Mepindolol protection of prostacyclin formation. Subsequent increase in arachidonic acid-induced prostacyclin release in isolated guinea pig heart.

The infusion of arachidonic acid through Langendorff-perfused guinea pig hearts in vitro for 15 min was associated with an increased PGI2 formation and release. This was a transient reaction, which showed a peak after 3-5 min and declined thereafter. Simultaneous infusion of washed human platelets (4 X 10(8)/min) stimulated the peak PGI2 formation (measured as immunoreactive 6-oxo-PGF1 alpha) but did not antagonize the inactivation of the PGI2-forming mechanism(s) in the vessel wall. The beta-adrenoceptor-blocking agent mepindolol (0.3 and 3 microgram/ml) significantly enhanced the peak release of PGI2 at 3 microgram/ml (P less than 0.05). Its major effect, however, was to inhibit the decline in PGI2 release during arachidonic acid infusion. In this case the PGI2 release during arachidonic acid infusion (area under the curve) was doubled in the presence of mepindolol at both concentrations. It is concluded that protection of vascular PGI2 formation from inactivation might be an important mechanism for the maintenance of PGI2 release in response to continuous stimuli.

Animals↗