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PubMed1985

Prostacyclin and thromboxane in gynecology and obstetrics.

The gynecologic and obstetric implications of the smooth muscle-relaxing, antiaggregatory prostacyclin and its endogenous antagonist, thromboxane A2, are reviewed. In addition to the vascular wall and circulating platelets, which are primary sources for prostacyclin and thromboxane A2, respectively, reproductive tissues produce great amounts of these prostanoids, evidently for the regulation of the vascular tone and/or vascular platelet interaction. Several gynecologic and obstetric disorders are characterized by abnormalities in prostacyclin and/or thromboxane A2. In primary menorrhagia the uterine release of prostacyclin is increased, and consequently menstrual blood loss can be reduced with various prostaglandin synthesis inhibitors. Prostacyclin relaxes the nonpregnant myometrium in vitro and may also do so in vivo, although intravenous infusion of prostacyclin has no effect upon the uterine contractility in nonpregnant or pregnant subjects. Patients with pelvic endometriosis may have increased levels of prostacyclin and thromboxane A2 metabolites in the peritoneal fluid. The prostacyclin/thromboxane A2 balance shifts to thromboxane A2 dominance in patients with gynecologic cancer. During pregnancy the production of prostacyclin and thromboxane A2 increases in the mother and fetoplacental tissue. Preeclampsia and other chronic placental insufficiency syndromes are accompanied by prostacyclin deficiency in the mother and in fetomaternal tissues and by an overproduction of thromboxane A2, at least in the placenta. These changes may account for the vasoconstriction and platelet hyperactivity, which are pathognomonic for hypertensive pregnancies. By directing the prostacyclin/thromboxane A2 balance to prostacyclin dominance (by dietary manipulation, administration of prostacyclin and/or its analogues, drugs with prostacyclin-stimulating and/or thromboxane A2-inhibiting action), it may be possible to prevent and/or treat hypertensive pregnancy complications in the future.

6-Ketoprostaglandin F1 alpha↗

PubMed1983

Comparative effects of nitroglycerin and nitroprusside on prostacyclin generation in adult human vessel wall.

The precise mechanism of vasodilatory actions of nitroso-compounds is not clear. It has been suggested that these drugs might modulate release of the vasodilator, prostacyclin, from cultured endothelial cells and bovine arteries or potentiate actions of prostacyclin. This study was designed to examine the effects of nitroglycerin and nitroprusside on prostacyclin release from adult human vasculature. Saphenous vein ring preparations were incubated with nitroglycerin or nitroprusside and arachidonic acid, the substrate for prostacyclin. Vascular rings incubated with nitroglycerin released significantly more prostacyclin (measured as 6-keto-prostaglandin F1 alpha, a stable hydrolysis product of prostacyclin by radioimmunoassay) compared with the control vascular rings (p less than 0.02). This increase was observed at the therapeutic concentrations of nitroglycerin (5 to 10 ng/ml). However, incubation of saphenous vein rings with nitroprusside in concentrations as high as 1 microgram/ml was not associated with any increase in prostacyclin release. Prior incubation of vascular rings with the cyclooxygenase blocker, indomethacin, inhibited nitroglycerin-induced prostacyclin release. Incubation of vascular rings with the selective thromboxane A2 blocker, OKY 1581, resulted in additional prostacyclin release with nitroglycerin treatment, presumably by inhibiting vessel wall-generated thromboxane A2. Nitroprusside had no significant effect on prostacyclin release from indomethacin-treated or OKY 1581-treated vascular rings. This study suggests significant stimulatory effects of nitroglycerin, but not of nitroprusside, on prostacyclin release from human saphenous vein. Nitroglycerin-induced prostacyclin release may be an important mechanism of its antiischemic actions in human subjects.

6-Ketoprostaglandin F1 alpha↗

PubMed1993

Calcium modulation of endothelium-derived prostacyclin production in ovine pregnancy.

Refractoriness to angiotensin-II (ANG II)-induced vasoconstriction is greater in the uteroplacental vs. systemic vascular beds during pregnancy, possibly reflecting enhanced uterine artery prostacyclin production. We determined the role(s) of calcium and calcium channels in regulating basal and ANG II-induced vascular prostacyclin production in uterine and omental (systemic) arteries obtained from pregnant (P) and nonpregnant (NP) ewes. To evaluate the endothelial contribution to basal and stimulated prostacyclin production, arteries with and without endothelium also were incubated in the absence and presence of 50 nM ANG II, 5 microM A23187, or 5 microM arachidonate. Basal prostacyclin production by intact and denuded uterine and systemic arteries was P > NP (P < 0.05), plus in intact arteries, production fell approximately 33% in calcium-free Krebs-Henseleit and 5 microM EGTA. Although basal prostacyclin production by P and NP uterine and NP systemic arteries was unaffected by 5 microM verapamil, P systemic artery synthesis fell 41% (P < 0.05). P uterine artery prostacyclin production increased similarly with ANG II (61%) and A23187 (78%) in the presence of calcium (2 mM), whereas NP uterine arteries responded only to A23187 (71%). Verapamil inhibited ANG II-induced increases in prostacyclin synthesis by P uterine arteries. Neither calcium removal nor verapamil altered prostacyclin responses to arachidonate (5 microM). The endothelium accounted for approximately 68% of basal prostacyclin production by all arteries studied and for 100% of ANG II-induced increases by P uterine arteries (P < 0.01). A23187 and arachidonate increased both endothelial and smooth muscle prostacyclin production (P < 0.01). During ovine pregnancy, extracellular calcium entry via activation of potential-gated calcium channels are involved in modulating basal vascular prostacyclin production as well as ANG II-induced increases in uterine artery production. Furthermore, the endothelium is the primary source of basal vascular prostacyclin synthesis and the sole source of ANG II-stimulated increases by uterine arteries during pregnancy.

6-Ketoprostaglandin F1 alpha↗

PubMed1992

Effects of normal and sickle erythrocytes on prostacyclin release by perfused human umbilical cord veins.

We compared the effects of normal (AA) and sickle (SS) erythrocytes (RBC) on endothelial cell release of prostacyclin by perfused human umbilical cord veins. Two equal-length segments of fresh umbilical cords were perfused first with serum-free Dulbecco's modified Eagle's medium (DMEM) to establish the basal prostacyclin production rate for each segment; then one segment was perfused with SS RBC and/or plasma, while the other segment was simultaneously perfused with AA RBC and/or plasma. Aliquots of perfusate were removed at intervals for measurement of the stable prostacyclin metabolite 6-keto-prostaglandin F1 alpha (6-keto-PGF). Basal prostacyclin production by segments from the same cord was very similar, but it varied considerably among segments from different cords. Therefore, the ratio of prostacyclin release with RBC and/or plasma to basal prostacyclin release for each segment was used to compare prostacyclin release among segments from different cords. Mean prostacyclin release was significantly higher from segments perfused with SS RBC in autologous plasma than from segments perfused with AA RBC in autologous plasma at 15, 30, and 60 min. However, no significant differences in mean prostacyclin production were observed between segments perfused with SS vs. AA RBC in DMEM or between segments perfused with SS vs. AA plasma alone. No significant correlations were observed between prostacyclin production and either the viscosity of SS and AA RBC in autologous plasma or DMEM or the adhesiveness of SS and AA RBC to cultured human umbilical vein endothelial cells. We conclude that SS RBC in autologous plasma cause increased prostacyclin release from perfused human umbilical cord veins. The perfused human umbilical cord vein system may be a useful model for comparing the response of vascular endothelium to SS and AA RBC and plasma under controlled-flow conditions.

6-Ketoprostaglandin F1 alpha↗

PubMed1985

Placental prostacyclin production in normal and toxemic pregnancies.

Prostacyclin is a potent vasodilator and inhibitor of platelet aggregation. Because toxemia is characterized by increased vasoconstriction frequently associated with increased platelet aggregation and reduced uteroplacental blood flow, a deficiency in prostacyclin production during pregnancy could contribute to the development of toxemia. Placentally produced prostacyclin could have both local effects on the uteroplacental vasculature and systemic effects because prostacyclin, unlike the other prostaglandins, is not extensively metabolized by the lungs. Fresh human term placentas were obtained immediately after delivery from 12 normal and 12 toxemic (blood pressure greater than or equal to 140/90 mm Hg, urinary protein greater than 0.3 gm/24 hours) pregnancies. Tissues (300 mg) were incubated in a sterile manner in 5 ml of Dulbecco's Modified Eagle's Medium for 48 hours at 37 degrees C with 95% oxygen and 5% carbon dioxide in a metabolic shaker. Samples were collected at 8, 20, 32, and 48 hours and analyzed for prostacyclin by radioimmunoassay of its stable metabolite, 6-keto-prostaglandin F1 alpha. Prostacyclin production was significantly decreased in toxemic placental tissue compared with normal placental tissue (2.72 +/- 0.49 versus 7.22 +/- 0.44 pg/mg/hr, mean +/- SE, p less than 0.01). In both normal and toxemic placentas, prostacyclin production was inhibited by indomethacin (5 or 50 mumol/L) and not affected (p greater than 0.10) by arachidonic acid (5 or 100 mumol/L). Lowering the oxygen concentration from 95% to 20% significantly (p less than 0.01) decreased prostacyclin production in normal but not toxemic placentas. Prostacyclin production rates in the amnion and chorion were not affected (p greater than 0.10) by toxemia. The amniotic and chorionic prostacyclin production rates were not different from each other (p greater than 0.10) and were only one seventh of the normal placental production rate. These data indicate that placental prostacyclin production is decreased in toxemia; therefore, this vasoactive prostaglandin may be involved in the causation and the associated hypertension and coagulation abnormalities of this disorder.

6-Ketoprostaglandin F1 alpha↗

PubMed1999

Changes in prostacyclin synthase in pregnant sheep myometrium, endometrium, and placenta at spontaneous term labor and regulation by estradiol and progesterone.

OBJECTIVE: Our purpose was to investigate, first, whether there were changes in the abundance of prostacyclin synthase protein in intrauterine tissues of pregnant ewes in association with spontaneous term labor. Second, we examined the effect of either estradiol or progesterone, or both, on regulation of prostacyclin synthase protein abundance in uterine tissues using an ovariectomized nonpregnant sheep model. STUDY DESIGN: The abundance of prostacyclin synthase protein was quantified by Western blot analysis in the myometrium, endometrium, and placenta of pregnant ewes in spontaneous term labor (n = 6) and term control ewes not in labor (n = 6). The changes of prostacyclin synthase in the myometrium and endometrium of 20 ovariectomized nonpregnant sheep (n = 5 for each group) were evaluated after treatment with estradiol, progesterone, or both. RESULTS: Prostacyclin synthase protein was present in pregnant and nonpregnant sheep myometrium, endometrium, and placenta at a molecular weight of about 55 kd. At spontaneous term labor the level of prostacyclin synthase decreased in endometrium (P <.05), increased in myometrium (P <.05), and remained unchanged in placenta. Estradiol and progesterone had no effect on prostacyclin synthase protein abundance in nonpregnant ovine endometrium and myometrium. CONCLUSIONS: The decrease in prostacyclin synthase in pregnant sheep endometrium during labor may indicate paracrine interactions between the endometrium, the myometrium, fetal membranes, or a combination of these. The significant increase of prostacyclin synthase in pregnant sheep myometrium at spontaneous term labor may contribute to the increased uterine sensitivity to oxytocin or stimulate vasodilatation during labor to increase myometrial blood flow. Neither estradiol nor progesterone at the dosages studied changed prostacyclin synthase expression in the nonpregnant myometrium and endometrium. The molecular mechanism or mechanisms that differentially regulate prostacyclin synthase expression in pregnant uterine tissues merit further study.

Animals↗

PubMed1996

Prostacyclin and thromboxane production of rat and cat arterial tissue is altered independently by several vasoactive substances.

The modulation of the production of prostacyclin and thromboxane from cat and cat aortic tissue slices by different vasoactive agents has been studied in order to reveal whether the release of these main two vasoactive prostanoids goes in parallel or may be controlled independently. Norepinephrine, isoproterenol, phentolamine, propranolol, angiotensin II, vasopressin, bradykinin, thrombin, verapamil, gallopamil, dopamine or methionin enkephalin were added to the incubation medium and 6-keto-PGF1 alpha (the stable metabolite of prostacyclin) and TxB2 (the stable metabolite of thromboxane) were determined in the supernatant by radioimmunoassay. The ratio of the release of prostacyclin and thromboxane was computed. Norepinephrine increased both prostacyclin and thromboxane release. Isoproterenol increased the ratio of prostacyclin and thromboxane released in cat aortic tissue slices. Phentolamine and propranolol had no effects. Angiotensin II induced a slight but statistically insignificant increase in the ratio of the two prostanoids released. Vasopressin increased thromboxane release only. Bradykinin stimulated the prostacyclin while thrombin stimulated the thromboxane release. Verapamil decreased both prostacyclin and thromboxane production. Gallopamil decreased prostacyclin release and increased thromboxane release from vessel wall slices in a certain concentration range causing a characteristic dose dependent minimum in the ratio of prostacyclin and thromboxane release. Dopamine separately increased prostacyclin release while enkephalin had no significant effect. The data obtained show that in vascular tissue some unidentified yet cytophysiological mechanisms might exist which specifically control the activities of the prostacyclin synthase and thromboxane synthase enzymes.

6-Ketoprostaglandin F1 alpha↗

PubMed1981

Prostacyclin: its biosynthesis, actions and clinical potential.

Prostacyclin (PGI2) is the product of arachidonic acid metabolism generated by the vessel wall of all mammalian species studied, including man. Prostacyclin is a potent vasodilator and the most potent inhibitor of platelet aggregation so far described. Prostacyclin inhibits aggregation through stimulation of platelet adenyl cyclase leading to an increase in platelet cyclic AMP. In the vessel wall, the enzyme that synthesizes prostacyclin is concentrated in the endothelial layer. Prostacyclin can also be a circulating hormone released from the pulmonary circulation. Based on these observations we proposed that platelet aggregability in vivo is controlled via a prostacyclin mechanism. The discovery of prostacyclin has given a new insight into arachidonic acid metabolism and has led to a new hypothesis about mechanisms of haemostasis. Reductions in prostacyclin production in several diseases, including atherosclerosis and diabetes, have been described and implicated in the pathophysiology of these diseases. Additionally, since prostacyclin powerfully inhibits platelet aggregation and promotes their disaggregation, this agent could have an important use in the therapy of conditions in which increased platelet aggregation takes place and in which, perhaps, a prostacyclin deficiency exists. Prostacyclin has been used beneficially in humans during extracorporeal circulation procedures such as cardiopulmonary bypass, charcoal haemoperfusion and haemodialysis. Its possible use in other conditions such as peripheral vascular disease or transplant surgery is at present being investigated.

Angiotensin I↗

PubMed1994

Molecular cloning of human prostacyclin receptor cDNA and its gene expression in the cardiovascular system.

BACKGROUND: Prostacyclin elicits a potent vasodilation and inhibition of platelet aggregation through binding to its membrane receptor. The impairment of prostacyclin receptor activity is implicated in various human cardiovascular diseases. In the present study, we succeeded in the isolation and characterization of human prostacyclin receptor cDNA and elucidated its gene expression in human tissues. METHODS AND RESULTS: We isolated a cDNA clone encoding the human prostacyclin receptor from a human lung cDNA library. The isolated cDNA clone encodes a 386-amino acid protein with seven putative transmembrane domains, which belongs to the G protein-coupled receptor superfamily. [3H]iloprost, a prostacyclin receptor agonist, specifically bound to the receptor transiently expressed in COS-7 cells. The binding was inhibited in the rank order of iloprost = cicaprost, another prostacyclin receptor agonist, > prostaglandin E1 (PGE1) >> PGE2, PGF2 alpha, PGD2, STA2. In addition, iloprost dose-dependently stimulated cAMP generation in these COS-7 cells. These results are consistent with the characteristics of the human prostacyclin receptor. Northern blotting analysis on human tissues revealed that prostacyclin receptor mRNA is abundantly expressed in the aorta, lung, atrium, ventricle, and kidney. CONCLUSIONS: We cloned human prostacyclin receptor cDNA and elucidated its abundant gene expression in the human cardiovascular system. The present study will lead to better understanding of the significance of prostacyclin in humans and further facilitate the clinical application of prostacyclin.

Amino Acid Sequence↗

PubMed1982

Prostacyclin substitution for heparin in long-term hemodialysis.

We studied prostacyclin as a substitute for heparin in 12 patients who underwent maintenance hemodialysis. All subjects underwent initial hemodialysis with prostacyclin as the sole anticoagulant; 10 of the 12 were restudied during heparin hemodialysis. Few adverse reactions occurred during prostacyclin hemodialysis in the 10 patients in whom dialysis was performed against a bicarbonate-containing dialysate; however, significant hypotension developed in two subjects when an acetate bath was used. Platelet aggregation progressively decreased during prostacyclin hemodialysis (p less than 0.02), but not during heparin hemodialysis, and returned toward control values after hemodialysis. Platelet thromboxane release decreased during both prostacyclin and heparin hemodialysis. Intradialytic percent decrements in serum urea nitrogen and creatinine were greater during prostacyclin than heparin administration (42 +/- 2.9 percent versus 36 +/- 2.6 percent [p less than 0.05] and 33 +/- 2.6 percent versus 29 +/- 2.1 percent [0.05 less than p less than 0.1], respectively). The plasma concentrations of 6-keto-prostaglandin-F1 alpha, a prostacyclin metabolite, reached peak levels by 120 minutes of hemodialysis and declined biexponentially toward predialysis concentrations during 120 minutes after hemodialysis, thereby providing an index of cumulative prostacyclin dosage. We conclude that prostacyclin is not only a safe alternative to heparin anticoagulation during hemodialysis, but that prostacyclin might also increase the efficiency of hemodialysis.

6-Ketoprostaglandin F1 alpha↗

PubMed1989

Increased placental progesterone may cause decreased placental prostacyclin production in preeclampsia.

UNLABELLED: Placentas obtained from women with preeclampsia produce more thromboxane and less prostacyclin than normal. They also produce more progesterone than normal. This study tested whether a progesterone concentration equivalent to that in the medium after in vitro incubation of placentas from women with preeclampsia (greater than or equal to 1.5 x 10(-5) mol/L) could cause an imbalance of increased thromboxane and decreased prostacyclin production by normal placentas. Fresh term placental tissues were incubated for 48 hours in the absence or presence of various concentrations of progesterone and/or estradiol. Prostacyclin and thromboxane were determined by radioimmunoassay of their stable metabolites, 6-keto-prostaglandin F1 alpha and thromboxane B2. A progesterone concentration of 1.5 x 10(-5) mol/L significantly (p less than 0.001) inhibited prostacyclin production, compared with control, but lower concentrations did not. Estradiol at concentrations present in the medium after incubation of either normal or preeclamptic placental tissue did not significantly affect prostacyclin production, nor did it prevent progesterone at 1.5 x 10(-5) mol/L from inhibiting prostacyclin. Thromboxane production was not affected by either progesterone or estradiol. CONCLUSION: In vitro addition of progesterone at a concentration equivalent to that in the medium after incubation of preeclamptic placentas inhibited prostacyclin production by normal placentas to a rate characteristic of preeclampsia. However, it did not increase thromboxane. SPECULATION: Increased trophoblast progesterone in preeclampsia may act by a paracrine mechanism to inhibit prostacyclin synthesis in placental vasculature. Progesterone's selective inhibition of prostacyclin without affecting thromboxane may be due to the compartmentalization of thromboxane production to trophoblast and stroma and prostacyclin production to placental vasculature.

Dose-Response Relationship, Drug↗

PubMed1991

The imbalance between thromboxane and prostacyclin in preeclampsia is associated with an imbalance between lipid peroxides and vitamin E in maternal blood.

Preeclampsia is associated with an imbalance between thromboxane and prostacyclin. The cause of the imbalance is unknown. Preeclampsia sera contain cytotoxic factors that can damage endothelial cells. Lipid peroxides can damage cell membranes, so elevated levels in the mother's blood could be related to endothelial cell injury and decreased prostacyclin in preeclampsia. This study determined maternal plasma levels of thromboxane and prostacyclin and serum levels of lipid peroxides and vitamin E in women with normal pregnancy (n = 12), mild preeclampsia (n = 16), and severe preeclampsia (n = 19) between 36 and 40 weeks' gestation. In normal pregnancy the ratio of thromboxane to prostacyclin (0.63) favored prostacyclin, and the ratio of lipid peroxides to vitamin E (0.43) favored vitamin E. Prostacyclin was significantly decreased in both mild and severe preeclampsia. Thromboxane was not increased in mild preeclampsia but was significantly increased in severe preeclampsia. The ratio of thromboxane to prostacyclin was increased in mild preeclampsia (0.77) and greatly increased in severe preeclampsia (1.94). Lipid peroxides were significantly increased in mild preeclampsia and increased further in severe preelcampsia. Vitamin E levels were unaltered in mild preeclampsia but significantly decreased in severe preeclampsia. The ratio of lipid peroxides to vitamin E was increased in mild (0.52) and greatly increased in severe (1.09) preeclampsia. We concluded the following: (1) Maternal plasma prostacyclin is decreased in both mild and severe preeclampsia, but thromboxane is increased only in severe cases. (2) Lipid peroxides are significantly increased in both mild and severe preeclampsia and vitamin E is significantly decreased in severe preeclampsia. We speculate that this imbalance could result in endothelial and platelet cell damage and in decreased prostacyclin and increased thromboxane synthesis. (3) Preeclampsia is associated with an imbalance not only between thromboxane and prostacyclin but also between lipid peroxides and vitamin E in maternal blood. The imbalances progressively favor thromboxane and lipid peroxides with the increasing severity of preeclampsia, which is consistent with the clinical symptoms of this disorder.

6-Ketoprostaglandin F1 alpha↗

PubMed2006

Cardioprotective prostacyclin signaling in vascular smooth muscle.

Prostacyclin plays an important cardioprotective role, which has been increasingly appreciated in recent years in light of adverse effects of COX-2 inhibitors in clinical trials. This cardioprotection is thought to be mediated, in part, by prostacyclin inhibition of platelet aggregation. Multiple lines of evidence suggest that prostacyclin additionally protects from cardiovascular disease by pleiotropic effects on vascular smooth muscle. Genetic deletion of the prostacyclin receptor in mice revealed an important role for prostacyclin in preventing the development of atherosclerosis, intimal hyperplasia, and restenosis. In vitro studies have shown these effects may be due to prostacyclin inhibition of vascular smooth muscle cell proliferation and migration. Prostacyclin has also been shown to promote vascular smooth muscle cell differentiation at the level of gene expression through the Gs/cAMP/PKA pathway. Recently identified single nucleotide polymorphisms in the prostacyclin receptor that compromise receptor function suggest that some genetic variations may predispose individuals to increased cardiovascular disease. Herein, we review the literature on the cardioprotective effects of prostacyclin on vascular smooth muscle, and the underlying molecular signaling mechanisms. Understanding the role of prostacyclin and other eicosanoid mediators in the vasculature may lead to improved therapeutic and preventative options for cardiovascular disease.

Animals↗

PubMed1999

Bridging to heart transplantation: prostaglandin E1 versus prostacyclin versus dobutamine.

BACKGROUND: Prostaglandin E1 (PGE1) and prostacyclin have potent pulmonary and systemic vasodilating properties. This prospective, randomized trial compared PGE1 vs prostacyclin vs. low-dose dobutamine in patients with low-output heart failure awaiting heart transplantation (HTx) who were refractory to oral treatment. METHODS: Patients in advanced heart failure in New York Heart Association (NYHA) Class IV, with a cardiac index < or = 2.5 L/minute/m2 and a pulmonary capillary wedge pressure > or = 20 mmHg, who were listed for HTx were studied. In an inpatient study phase of 12 hours duration, therapy was aimed to increase cardiac output by 20% or more, when compared to baseline values, and to achieve a reduction of pulmonary vascular resistance below 550 dyn.s/cm-5m-2. During a long-term outpatient phase, the drugs were continuously infused to bridge these patients to HTx using three combined negative endpoints (worsening heart failure, serious adverse events, death) for analysis. RESULTS: Sixty-eight patients were enrolled, 30 patients on PGE1, 8 patients on prostacyclin, and 30 patients on dobutamine. During the inpatient study phase, maximum doses were 22 +/- 1.8 ng/kg/minute for PGE1, 7 +/- 1 ng/kg/minute for prostacyclin and 5 +/- 0.4 micrograms/kg/minute for dobutamine. During the inpatient study phase 21 patients failed, 4/30 (13%) patients on PGE1, 4/8 patients on prostacyclin (50%), and 13/30 (43%) on dobutamine (p < 0.05). Long-term continuous intravenous drug infusion in outpatients was begun in 26 patients on PGE1, in 4 patients on prostacyclin, and in 17 patients on dobutamine. Infusion therapy lasted for 88 +/- 14 days in the PGE1 group with 31 +/- 22 days in the prostacyclin group, and 30 +/- 8 days in the dobutamine group (NS). During the outpatient phase 23 patients reached a negative endpoint with 16 patients developing worsening heart failure, 5 severe adverse events and 2 deaths. Seven out of 26 (27%) failed on PGE1, 4/4 (100%) failed on prostacyclin, and 12/17 (71%) failed on dobutamine (p < 0.05, log rank test). Because prostacyclin treatment was ineffective in the first 8 patients, this trial arm was stopped prematurely. CONCLUSIONS: The findings from this prospective open pilot trial suggest that continuous PGE1 infusions at individualized dosages can be useful in certain patients as a pharmacologic bridging procedure with reduced risk to develop worsening heart failure before HTx compared to prostacyclin and dobutamine. Further comparative studies are warranted to investigate the effects of PGE1 among other bridging agents.

Alprostadil↗

PubMed1996

A novel subtype of the prostacyclin receptor expressed in the central nervous system.

By use of several prostacyclin analogs and an in vitro autoradiographic technique, we have found a novel subtype of the prostacyclin receptor, one having different binding properties compared with those of the known prostacyclin receptor in the rat brain. Isocarbacyclin, which is a potent agonist for the known prostacyclin receptor, had high affinity for the novel subtype (dissociation constant (Kd) of 7.8 nM). However, iloprost, which is usually used as a stable prostacyclin analog, showed low affinity binding (Kd = 159 nM) for the subtype. Other prostaglandins showed no or little affinity for the subtype. [3H]Isocarbacyclin binding was high in the thalamus, lateral septal nucleus, hippocampus, cerebral cortex, striatum, and dorsal cochlear nucleus. Although the nucleus of the solitary tract and the spinal trigeminal nucleus showed a high density of [3H]isocarbacyclin binding, [3H]iloprost also had high affinity in these regions, and the binding specificity was similar to that for the known prostacyclin receptor. Hemilesion studies of striatal neurons lesioned by kainate or of dopaminergic afferents lesioned by 6-hydroxydopamine revealed that the binding sites of the novel subtype exist on neuronal cells in the striatum, but not on the presynaptic terminal of afferents or on glial cells. Electrophysiological studies carried out in the CA1 region of the hippocampus revealed that prostacyclin analogs have a facilitatory effect on the excitatory transmission through the novel prostacyclin receptor. The widespread expression of the prostacyclin receptor in the central nervous system suggests that prostacyclin has important roles in neuronal activity.

Animals↗

PubMed2003

Low-dose prostacyclin improves cortical perfusion following experimental brain injury in the rat.

It was recently shown that prostacyclin at a low dose reduces cortical cell death following brain trauma in the rat. Conceivably, prostacyclin with its vasodilatory, anti-aggregatory, anti-adhesive and permeability-reducing properties improved a compromised perfusion caused by post-traumatic vasoconstriction, microthrombosis and increased microvascular permeability. The objective of the present study was therefore to investigate the hemodynamic effects of low-dose prostacyclin in the traumatized rat cortex. Following a fluid percussion brain injury or a sham procedure, animals were treated with a continuous intravenous infusion of prostacyclin of 1 or 2 ng x kg(-1) x min(-1), or vehicle. Blood flow ([(14)C]-iodoantipyrine), the permeability-surface area product (PS) for [(51)Cr]-EDTA, and brain water content were measured after 3 or 48 h of treatment. Blood flow values in the injured cortex were transiently reduced to 0.42 +/- 0.2 mL x min(-1) in the vehicle group 3 h following trauma from a corresponding value of about 1.6 mL x min(-1) in the sham group, with recovery of blood flow after 48 h. Prostacyclin treatment caused a dose-dependent increase in blood flow which reached statistical significance 48 h following trauma. Brain water content and PS increased in the injured cortex post trauma and the higher dose of prostacyclin increased these parameters further at 48 h compared to the vehicle group (p < 0.05). The latter effects of prostacyclin cannot be attributed to an increase in permeability, as prostacyclin did not influence PS or brain water content following sham trauma. In fact prostacyclin has been shown to have permeability-decreasing properties. We conclude that prostacyclin improves cortical perfusion following brain trauma. The simultaneous aggravation of brain edema can be explained by an increased surface area, perhaps in combination with increased capillary hydrostatic pressure.

Animals↗

PubMed2001

Effect of inhaled prostacyclin in combination with almitrine on ventilation-perfusion distributions in experimental lung injury.

BACKGROUND: Inhaled prostacyclin and intravenous almitrine have both been shown to improve pulmonary gas exchange in acute lung injury (ALI). This study was performed to investigate a possible additive effect of prostacyclin and almitrine on pulmonary ventilation-perfusion (VA/Q) ratio in ALI compared with inhaled prostacyclin or intravenous almitrine alone. METHODS: Experimental ALI was established in 24 pigs by repeated lung lavage. Animals were randomly assigned to receive either 25 ng.kg(-1).min(-1) inhaled prostacyclin alone, 1 microg.kg(-1).min(-1) almitrine alone, 25 ng.kg(-1).min(-1) inhaled prostacyclin in combination with 1 microg.kg(-1).min(-1) almitrine, or no specific treatment (controls) for 30 min. For each intervention, pulmonary gas exchange and hemodynamics were analyzed and VA/Q distributions were calculated using the multiple inert gas elimination technique. The data was analyzed within and between the groups by analysis of variance for repeated measurements, followed by the Student-Newman-Keuls test for multiple comparison when analysis of variance revealed significant differences. RESULTS: All values are expressed as mean +/- SD. In controls, pulmonary gas exchange, hemodynamics, and VA/Q distribution remained unchanged. With prostacyclin alone and almitrine alone, arterial oxygen partial pressure (PaO2) increased, whereas intrapulmonary shunt (QS/QT) decreased (P < 0.05). Combined prostacyclin and almitrine also increased PaO2 and decreased QS/QT (P < 0.05). When compared with either prostacyclin or almitrine alone, the combined application of both drugs revealed no additional effect in gas exchange or VA/Q distribution. CONCLUSIONS: The authors conclude that, in this experimental model of ALI, the combination of 25 ng.kg(-1).min(-1) prostacyclin and 1 microg.kg(-1).min(-1) almitrine does not result in an additive improvement of pulmonary gas exchange or VA/Q distribution when compared with prostacyclin or almitrine alone.

Almitrine↗

PubMed1996

Plasma of preeclamptic women stimulates and then inhibits endothelial prostacyclin.

We propose that the dichotomy between the in vivo reduction in intravascular prostacyclin production that occurs in preeclampsia and the in vitro stimulatory effect of plasma from preeclamptic patients on endothelial cell prostacyclin production is due to differential effects of chronic versus acute exposure to the plasma. We studied the acute versus chronic effects of 2% plasma from healthy pregnant and preeclamptic subjects by measuring endothelial prostacyclin production at different time periods after exposure to plasma. To determine whether such effects were specific to prostacyclin, we also measured prostaglandin E2 production. To determine whether chronic changes in prostacyclin production resulted from altered cellular responsiveness, we stimulated cells that had been exposed to plasma for 72 hours with arachidonic acid and measured prostaglandin production. Preliminary characterization of the plasma factor or factors responsible for alterations in prostaglandin production was performed. After 24 hours cells exposed to plasma from preeclamptic women produced more prostacyclin and prostaglandin E2 than cells exposed to plasma from healthy pregnant women. In contrast, after 72 hours exposure to plasma from preeclamptic women resulted in less endothelial cell prostacyclin production than exposure to plasma from healthy pregnant women, but there were no such differences in prostaglandin E2 production. Cells that had been exposed to plasma from preeclamptic women for 72 hours produced less prostacyclin but the same quantity of prostaglandin E2 after stimulation with arachidonic acid than cells exposed to plasma from healthy pregnant women. The plasma factor or factors responsible for altered prostacyclin production were sensitive to heat, acid, and proteases. In contrast to acute exposure, chronic exposure to plasma from preeclamptic women alters endothelial cells to result in decreased prostacyclin production, an observation consistent with in vivo findings.

Adult↗