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PubMed1978

An antiserum to 5,6-dihydro prostacyclin (PGI1) which also binds prostacyclin.

An antiserum was raised in rabbits using 5,6-dihydro prostacyclin, a stable analogue of prostacyclin, as the hapten, conjugated to bovine serum albumin. When added to platelet rich plasma the antiserum neutralised the inhibitory activity of prostacyclin, prostaglandin E1 and D2. The amount of antiserum required to neutralise completely a dose of prostacyclin giving 90-95% inhibition of ADP induced aggregation was 10-30 times less than that required for the other two prostaglandins. Small amounts of antiserum prevented the inhibitory activity of prostacyclin generated from endothelial cells in platelet rich plasma.

Animals↗

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↗

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↗

PubMed1978

Prostacyclin (PGI2) induces coronary vasodilatation in anaesthetised dogs.

Prostacyclin (PGI2), the predominant metabolite of arachidonic acid in isolated hearts, relaxes strips of bovine coronary artery and is a potent vasodilator in isolated perfused hearts. We have examined the actions of prostacyclin on coronary blood flow in open chest dogs anaesthetised with chloralose. An electromagnetic flow probe was fitted to the left circumflex artery and phasic coronary flow, mean coronary flow (a measure of coronary volume flow over 4 s intervals), and coronary vascular resistance were recorded together with aortic pressure and heart rate. Intravenous infusion of prostacyclin (0.05 to 1.0 microgram.kg.1.min.1), reduced coronary vascular resistance and aortic pressure according to dose, but had only small effects on phasic coronary flow or mean coronary flow. Both tachycardia and bradycardia occurred during infusion of prostacyclin, but 6-oxo-prostaglandin F1alpha (infused at 10 micrograms.kg-1.min-1), the stable degradation produce of prostacyclin, had no cardiovascular effects. The coronary vasodilator effects of prostacyclin were clear when it was injected into the left circumflex artery via a fine catheter distal to the flow probe. Prostacyclin (0.05 to 0.5 microgram) increased phasic coronary flow and mean coronary flow up to 3 fold and reduced coronary vascular resistance without affecting aortic pressure or heart rate, although higher doses had systemic effects. Prostaglandin E1 (0.1 to 0.5 microgram), which also dilated the coronary vessels, had a longer lasting effect and was 1 to 4 times more potent than prostacyclin. Prostaglandin E2, (0.5 to 4 microgram) was less potent than prostacyclin. In four dogs prostacyclin (20 to 500 micrograms) applied epicardially to the left ventricle caused marked and prolonged coronary vasodilatation. Epicardial application of prostacyclin (10 to 25 micrograms) to the right ventricle increased coronary sinus oxygen content with minimal changes in blood pressure. The endoperoxide prostaglandin H2 was a coronary vasodilator of similar potency to prostacyclin, but its analogue U46619 is a vasoconstrictor. Inhibition of cyclo-oxygenase with indomethacin (5 mg.kg-1 i.v.) or sodium meclofenamate (2 mg.kg-1 i.v.) potentiated the coronary dilator effects of prostacyclin given intravenously or into the coronary artery. Cyclo-oxygenase inhibition did not alter the hypotensive effects and increased the coronary vasodilator potency of prostacyclin relative to prostaglandin E2. Thus the sensitivity of the coronary vascular bed to prostacyclin is enhanced when endogenous biosynthesis of prostaglandin-like substances is inhibited. Although the importance of arachidonic acid metabolites in the coronary circulation still requires validation in vivo, it is clear that prostacyclin, and not prostaglandin E2, is the prostaglandin most likely to be involved.

Animals↗

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↗

PubMed1992

Effects of prostacyclin infusion on blood pressure and plasma renin activity in patients with essential hypertension.

The effects of prostacyclin infusion (6.7 +/- 2.7 ng/kg/min, 3 to 10 ng/kg/min) on blood pressure, plasma renin activity (PRA), and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were studied in 7 patients with essential hypertension (4 men and 3 women) with a mean age of fifty-eight +/- eleven years (forty-six to seventy-four years). The baseline value of 6-keto-PGF1 alpha for patients with essential hypertension was not lower than in healthy subjects. Blood pressure immediately dropped following prostacyclin infusion. Systolic blood pressure returned to the baseline value after prostacyclin infusion was discontinued. However, diastolic blood pressure and mean arterial blood pressure were still significantly decreased thirty minutes after termination of infusion. Heart rate did not change during prostacyclin infusion but decreased significantly when infusion was terminated. PRA was not significantly affected by prostacyclin infusion. The 6-keto-PGF1 alpha level was about 8 times higher than the baseline value thirty minutes after initiation of prostacyclin infusion and approximately twice as high as the baseline value thirty minutes after termination of infusion. The decrease in mean arterial blood pressure coincided with the increase in 6-keto-PGF1 alpha. There was no correlation between mean arterial blood pressure and PRA, nor between PRA and 6-keto-PGF1 alpha. These results demonstrate that production of prostacyclin is not reduced in patients with essential hypertension, and heart rate and PRA are not changed by prostacyclin infusion, although prostacyclin decreases blood pressure.

6-Ketoprostaglandin F1 alpha↗

PubMed1979

Vasodilation and inhibition of platelet aggregation by prostacyclins with modified omega-side chain.

Prostacyclin analogs with modified omega-side chain were synthetized in search of therapeutically useful agents. To characterize the vasodilator and platelet-antiaggregating properties, prostacyclin analogs were tested on systemic blood pressure in anesthetized rats, relaxation of bovine coronary artery and inhibition of arachidonic acid induced human platelet aggregation. The sodium salt of prostacyclin induced a dose dependent decrease of blood pressure with an ED25 of 0.23 microgram/kg i.v., a marked relaxation of bovine coronary artery with an IC50 of 5.9 ng/ml and a strong inhibition of platelet aggregation with an ED50 of 3x10(-9) M. Similar results were obtained with prostacyclin-methylester. Replacement of the n-pentyl moiety attached to C-15 of prostacyclin by cyclohexyl, 2-(2-furyl)ethyl, 2-(3-thienyl)ethyl and especially by 3-thienyl-oxymethyl yielded analogs with comparable prostacyclin properties, while substitution by 1,1-dimethyloxaalkyl residues was followed by a marked loss of activity. The order of potency among the analogs of the sodium salt and methylester of prostacyclin with strong vasodepressor and antiaggregatory properties was identical in all three models used. The three test systems used for evaluation have demonstrated that suitable modifications of the omega-side chain of prostacyclin result in potent vasodilator and platelet-antiaggregating agents.

Animals↗

PubMed1991

Role of endothelium on alpha-adrenoceptor responsiveness and prostacyclin release from the mesenteric arterial bed of the rat.

1 Removal of endothelium from the isolated perfused mesenteric arterial bed (MAB) of the rat was associated with an increase in both basal release of prostacyclin and the pressor response to administered noradrenaline (NA). Under these conditions, the NA-stimulated release of prostacyclin was not altered. 2 In this preparation, prazosin, an alpha 1-adrenoceptor antagonist, caused a dose-dependent (10(-10)-10(-8) M) decrease in NA-stimulated prostacyclin production, whereas rauwolscine, an alpha 2-adrenoceptor antagonist (10(-8)-10(-7) M) had no significant effect. In addition, prazosin inhibited the NA-induced pressor responses (10(-10)-10(-8) M) while rauwolscine was only effective at a concentration of 10(-7) M. 3 L-NG mono-methyl-arginine (L-NMMA), an inhibitor of endothelial nitric oxide (NO) synthesis, was used to assess whether elimination of this substance was responsible for the increased basal release of prostacyclin and/or increased pressor responses observed after endothelium removal in the MAB. Concentrations of 3 x 10(-7)-3 x 10(-6) M of L-NMMA were without effect on either prostacyclin release or pressor responses to NA in the intact MAB. 4 These results indicate that in the endothelial denuded MAB, NA-induced release of prostacyclin is, mainly, alpha 1-adrenoceptor-mediated, in contrast to the intact MAB where it is alpha 2-adrenoceptor-dependent. It therefore appears that, in the MAB of the rat, the presence of endothelium obscures the alpha 1-mediated release of prostacyclin from vascular smooth muscle cells. In this preparation the endothelium may regulate both the release of prostacyclin and the contractile responses of the underlying smooth muscle via mechanisms independent of NO formation.

Animals↗

PubMed1991

Effects of hypoxia and metabolic inhibitors on production of prostacyclin and endothelium-derived relaxing factor by pig aortic endothelial cells.

1. The content of adenosine triphosphate (ATP) and basal and bradykinin-stimulated production of prostacyclin and endothelium-derived relaxing factor (EDRF) was measured in primary cultures of porcine aortic endothelial cells under normoxic (14.4% O2) and hypoxic (2.8% O2) conditions, and following treatment with rotenone and 2-deoxy glucose, which inhibit oxidative and glycolytic metabolism, respectively. 2. ATP content and basal and bradykinin-stimulated production of prostacyclin were similar under normoxic and hypoxic conditions. EDRF production, assessed as endothelial guanosine 3':5'-cyclic monophosphate (cyclic GMP) content, was also similar under both conditions. 3. Treatment with rotenone (0.3 microM) had no effect on ATP content or basal or bradykinin-stimulated production of prostacyclin or of EDRF, measured as endothelial cyclic GMP content. Elevation of cyclic GMP content by atriopeptin II was also unaffected. 4. Treatment with 2-deoxy glucose (20 mM) in glucose-free Krebs solution lowered ATP content, reduced bradykinin-stimulated production of prostacyclin and abolished the bradykinin-stimulated elevation of cyclic GMP content. Resting production of prostacyclin was unaffected but basal content of cyclic GMP was lowered in some experiments. Elevation of cyclic GMP content by atriopeptin II was abolished. 5. Combined treatment with rotenone (0.3 microM) and 2-deoxy glucose (20 mM) lowered ATP content more than with 2-deoxy glucose alone. Basal production of prostacyclin rose slightly and bradykinin-stimulated production was powerfully inhibited. Basal content of cyclic GMP was unaffected, but bradykinin-stimulated production was abolished. Elevation of cyclic GMP by atriopeptin II was also abolished. 6. Cascade bioassay experiments using endothelium-denuded rings of rabbit aorta as a detector system confirmed that bradykinin-stimulated production of EDRF was blocked by 2-deoxy glucose, but not by rotenone. 7. These data indicate that porcine aortic endothelial cells in culture operate under mainly glycolytic metabolism and this probably explains why production of prostacyclin and EDRF is unaffected under hypoxic conditions. They also indicate that glycolytic metabolism is required for agonist-stimulated production of prostacyclin and EDRF by these cells.

6-Ketoprostaglandin F1 alpha↗

PubMed1992

A role for prostacyclin in bruising symptomatology.

The relationship between bleeding and bruising and the production of prostacyclin and thromboxane was assessed in children who were to have a tonsillectomy and/or an adenoidectomy. Eicosanoids in the blood oozing from the bleeding time incision were measured and correlated with the reported frequency of bruising and epistaxis. A striking association (P = .0003) between prostacyclin production and the frequency of bruising was found; children reporting bleeding at least biweekly had the highest prostacyclin synthesis. Successively lower levels of the prostacyclin metabolite, 6-keto-prostaglandin F1 alpha, were found in children reporting less frequent bruising. Prostacyclin production in bleeding time blood was also correlated inversely with systolic blood pressure and hemoglobin level, although neither of these variables could explain the association between prostacyclin production and bruising. There was no correlation between thromboxane formation, systolic blood pressure, hemoglobin level, age, or bleeding time and the frequency of bruising. The ratio of thromboxane B2 to 6-keto-prostaglandin F1 alpha was correlated inversely with the length of the bleeding time (P = .016). It is concluded that vascular prostacyclin production may have a role in bruising symptomatology. It is suggested that prostacyclin formed at the injured vessel surface collects within the first few seconds after injury inside the tissue space at the site of the bruise and, by influencing the formation of the platelet/fibrin plug and/or the leakage of blood from the vessels, plays a significant role in modifying the development of bruising.

6-Ketoprostaglandin F1 alpha↗

PubMed1979

The role of prostacyclin in vascular tissue.

Prostacyclin (PGI2) generated by the vascular wall is a potent vasodilator, and the most potent endogenous inhibitor of platelet aggregation so far discovered. Prostacyclin inhibits platelet aggregation by increasing cyclic AMP levels. Prostacyclin is a circulating hormone continually released by the lungs into the arterial circulation. Circulating platelets are, therefore, subjected constantly to prostacyclin stimulation and it is via this mechanism that platelet aggregability in vivo is controlled. Moreover, phosphodiesterase inhibitors such as dipyridamole or theophylline exert their antithrombotic actions by potentiating circulating prostacyclin. The prostacyclin:thromboxane A2 ratio is important in the control of thrombus formation; manipulation of this ratio by small doses of aspirin (which will inhibit mainly platelet cyclooxygenase), a selective inhibitor of thromboxane formation, or the dietary use of a fatty acid like eicosapentaenoic acid (which would be the precursor for a delta17-prostacyclin (PGI3) but is transformed by the platelets into nonaggregating thromboxane A3) might have beneficial effects as antithrombotic therapies. Prostacyclin has interesting potential for clinical application in conditions where enhanced platelet aggregation is involved or to increase biocompatibility of extracorporeal circulation systems.

Animals↗

PubMed1977

Prostacyclin (PGX) is the endogenous metabolite responsible for relaxation of coronary arteries induced by arachindonic acid.

The actions of prostacyclin (PGX) and several other derivatives of arachidonic acid were examined on spiral-strips of bovine coronary artery. The strips were contracted by PGE2 and thromboxane A2. Although PGH2 usually cause a transient contraction followed by a relaxation, a few strips were only contracted whilst others were only relaxed. Prostacyclin invariably relaxed coronary artery strips. Sodium arachidonate usually relaxed the strips but occasionally had no effect. Indomethacin increased the resting tone and abolished or substantially reduced the relaxation induced by sodium arachidonate. 15-hydroperoxy arachidonic acid (15-HPAA), a specific inhibitor of prostacyclin synthetase, also increased the resting tone, abolished the effects of sodium arachidonate and the relaxation component of the PGH2 response, but did not greatly modify the relaxation induced by exogenous prostacyclin. These results strongly suggest that prostacyclin mediates the relaxation induced by arachidonic acid in bovine coronary artery strips. As PGH2 is avidly converted into prostacyclin by the vascular tissue of several species including man, prostacyclin is probably involved in the local regulation of the coronary vascular bed.

Animals↗

PubMed1978

De-aggregatory action of prostacyclin in vivo and its enhancement by theophylline.

In the mixed venous blood of anaesthetized, heparinized cats prostacyclin de-aggregated platelet thrombi, which were formed on the surface of blood-superfused collagen strips or on the surface of blood-superfused aortic strips from atherosclerotic rabbits. The reversal of platelet aggregation by prostacyclin was still achieved 3 hrs after the formation of platelet clumps. After an intravenous injection of prostacyclin the ID50 for its de-aggregatory action was 7.5 microgram/kg. Theophylline ethyl-diamine (aminophylline), at a dose of 3 mg/kg i.v., did not reverse platelet aggregation but it enhanced the duration of the de-aggregatory action of prostacyclin; it had little effect on the hypotensive action of prostacyclin. It is concluded that prostacyclin disintegrates platelet clumps long after they are formed in heparinized blood in vivo and that its anti-platelet action, but not hypotensive action, is selectively potentiated by a phosphodiesterase inhibitor. The above experimental data indicate the possibility of the combined use of theophylline and prostacyclin in arterial thrombosis.

Animals↗

PubMed1992

Pharmacological modulation of prostacyclin and thromboxane production of rat and cat venous tissue slices.

To reveal a potential modulating effect of vasoactive pharmacological agents on the prostanoid production of the venous wall, prostacyclin and thromboxane release from venous tissue slices was studied. Aortic and caval vein samples from 20 rats as well as from 21 cats were studied. Prostacyclin and thromboxane productions were determined by radioimmunoassay as 6-keto-PGF1 alpha and TxB2 released into the incubation medium. Venous tissue produced significantly less prostacyclin per unit weight than arterial tissue in rats (30.7 +/- 4.6 vs. 52.1 +/- 8.2 pg/mg/min), while in cats an opposite situation was found (16.6 +/- 3.2 vs. 7.06 +/- 1.9 pg/mg/min). Thromboxane production of venous tissue was consequently higher than corresponding values for aortic tissue (3.72 +/- 0.46 vs. 1.54 +/- 0.14 in rats and 3.4 +/- 0.6 vs. 1.33 +/- 0.19 in cats, all values in pg/mg/min). Norepinephrine and dopamine significantly increased both the prostacyclin and the thromboxane release from venous tissue, while isoproterenol had no effect. Vasopressin significantly increased thromboxane release and decreased the ratio of prostacyclin vs. thromboxane production (from 10.4 +/- 1.6 to 7.5 +/- 1.6, in acetylsalicylic acid pretreated cats). Angiotensin and thrombin had no significant effects. Bradykinin (0.5 microgram/ml) significantly augmented prostacyclin release from venous tissue (14.4 +/- 2.6 from 10.9 +/- 2.4 pg/mg/min) and decreased thromboxane release (0.65 +/- 0.18 from 1.35 +/- 0.22 pg/mg/min). Methionine-enkephalin (5 micrograms/ml) significantly reduced the thromboxane release from venous tissue slices. The presented material demonstrates that several vasoactive agents modulate the vasoactive prostanoid release of the venous wall. In some cases, the prostacyclin and the thromboxane productions are influenced separately, which in turn will have its impact on smooth muscle activity and thrombocyte aggregation.

6-Ketoprostaglandin F1 alpha↗

PubMed1992

Placental lipid peroxides and thromboxane are increased and prostacyclin is decreased in women with preeclampsia.

OBJECTIVE: There is an imbalance of increased thromboxane and decreased prostacyclin in placentas of women with preeclampsia, but this may not be the only imbalance. There is also an abnormal increase in serum lipid peroxides in preeclamptic women. Lipid peroxides are toxic compounds that damage cells and inhibit prostacyclin synthesis. The following study examined lipid peroxides to determine if they were also increased in placentas of preeclamptic women. STUDY DESIGN: Placental tissue for nine normal and eight preeclamptic women were frozen in liquid nitrogen immediately after delivery. Frozen tissue samples (1 gm) were homogenized and analyzed for lipid peroxides by malondialdehyde and hydrogen peroxide equivalents and for thromboxane and prostacyclin by radioimmunoassay of their stable metabolites, thromboxane B2 and 6-keto prostaglandin F1 alpha. RESULTS: Lipid peroxides were significantly higher in preeclamptic placentas than in normal placentas by both analytic methods (49 +/- 5 vs 31 +/- 1 nmol/gm for malondialdehyde and 5.3 +/- 0.3 vs. 3.2 +/- 0.3 mumol/gm for hydrogen peroxide equivalent; mean +/- SE; p < 0.01, respectively). Thromboxane was significantly higher and prostacyclin significantly lower in preeclamptic placentas than in normal placentas (213 +/- 23 vs 158 +/- 14 ng/gm for thromboxane and 24 +/- 3 vs 53 +/- 7 ng/gm for prostacyclin, p < 0.05). The thromboxane/prostacyclin and lipid peroxides/prostacyclin ratios were threefold higher in preeclamptic placentas than in normal placentas. CONCLUSION: Placental levels of both lipid peroxides and thromboxane are increased and prostacyclin decreased in preeclampsia. We speculate that abnormally increased levels of lipid peroxides in preeclamptic placentas may be a cause of decreased prostacyclin.

6-Ketoprostaglandin F1 alpha↗

PubMed1978

Prostacyclin (PGI2) inhibits the formation of platelet thrombi in arterioles and venules of the hamster cheek pouch.

1 Isolated rings of hamster aorta produced an unstable substance which inhibited platelet aggregation in vitro and had the same characteristics as prostacyclin. 2 Prostacyclin inhibited adenosine diphosphate (ADP)-induced aggregation of hamster platelets in vitro. 3 The effects of prostacyclin on ADP-induced platelet thrombi in the microcirculation of the hamster cheek pouch were studied with a television microscope. 4 Prostacyclin caused a dose-dependent increase in the time of iontophoretic application of ADP which was required to induce platelet thrombi formation and embolization in venules (30 to 40 micron diameter). 5 Prostacyclin caused a dose-dependent reduction in the total time during which ADP-induced thrombi were observed following local electrical damage to arterioles (40 to 80 micron diameter). 6 Thrombus formation in venules and arterioles was abolished by 500 ng/ml prostacyclin in the Krebs solution superfusing the hamster cheek pouch. 7 Prostacyclin was approximately twenty times more potent than prostaglandin E1 in preventing thrombus formation in the microcirculation.

Animals↗

PubMed1992

Effects of tolazoline and prostacyclin on pulmonary hypertension in infants after cardiac surgery.

OBJECTIVE: To evaluate the hemodynamic effects of tolazoline and prostacyclin in infants with pulmonary vasospasm after cardiac surgery. DESIGN: Prospective cohort study. SETTING: Pediatric ICU. PATIENTS: The cohort consisted of 42 infants and children with congenital heart disease and pulmonary hypertension who underwent corrective surgery and were monitored postoperatively using pulmonary artery catheters. Fourteen infants (2 to 12 months old) in this group required postoperative treatment with tolazoline or prostacyclin. INTERVENTIONS: Tolazoline was administered as a bolus of 0.5 mg/kg for treatment of persistent pulmonary hypertension or acute pulmonary hypertensive crisis. If its effectiveness was proved after 30 mins by hemodynamic measurements, a continuous iv infusion of 0.5 mg/kg/hr was established. Higher doses of tolazoline were avoided. If tolazoline treatment did not fulfill the criteria for pulmonary vasodilation, prostacyclin was given by continuous iv infusion at a starting rate of 5 ng/kg/min, followed by 10 ng/kg/min. In three patients, the infusion rate was increased to 15 ng/kg/min. RESULTS: Bolus administration of tolazoline resulted in a distinct pulmonary vasodilation in seven infants: mean pulmonary artery pressure and pulmonary vascular resistance decreased by an average of 35% and 45%, respectively. In these patients, tolazoline was infused over the following 12 to 72 hrs. One infant who received tolazoline for 72 hrs developed a clinically important gastrointestinal hemorrhage. In seven nonresponders to tolazoline, prostacyclin (PGI2) at an infusion rate of 5 ng/kg/min led to pulmonary vasodilation in five patients, at an iv infusion rate of 10 ng/kg/min in all seven infants studied. The latter dose of PGI2 reduced the mean pulmonary artery pressure by an average of 37%, and pulmonary vascular resistance by 43%. Transient withdrawal of prostacyclin in five infants demonstrated its short half-life and clinical effectiveness. Apart from a facial flush, no side-effects were encountered using PGI2 as an infusion over durations ranging from 12 to 504 hrs. CONCLUSIONS: These data suggest that, if tolazoline in a relatively low dose proves to be inefficient, prostacyclin can still be used as a safe and effective drug for treatment of pulmonary vasospasm. Prostacyclin offers more than a pharmacologic alternative to increased tolazoline dosages.

Drug Evaluation↗

PubMed1991

Age-related decline in prostacyclin synthesis by human aortic endothelial cells. Qualitative and quantitative analysis.

To investigate the functional alteration of human aortic endothelial cells with aging, prostacyclin synthesis was qualitatively and quantitatively examined. The endothelial cells of human aortas and umbilical veins or inferior vena cavae were immunohistochemically examined and found positive for prostacyclin, but the intensity of aortic endothelial cells from older subjects was low. In addition to the endothelial cells, smooth muscle cells in the thickened intima, not the media, of the aorta were also immunoreactive. Endothelial cells were successfully cultured from human aortas obtained from infants through aged subjects and were subdivided into three groups: young, middle, and old. Prostacyclin synthesis by endothelial cells from all types of blood vessels was extremely great at the primary culture, but decreased abruptly in the following subcultures. Among the aortic endothelial cells, the young group synthesized the largest amount of prostacyclin in a conventional culture condition, with synthesis progressively decreasing in the older groups. The in vitro prostacyclin biosynthesis was supported by the qualitative analysis on the tissue sections. These results indicate that prostacyclin synthesis of the aortic endothelial cells decreases with age, but intimal smooth muscle cells potentially have a back-up mechanism and substitute this synthesis to some extent. The decreased synthesis of prostacyclin with age may play an important role in the development and advancement of thrombosis and atherosclerosis.

6-Ketoprostaglandin F1 alpha↗