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PubMed1996

Anti-metastatic prostacyclins inhibit the adhesion of colon carcinoma to endothelial cells by blocking E-selectin expression.

Prostacyclins have long been shown to have anti-metastatic activity. One hypothesis is their modulation of cell adhesion molecule (CAM) expression by target organ endothelial cells. We have postulated that prostacyclin, its analogs, and mechanistic mimics decrease colon carcinoma adhesion to cytokine-stimulated endothelial cells by blocking endothelial expression of the adhesion molecule E-selectin, but not the vascular cell adhesion molecule-1 (VCAM-1). Cultured human microvascular endothelial cells (HDMEC) were pre-incubated with prostacyclin (PGI2), dibutyrl-cAMP (dbcAMP), forskolin (FOR), and/or iso-methylbutylxanthine (IBMX) for 15 min, then co-incubated with the cytokine tumor necrosis factor (TNF) for 4 h. HDMEC surface expression of E-selectin and VCAM-1 was evaluated by flow cytometry and ELISA. Adherence of 51Cr-labeled colon carcinoma cells to HDMEC monolayers was then determined. In parallel assays, HDMECs were incubated with anti-E-selectin and anti-VCAM-1 monoclonal antibody (1:100) prior to the addition of tumor cells. Prostacyclins, its analogs, and mimics significantly reduced E-selectin expression by HDMEC, while the reduction of VCAM-1 expression was much less pronounced. Prostacyclins also significantly decreased colon carcinoma adherence to stimulated HDMECs. The inhibition of E-selectin expression, but not VCAM-1 expression, corresponded to the reduction of tumor cell adherence. Prostacyclin's effects on tumor adhesion were nullified by pre-incubation with E-selectin antibody. The inhibition of colon carcinoma adherence to cytokine-stimulated endothelial cells treated with prostacyclin, its analogs, and mimics appears to result from blocking endothelial E-selectin, but not VCAM-1, expression. These data support the hypothesis that prostacyclins may exert their anti-metastatic effect, in part, by inhibiting CAM-mediated adherence of colon carcinoma to endothelial cells in metastatic target organs.

1-Methyl-3-isobutylxanthine↗

PubMed1982

Reduced prostacyclin production in patients with different manifestations of ischemic heart disease.

Prostacyclin, a substance produced by vessel wall, has a sustained vasodilating and platelet antiaggregating activity and therefore the variations in its production in patients with ischemic heart disease are of interest. Prostacyclin production was assessed in 59 patients with ischemic heart disease and 59 control subjects matched for age, sex, body weight, smoking habits, blood pressure and serum cholesterol levels. Of the 59 patients examined, 23 had had a myocardial infarction 3 to 12 months earlier; 21 had had spontaneous angina and 15 effort angina for at least 3 months. Patients with myocardial infarction and spontaneous angina were also classified in subgroups with and without acute coronary insufficiency, according to the occurrence of ischemic attacks in the week preceding the study. Both circulating prostacyclin levels and prostacyclin produced after 3 minutes of ischemia were measured by bioassay. Circulating prostacyclin was significantly less in patients with ischemic heart disease than in matched control subjects independent of the clinical type of ischemic heart disease. Circulating prostacyclin was particularly reduced in patients with acute coronary insufficiency in comparison to patients without, both in the group with myocardial infarction (1.11 +/- 0.22 ng/ml and 2.09 +/- 1.32, respectively) and in the group with spontaneous angina (1.24 +/- 0.42 and 2.17 +/- 1.16, respectively). No differences could be found for prostacyclin produced after 3 minutes of ischemia in relation to the presence of acute coronary insufficiency. The lower level of prostacyclin production in patients with ischemic heart disease and especially in those with acute coronary insufficiency may be an important factor in the occurrence of coronary occlusion or spasm.

Adult↗

PubMed1995

Plasma from preeclamptic women increases human endothelial cell prostacyclin production without changes in cellular enzyme activity or mass.

OBJECTIVE: We investigated differences in prostacyclin production by endothelial cells exposed to plasma from either preeclamptic women or normal pregnant women. STUDY DESIGN: A case-control study of matched preeclamptic and normal pregnancies was used to compare prostacyclin synthesis by human umbilical vein endothelial cells incubated with pregnancy plasma for 24 hours. Prostacyclin concentrations in conditioned media were measured by radioimmunoassay of its stable metabolite (6-keto-prostaglandin F1 alpha). Human umbilical vein endothelial cell lysates were used to determine concentrations of the enzymes cyclooxygenase and prostacyclin synthase. RESULTS: Prostacyclin production by human umbilical vein endothelial cells incubated with plasma from preeclamptic women was significantly greater than that by cells exposed to normal pregnancy plasma. Differences in prostacyclin production under the two experimental conditions could be explained neither by differences in enzyme mass nor activities of cyclooxygenase and prostacyclin synthase. CONCLUSION: The stimulatory effect of preeclampsia plasma on prostacyclin biosynthesis in human umbilical vein endothelial cells appears to be manifested at a step(s) proximal to the activation of cyclooxygenase. Possible mechanisms are increased phospholipase A2, lipoprotein, or lipid peroxide activities in preeclampsia.

Case-Control Studies↗

PubMed1986

Effect of elastase on prostacyclin synthesis in aortic smooth muscle cells.

The effects of elastase on prostacyclin biosynthesis in cultured rat aortic smooth muscle cells were investigated. Prostacyclin is the major product formed from arachidonic acid by aortic smooth muscle cells. When intact cells were incubated with elastase, a significant stimulatory effect on prostacyclin biosynthetic activity in cells was evident. However, the addition of elastase directly to the cell-free homogenates did not show any effects on prostacyclin biosynthesis. The maximal effect of elastase on the stimulation of prostacyclin biosynthesis without any cellular damage was observed at a concentration of 50 unit/ml elastase. Elastase also caused a marked release of arachidonic acid. At higher concentrations of elastase (75-100 units/ml), the release of arachidonic acid and prostacyclin synthesis was observed, but, at these concentrations of elastase, cells were slightly damaged. On the other hand, the releases of prostacyclin and arachidonic acid were markedly enhanced, when cells were preincubated with elastase (1 unit/ml) for 3 days. These results indicate that elastase, even at low concentrations, causes the releases of arachidonic acid and prostacyclin, especially when aortic smooth muscle cells are pre-treated with elastase.

6-Ketoprostaglandin F1 alpha↗

PubMed1995

7-Oxo-prostacyclin affects the electrogenic Na+/K+ pump in mouse diaphragm fibers.

The effect of a stable prostacyclin derivative, 7-oxo-prostacyclin, on the electrogenic Na+/K+ pump in mouse diaphragm muscle was investigated. Resting membrane potentials of muscle cells were measured with glass microelectrodes. In fresh diaphragm preparations from 7-oxo-prostacyclin-pretreated mice (50 micrograms.kg-1 7-oxo-prostacyclin i.p. 30-34 h prior to the experiment) resting membrane potentials were significantly higher (-83.86 +/- 1.40 mV, mean +/- S.E.M.) than in control preparations (-70.78 +/- 1.07 mV). Ouabain at a concentration of 10(-4) mol.l-1 abolished this hyperpolarization (P < 0.05). The electrogenic effect induced by addition of 5 mmol.l-1 K+ to Na(+)-loaded muscles from 7-oxo-prostacyclin-pretreated animals was also enhanced (delta resting membrane potential = 21.73 +/- 3.13 mV) compared with that of the controls (delta resting membrane potential = 18.36 +/- 1.29 mV). Ouabain antagonized the increase in electrogenicity of Na(+)-loaded diaphragms induced by 7-oxo-prostacyclin pretreatment (P < 0.05). In contrast to control preparations, no inhibition of the electrogenic effect induced by 10 mmol.l-1 Ca2+ ions in Na(+)-loaded muscles was observed in diaphragms from 7-oxo-prostacyclin-pretreated animals. In acute experiments with Na(+)-loaded muscles, where 10(-7) mol.l-1 7-oxo-prostacyclin was added to the bath, resting membrane potential reached up to -100 mV. The electrogenic pump-induced increase in resting membrane potential amounted to approximately 30 mV. This effect could be also abolished by 10(-4) mol.l-1 ouabain (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1983

Changes of mean arterial pressure of the rat resulting from intracerebroventricular injections of prostacyclin or 6-keto-prostaglandin F1 alpha.

Repeated intracerebroventricular injections of 1 microgram prostacyclin reduce mean arterial pressure of conscious normotensive rats and reverse the elevation of blood pressure of conscious rats resulting from the intraventricular injection of angiotensin II. The reduction of blood pressure of normotensive rats by prostacyclin is enhanced by pretreatment with probenecid, an inhibitor of fatty-acid transport across biological membranes. Although probenecid does not completely inhibit the transport of fatty acids from the brain to the periphery, the greater effectiveness of prostacyclin in probenecid-treated animals suggests that centrally injected prostacyclin need not leak into the periphery to reduce blood pressure. When the dose of prostacyclin is reduced to 100 ng repeated each minute for 10 min, no change of blood pressure of normotensive rats is observed. The failure of the lower dose of prostacyclin to reduce blood pressure may be due to its rapid degradation. Ventricular injections of 6-keto-prostaglandin F1a, a major product of prostacyclin metabolism, causes an increase of blood pressure which may counteract the action of prostacyclin itself.

6-Ketoprostaglandin F1 alpha↗

PubMed1985

Are the renal functional changes of human pregnancy caused by prostacyclin?

To investigate the hypothesis of others that the many characteristic physiological alterations of pregnancy are due to prostacyclin, the effects of this vasodilator prostaglandin on renal function and related variables were measured. Intravenous infusion of prostacyclin (7 ng/kg/min) for 90 minutes in seven healthy male volunteers resulting in a significant fall in diastolic blood pressure and increase in heart rate. No significant change occurred in renal plasma flow or glomerular filtration rate in response to the prostacyclin, but there were significant falls in uric acid clearance (16 +/- 1.3----10 +/- 1.5 ml/min/ 1.73m2) and in free water clearance (4.0 +/- 1.1-----0.5 +/- 0.4 ml/min) both of which rose rapidly to pre-infusion levels upon cessation of prostacyclin infusion. Plasma renin and aldosterone levels rose sharply during prostacyclin infusion, falling to pre-infusion levels rapidly afterwards. Although the haemodynamic alterations were similar, the renal functional effects of prostacyclin infusion were quite different from (and often opposite in direction to) those of normal pregnancy. This acute study therefore does not add support to the hypothesis suggested by others that these alterations in pregnancy are due to prostacyclin, and that deficiency of prostacyclin will lead to the changes of pregnancy-associated hypertension.

Adult↗

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↗

PubMed1989

Mechanism(s) by which activation of protein kinase C is coupled to prostacyclin synthesis in granulosa cells.

We examined the mechanisms by which the phospholipid-sensitive, calcium-dependent protein kinase (protein kinase C) regulates prostacyclin synthesis by ovarian cells. In monolayer cultures of swine granulosa cells, specific phorbol esters significantly augmented production of the stable immunoreactive metabolite of prostacyclin, 6-keto-prostaglandin F1 alpha by 3- to 8-fold. These stimulatory actions were dose (0.03-30 ng/ml) and time (24-96 h) dependent, could be reproduced by non-diterpene activators of protein kinase C, and were corroborated by high performance liquid chromatography and mass spectrometry. The rank order of potency of phorbol esters was 12-O-tetradecanoylphorbol 13-acetate (TPA) greater than phorbol 12,13-dibenzoate greater than phorbol 12,13-dibutyrate greater than pure phorbol base. TPA enhanced de novo synthesis of prostacyclin, and synergized with the divalent cation ionophore, A23187. Although prostacyclin synthetase activity was not induced, microsomal cyclooxygenase activity was significantly increased by phorbol treatment. Moreover, TPA doubled the intracellular accumulation of free arachidonic acid. An inhibitor of phospholipase A2 (quinacrine 100 microM) impeded, whereas melittin (0.01 microM), an activator of cellular phospholipase A2, and purified bacterial phospholipase A2 (5 and 50 mU/ml) both augmented prostacyclin production. RH 59022 (30 microM), an inhibitor of diacylglyceride lipase, also suppressed prostacyclin synthesis. We conclude that the protein kinase C effector pathway is functionally coupled to de novo prostacyclin production in the swine granulosa cell. Increased eicosanoid synthesis can be accounted for by enhanced phospholipase A2 and diacylglyceride lipase-mediated availability of arachidonic acid substrate and an activated cyclooxygenase enzyme without a change in prostacyclin synthetase activity.

6-Ketoprostaglandin F1 alpha↗

PubMed1989

Effect of hyperlipidemic serum on lipid peroxidation, synthesis of prostacyclin and thromboxane by cultured endothelial cells: protective effect of antioxidants.

An increased lipid peroxides and a decreased production of prostacyclin have been shown in advanced atherosclerotic lesions and plasma. Our purpose was to determine whether the similar findings could be observed in cultured endothelial cells, and whether antioxidants could protect the cell against peroxide injury. In these experiments we have used bovine aortic endothelial cells in culture to address the issue of hyperlipidemia-induced arterial damage. Results of the present study showed that different concentration of hyperlipidemic sera from atherogenic rabbits induced a time- and dose-dependent alteration in the production of prostacyclin and levels of lipid peroxides in endothelial cells. Endothelial cells incubated with hyperlipidemic serum increased prostacyclin generation significantly during the initial stages and then continuously decreased. When endothelial cells were incubated for 36 h, TXA2 generation was also impaired and at the same time the cellular lipid peroxides content increased. There was a positive correlation between the concentration of hyperlipidemic serum and lipid peroxides and an inverse correlation with prostacyclin synthesis. The medium supplemented with antioxidant selenium or vitamin E showed a significant decrease in lipid peroxides and an increase in prostacyclin synthesis. These results suggest that both hyperlipidemic serum and lipid peroxides injury endothelial cells and inactivate prostacyclin synthetase, resulting in a decrease of prostacyclin production, while antioxidants have a protective effect. We conclude that the increase in lipid peroxides in association with hyperlipidemia results in alteration of prostacyclin synthesis that may play an important role in the pathogenesis of atherosclerosis.

Animals↗

PubMed2001

Differential effects of prostacyclin and iloprost in the isolated carotid artery of the guinea-pig.

The effects on membrane potential of prostacyclin and iloprost were compared in smooth muscle cells of the guinea pig carotid artery. Both prostacyclin and iloprost induced hyperpolarization of the smooth muscle cells. In the presence of (3R)-3-(4-fluorophenyl-sulfonamido)-1,2,3,4-tetrahydro-9-carbazolepropanoic acid (Bay U3405), an antagonist of TP receptors, the response to iloprost was unaffected while that to prostacyclin was increased. Iloprost-induced hyperpolarizations were abolished by glibenclamide while those to prostacyclin were either not affected, or converted to either depolarization or to rhythmic electrical activity. The latter effects of prostacyclin were abolished by Bay U3405. After removal of the endothelium, iloprost and prostacyclin produced hyperpolarizations similar to those observed in control blood vessels. However, in the presence of glibenclamide, prostacyclin produced only depolarizations inhibited by Bay U3405. These results suggest that iloprost activates IP receptors and K(ATP) channels in smooth muscle. In contrast, prostacyclin produces additional endothelium-dependent and -independent effects via activation of TP receptors.

Animals↗

PubMed2003

Sevoflurane but not isoflurane can reduce prostacyclin production of endothelial cells.

BACKGROUND AND OBJECTIVE: Little is known about the interaction of newer volatile anaesthetics with endothelial eicosanoid production. Sevoflurane may possibly reduce prostacyclin formation. Thus, we compared the influences of sevoflurane and isoflurane on endothelial prostacyclin production. METHODS: Production of prostacyclin of human umbilical vein endothelial cells was measured by the ELISA technique under basal conditions and after stimulation with calcium ionophore A 23187 10 micromol or histamine 0.1 micromol in the absence and presence of 1 and 2 minimal alveolar concentrations (MAC) of sevoflurane or isoflurane. RESULTS: The basal production of prostacyclin was unaffected by the volatile anaesthetics. Stimulation of endothelial cells increased prostacyclin formation 3-5-fold. Sevoflurane at 2 MAC, but not at 1 MAC, could reduce stimulated prostacyclin production by about half (P < 0.05). Isoflurane had no inhibitory effect. Inhibition of cyclo-oxygenase function by acetylsalicylic acid abolished the induced burst of prostacyclin formation completely. CONCLUSIONS: Sevoflurane, but not isoflurane, can reduce stimulated endothelial prostacyclin production in a concentration-dependent manner. Because at least 2 MAC of sevoflurane were required, this effect should be of minor importance under clinical conditions of balanced anaesthesia.

Analysis of Variance↗

PubMed2000

Low-dose prostacyclin in treatment of severe brain trauma evaluated with microdialysis and jugular bulb oxygen measurements.

BACKGROUND: The endogenous substance prostacyclin is a substance with the potential to improve microcirculation and oxygenation around contusions in the brain following a head trauma by its vasodilatory, antiaggregatory and antiadhesive effects. Microdialysis measurements of local concentrations of selected interstitial substances in the brain, and measurements of venous jugular bulb oxygenation reflecting overall brain oxygenation, might be useful to evaluate possible therapeutic effects of a specific therapy, such as treatment with prostacyclin. METHODS: This case report study on six patients, of whom five were given prostacyclin, includes cerebral microdialysis measurements of interstitial lactate (n=5), pyruvate (n=3), glycerol (n=5) and glucose (n=4), and is combined with measurements of venous jugular bulb oxygenation in three of the patients. One microdialysis catheter was placed adjacent to a contusion, and in four of the patients another catheter was also placed in the contralateral less injured side for comparison. Low-dose prostacyclin infusion (0.5-1.0 ng kg(-1) min(-1)) was started when lactate concentrations in the more injured side was raised at a constant level for more than 10 h. The study also includes one patient used as control to whom no prostacyclin was given. RESULTS: Lactate was markedly lower in the less injured than in the more injured area of the brain. During the prostacyclin infusion elevated lactate and lactate/pyruvate ratio were reduced. Elevated glycerol decreased, a low glucose increased and jugular bulb blood oxygenation increased following start of prostacyclin. The control patient showed an increase in lactate and lactate/pyruvate ratio. CONCLUSION: The microdialysis data combined with the jugular bulb oxygenation data indicated that low-dose prostacyclin exerts effects compatible with improved oxygenation and reduced cell damage in the severely traumatised brain.

Adult↗

PubMed1984

Effects of prostacyclin infusion on platelets and hemodynamics in coronary bypass surgery.

Twenty patients undergoing aorto-coronary bypass were randomly assigned to a prostacyclin treatment group or control group. Eight patients received 2 mg/kg heparin and 10 ng/kg/min prostacyclin before cardiopulmonary bypass (CPB) and 50 ng/kg/min during CPB. Twelve patients, serving as controls, received 3 mg/kg heparin. Heparinization resulted in a slight but significant increase of plasma beta-thromboglobulin in the control group but not in the prostacyclin group, and of plasma platelet factor 4 (PF-4) in both groups. After 90 minutes of CPB, beta-thromboglobulin was 408 (SD 128) ng/ml in the control group and 111 (SD 50) ng/ml (p less than 0.001) in the prostacyclin group. Platelet count, corrected for hemodilution, was 92% (SD 10) of the pre-CPB value after 10 minutes of CPB and 89% (SD 7) one hour after CPB in the control group, as compared to 113% (SD 10) and 145% (SD 18), respectively, in the prostacyclin group. Prostacyclin infusion before CPB reduced systemic vascular resistance to half of that of the control group, lowered mean arterial blood pressure, and increased cardiac index by 60% to 80%. An infusion of prostacyclin before CPB does not add to the already excellent platelet protective effect of 50 ng/kg/min prostacyclin during CPB, but may be used for vasodilation.

Blood Platelets↗

PubMed1989

Low-dose aspirin: treatment for the imbalance of increased thromboxane and decreased prostacyclin in preeclampsia.

The discovery of the imbalance of increased thromboxane and decreased prostacyclin production in preeclamptic women has explained the cause of the major clinical symptoms of this disorder and has formed the basis and rationale for clinical studies with low-dose aspirin to treat preeclampsia. Low doses of aspirin (60 to 81 mg/day) have a remarkable ability to inhibit thromboxane production selectively without significantly inhibiting prostacyclin production. Therefore the actions of thromboxane to increase vasoconstriction, stimulate platelet aggregation, increase uterine contractility, and decrease uteroplacental blood flow are attenuated, and the ratio of thromboxane to prostacyclin is altered in favor of prostacyclin. Prostacyclin promotes vasodilation, inhibits platelet aggregation, decreases uterine contractility, and increases uteroplacental blood flow. The initial clinical studies with low doses of aspirin are very encouraging with respect to the treatment and prevention of preeclampsia. Substantial evidence already indicates that low-dose aspirin therapy decreases the incidence of preeclampsia; it decreases the maternal systemic arterial pressor response to angiotensin II; and it does not seem to be harmful to the fetus. Treatment of preeclampsia with prostacyclin appears to be contraindicated because prostacyclin is a potent systemic vasodilator and the clinical outcome of preeclamptic women infused with prostacyclin has been poor. The mechanism whereby low-dose aspirin preferentially inhibits thromboxane synthesis is not known.(ABSTRACT TRUNCATED AT 250 WORDS)

Aspirin↗

PubMed2001

Infusion of prostacyclin following experimental brain injury in the rat reduces cortical lesion volume.

Endothelial-derived prostacyclin is an important regulator of microvascular function, and its main actions are inhibition of platelet/leukocyte aggregation and adhesion, and vasodilation. Disturbances in endothelial integrity following traumatic brain injury (TBI) may result in insufficient prostacyclin production and participate in the pathophysiological sequelae of brain injury. The objective of this study was to evaluate the potential therapeutic effects of a low-dose prostacyclin infusion on cortical lesion volume, CA3 neuron survival and functional outcome following TBI in the rat. Anesthetized animals (sodium pentobarbital, 60 mg/kg, i.p.) were subjected to a lateral fluid percussion brain injury (2.5 atm) or sham injury. Following TBI, animals were randomized to receive a constant infusion of either prostacyclin (1 ng/kg x min(-1) i.v.) or vehicle over 48 h. All sham animals received vehicle (n = 6). Evaluation of neuromotor function, lesion volume, and CA3 neuronal loss was performed blindly. By 7 days postinjury, cortical lesion volume was significantly reduced by 43% in the prostacyclin-treated group as compared to the vehicle treated group (p < 0.01; n = 12 prostacyclin, n = 12 vehicle). No differences were observed in neuromotor function (48 h and 7 days following TBI), or in hippocampal cell loss (7 days following TBI) between the prostacyclin- and vehicle-treated groups. We conclude that prostacyclin in a low dose reduces loss of neocortical neurons following TBI and may be a potential clinical therapeutic agent to reduce neuronal cell death associated with brain trauma.

Animals↗

PubMed1994

Additive haemodynamic effects of piroximone and prostacyclin in severe chronic heart failure.

This study was undertaken to assess the haemodynamic effects of the combined infusion of prostacyclin and piroximone, a phosphodiesterase inhibitor, in 18 patients with severe congestive heart failure. Right heart catheterization was performed with a Swan-Ganz thermodilution catheter and arterial blood pressure was monitored using a radial line. After baseline haemodynamic measurements, prostacyclin was administered in all patients at the incremental infusion rate of 2, 4, 6 and 8 and 10 ng.kg-1.min-1 during 15 min each. After recovery of baseline haemodynamics, patients were randomly assigned to the piroximone infusion rate of 5 or 10 micrograms.kg-1.min-1 or placebo. After 24 h piroximone or placebo infusion, the same prostacyclin protocol was applied. Prostacyclin infusion added to piroximone resulted in a significant improvement in haemodynamics, as compared to the group receiving prostacyclin added to placebo. As compared to the curve observed with the placebo infusion, 10 ng.kg-1.min-1 prostacyclin infusion resulted in a further increase in cardiac index, by 41 and 38% (P < 0.01) at the piroximone-infusion rates of 5 and 10 micrograms.kg-1.min-1, respectively, whereas systemic vascular resistance decreased by 25 and 21%, respectively (P < 0.01). Additionally, a further decrease in pulmonary capillary wedge pressure by 13 and 11% (P < 0.05) and in pulmonary vascular resistance by 21 and 19% (P < 0.05) was observed at the piroximone-infusion rates of 5 and 10 micrograms.kg-1.min-1, respectively. Consequently, stroke work index increased significantly, as compared to the group receiving prostacyclin added to placebo. This haemodynamic improvement occurred without significant changes in heart rate and mean arterial pressure. Thus, this study shows that in patients with severe congestive heart failure, short-term infusion of prostacyclin is safe and has additive haemodynamic effects on phosphodiesterase inhibitors.

Adult↗

PubMed1996

Effects of inhaled nitric oxide and nebulized prostacyclin on hypoxic pulmonary vasoconstriction in anesthetized sheep.

OBJECTIVES: Inhaled nitric oxide has been shown to be a selective pulmonary vasodilator, leading to reduced pulmonary arterial pressure and improved ventilation/perfusion ratio in the acute respiratory distress syndrome. This local pulmonary vasodilation theoretically can be achieved by the airway application of a short-acting vasodilator, such as prostacyclin. We hypothesized that nebulized prostacyclin has the same properties for selective pulmonary vasodilation as inhaled nitric oxide. DESIGN: Prospective, experimental study in sheep. SETTING: Investigational intensive care unit in a university hospital. SUBJECTS: Six adult ewes of the Merino breed. INTERVENTIONS: Sheep (n = 6) were surgically prepared for chronic study. After 5 days of recovery, the sheep had tracheostomies performed under anesthesia. Intubation with a modified Robert-Shaw tube allowed side-separated ventilation. The entire left lung was ventilated with pure nitrogen, whereas the right lung was ventilated with pure oxygen. Nitric oxide and prostacyclin were added in different concentrations to the nitrogen, with which the left lung was ventilated. MEASUREMENTS AND MAIN RESULTS: The blood flows to the left and right lungs were measured with ultrasonic flow probes on the common and left pulmonary artery. Measurements were taken after each compound had been administered for 10 mins at a predefined dose. Both inhaled nitric oxide and nebulized prostacyclin caused effective, selective, dose-dependent pulmonary vasodilation. Inhaled nitric oxide was able to abolish hypoxic pulmonary vasoconstriction when insufflated into the animals at a concentration of 50 ppm of nitrogen, but 100 ppm of nitric oxide had no further effect. Prostacyclin, at a dosage of 10 micrograms/min, showed maximum pulmonary vasodilation, which could not be further increased by doubling the dosage. However, prostacyclin produced less dilation than high doses of nitric oxide, and its maximum pulmonary vasodilation was comparable with that effect obtained under ventilation with 20 ppm of nitric oxide. CONCLUSIONS: Both drugs selectively dilated the pulmonary vasculature in ventilated alveoli. Prostacyclin nebulization is an excellent tool to reduce pulmonary hypertension and to improve the ventilation/perfusion ratio. Prostacyclin nebulization can be used without the highly sophisticated technical equipment that is needed for controlled nitric oxide inhalation, and may therefore become a new, noninvasive therapeutic approach for treatment of adult respiratory distress syndrome in hospitals that cannot provide nitric oxide inhalation.

Administration, Inhalation↗