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PubMed1994

Halothane inhibits bradykinin-stimulated prostacyclin production in endothelial cells.

BACKGROUND: Halothane and isoflurane alter signal transduction and function in several cell types. Vascular responses to these anesthetics may be attributable to agent-specific effects on vasoactive mediator production. This study investigated the effects of halothane and isoflurane on basal and agonist-stimulated prostacyclin production by endothelial cells. METHODS: Prostacyclin production by cultured bovine aortic endothelial cells was monitored by radioimmunoassay of 6-keto-prostaglandin F1 alpha, the stable breakdown product of prostacyclin. RESULTS: Neither halothane nor isoflurane (0.3-1 mM), altered prostacyclin production. Bradykinin (1 microM), adenosine triphosphate (ATP) (10 microM), and melittin (1 microgram.ml-1) stimulated prostacyclin production. Isoflurane had no effect on responses to bradykinin, ATP, or melittin. Halothane inhibited the response to bradykinin but not the response to ATP or melittin. Pretreatment with pertussis toxin (100 ng.ml-1), to inhibit the function of the guanosine triphosphate-binding protein G alpha i, did not alter the response to bradykinin in the presence or absence of halothane. Pretreatment with phorbol 12-myristate 13-acetate (100 nM), to stimulate protein kinase C activity, did not alter bradykinin-stimulated prostacyclin production and prevented the inhibition of the response to bradykinin by halothane. CONCLUSIONS: Isoflurane had no effect on the increase in prostacyclin production stimulated by bradykinin. Halothane inhibited the bradykinin-stimulated prostacyclin production but not that stimulated by ATP or melittin. These results suggest that the halothane-mediated inhibition of bradykinin-stimulated prostacyclin production does not involve a pertussis toxin-sensitive G-protein and may result from an interaction of halothane at some other step in the signal transduction pathway, including the inhibition of protein kinase C.

Adenosine Triphosphate↗

PubMed1986

Effect of prostacyclin on renal kallikrein release in man.

The aim of this research was to study exogenous prostacyclin effect on urinary kallikrein excretion (UKK) in man, to define whether prostacyclin-induced renin release and/or endogenously released cyclooxygenase products were responsible for prostacyclin-induced enhancement of UKK, to determine furosemide effect on UKK. Prostacyclin was infused in eight healthy men and repeated after propranolol and indomethacin treatment. Prostacyclin caused a dose-dependent increase of UKK. Pretreatment with propranolol and indomethacin did not affect prostacyclin-induced enhancement of UKK, although it reduced absolute values of plasma renin activity. Furosemide increased UKK and simultaneously urinary 6-keto-prostaglandin F1 alpha. We conclude that prostacyclin induces an increase in UKK in a dose-dependent manner; furosemide-induced renal prostacyclin synthesis is temporally related to enhancement of UKK; partial dissociation of UKK from plasma renin activity under propranolol and indomethacin treatment and in response to furosemide might suggest a direct effect of prostacyclin on UKK.

6-Ketoprostaglandin F1 alpha↗

PubMed1995

Gene expression of prostacyclin receptor in the hypertrophied heart of spontaneously hypertensive rats.

1. Prostacyclin elicits 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. We recently succeeded in molecular cloning of cDNA for the mouse, rat, and human prostacyclin receptors. 2. In the present study, we examined the mRNA expression of the prostacyclin receptor in various rat tissues, and further investigated its gene expression in the hypertrophied cardiac ventricles of stroke-prone spontaneously hypertensive rats (SHRSP). 3. In rat tissues, a single RNA band of approximately 3.7 kb was detected by northern blotting analysis using rat prostacyclin receptor cDNA as a probe. In adult Wistar rats, abundant mRNA expression was observed in the aorta, lung and spleen. Substantial amounts of transcript were expressed in the heart, pancreas, thymus and stomach. In contrast, no mRNA expression was detected in the brain. 4. We further examined the mRNA expression of the prostacyclin receptor in the ventricles of 21 week old SHRSP. The ventricles of SHRSP showed remarkable hypertrophy, compared with those of age-matched Wistar-Kyoto (WKY) rats. The expression of prostacyclin receptor mRNA in the hypertrophied ventricles of SHRSP was almost equivalent to that in the ventricles of WKY. 5. The present study revealed the gene expression of the prostacyclin receptor in various rat tissues, and further demonstrated the receptor mRNA expression in hypertensive cardiac hypertrophy. The present study will give a clue to investigate the clinical implication of prostacyclin and its receptor.

Animals↗

PubMed1983

Stimulation and inhibition of prostacyclin formation in the gastric mucosa and ileum in vitro by anti-inflammatory agents.

1 Homogenates of rat gastric mucosa, forestomach and ileum and dog gastric mucosa reproducibly generated prostacyclin from endogenous substrate.2 Prostacyclin formation was inhibited by pre-incubation with indomethacin, flurbiprofen, naproxen, ketoprofen or meclofenamate (0.1-10 muM).3 BW755C (3-amino-1[m-(trifluoromethyl)-phenyl]-2-pyrazoline) stimulated prostacyclin production in the rat gastric mucosa and ileum with inhibition occurring only at high concentrations (> 200 muM). The stimulation of prostacyclin production by BW755C in rat forestomach homogenates was less pronounced, with inhibition at concentrations > 20 muM.4 BW755C thus exhibits differential activity on prostacyclin production from different gastric tissues in vitro.5 The antioxidant-lipoxygenase inhibitor, nordihydroguiaretic acid (NDGA, 3-15 muM) likewise augmented rat mucosal prostacyclin formation.6 Paracetamol stimulated and, at higher concentrations, inhibited prostacyclin formation (> 1 mM), and had comparable activity in both rat gastric tissues.7 The ability of NDGA and BW755C to enhance prostacyclin generation may reflect the removal of a modulating influence of lipoxygenase products on prostacyclin formation, the diversion of substrate to the cyclo-oxygenase pathway, or free-radical scavenging.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗

PubMed1997

Prostacyclin receptor desensitization is a reversible phenomenon in human platelets.

BACKGROUND: Long-term exposure of platelets to endogenous or exogenous prostacyclin or its analogues might result in desensitization of the platelet prostacyclin receptor in vitro and in vivo accompanied by a loss in receptor density on the platelet surface and a reduced sensitivity toward the inhibitory effects of prostacyclins. However, the reversibility of this process in platelets has not yet been investigated. METHODS AND RESULTS: Human platelets desensitized by the chemically stable prostacyclin analogue iloprost showed a significant reduction in [3H]-iloprost binding sites that was reversed by saponin permeabilization. This indicates functionally active internalized prostacyclin receptors. To assess whether the internalized prostacyclin receptors recycle to the cell surface after withdrawal of the agonist, iloprost sensitivity and prostacyclin receptor binding properties of iloprost (30 nmol/L, 2 hours) desensitized platelets incubated in iloprost-free autologous plasma were investigated. While desensitized platelets showed a significant increase in IC50 for iloprost inhibition of thrombin-induced platelet aggregation, serotonin release, and p-selectin expression and a reduced iloprost-stimulated cAMP formation, platelet iloprost sensitivity was restored 3 hours after iloprost withdrawal. In addition, the significant reduction in Bmax and the increase in K(D) of prostacyclin receptors in desensitized platelets as revealed by [3H]-iloprost binding studies also returned to the initial values. CONCLUSIONS: These results indicate that prostacyclin receptors internalized during short-term desensitization are not degraded but can be recycled rapidly to the platelet surface in a functionally active form after withdrawal of the agonist.

Blood Platelets↗

PubMedDate not supplied

Intravenous prostacyclin in acute nonhemorrhagic stroke: a placebo-controlled double-blind trial.

The therapeutic efficacy of prostacyclin in nonhemorrhagic cerebral infarction was assessed in a placebo-controlled double-blind trial. A total of 80 patients with stroke onset within 24 hours were randomized into placebo (37 patients) and prostacyclin (43 patients) groups. Demographic data and risk factors were comparable. Patients in the prostacyclin group received a continuous i.v. infusion of prostacyclin at an average rate of 8.5 ng/kg/min for an average of 64 hours. The placebo group received vehicle only in a similar fashion. During treatment hemodynamic changes were more prominent in the patients receiving prostacyclin and included reduction of systolic and diastolic blood pressure and increase in pulse rate. In contrast there was only a slight (but significant) reduction of diastolic blood pressure in the placebo group. Neurologic deficit scores were determined on admission, at Day 3, and at Weeks 1, 2, and 4. Mean neurologic deficit scores upon entry were comparable in the placebo and prostacyclin groups, and a significant improvement in the score for neurologic deficit was noted in both. The placebo group tended to fare better throughout the study, with a significant difference in neurologic deficit score favoring the placebo group at Week 2 (p = 0.0048). Two patients in the placebo and one in the prostacyclin group died. The only difference in adverse reactions was flushing (6 patients in prostacyclin vs. 0 in placebo group, p less than 0.05). The results of this study suggest a lack of therapeutic efficacy of prostacyclin in a defined population of patients with nonhemorrhagic cerebral infarction.

Acute Disease↗

PubMed1987

Prostacyclin and PGE1 treatment of pulmonary hypertension.

Prostacyclin and PGE1 show promise in treatment of many forms of pulmonary hypertension. Their clinical use can be expected to increase as their pulmonary vasodilating effects become better known. There is as yet no unequivocal reason to choose one agent over the other, but several observations suggest that prostacyclin will eventually be preferred. First, prostacyclin appears to have a shorter half-life (1 to 2 min), which means that any drug-induced adverse effects will disappear more quickly. Although it is commonly said that up to 80% of PGE1 is metabolized with one passage through the lungs, in one study 34% of intravenously administered radiolabeled PGE1 remained in the bloodstream 20 min after administration. Second, prostacyclin causes less severe and less prolonged rebound platelet activation after discontinuation. Third, prostacyclin has been shown to reduce resting pulmonary vascular tone and hypoxic pulmonary vasoconstriction in virtually every published study in every species tested at every stage of development (fetal, newborn, and adult life); results with PGE1, although very impressive, have been less consistent. Nevertheless, there is little doubt that PGE1 is a powerful pulmonary vasodilator in most clinical situations complicated by pulmonary hypertension. Further, PGE1 is available for clinical use, while prostacyclin remains an investigational drug. Thus, it is likely that PGE1 will become the "nitroprusside" of the lesser circuit for intensive care use, a position PGE1 will hold alone at least until prostacyclin becomes available. Chronic infusions of prostacyclin may prove particularly useful in patients with primary pulmonary hypertension awaiting heart-lung transplantation. Eventually, orally available prostacyclin and PGE1 analogs will offer a new therapeutic avenue in many diseases complicated by chronic pulmonary hypertension.

Alprostadil↗

PubMed1983

Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man.

To assess the pharmacologic effects of aspirin on endogenous prostacyclin and thromboxane biosynthesis, 2,3-dinor-6-keto PGF1 alpha (PGI-M) and 2,3-dinor-thromboxane B2 (Tx-M) were measured in urine by mass spectrometry during continuing administration of aspirin. To define the relationship of aspirin intake to endogenous prostacyclin biosynthesis, sequential urines were initially collected in individuals prior to, during, and subsequent to administration of aspirin. Despite inter- and intra-individual variations, PGI-M excretion was significantly reduced by aspirin. However, full mass spectral identification confirmed continuing prostacyclin biosynthesis during aspirin therapy. Recovery of prostacyclin biosynthesis was incomplete 5 d after drug administration was discontinued. To relate aspirin intake to indices of thromboxane biosynthesis and platelet function, volunteers received 20 mg aspirin daily followed by 2,600 mg aspirin daily, each dose for 7 d in sequential weeks. Increasing aspirin dosage inhibited Tx-M excretion from 70 to 98% of pretreatment control values; platelet TxB2 formation from 4.9 to 0.5% and further inhibited platelet function. An extended study was performed to relate aspirin intake to both thromboxane and prostacyclin generation over a wide range of doses. Aspirin, in the range of 20 to 325 mg/d, resulted in a dose-dependent decline in both Tx-M and PGI-M excretion. At doses of 325-2,600 mg/d Tx-M excretion ranged from 5 to 3% of control values while PGI-M remained at 37-23% of control. 3 d after the last dose of aspirin (2,600 mg/d) mean Tx-M excretion had returned to 85% of control, whereas mean PGI-M remained at 40% of predosing values. Although the platelet aggregation response (Tmax) to ADP ex vivo was inhibited during administration of the lower doses of aspirin the aggregation response returned to control values during the final two weeks of aspirin administration (1,300 and 2,600 mg aspirin/d) despite continued inhibition of thromboxane biosynthesis. These results suggest that although chronic administration of aspirin results in inhibition of endogenous thromboxane and prostacyclin biosynthesis over a wide dose range, inhibition of thromboxane biosynthesis is more selective at 20 than at 2,600 mg aspirin/d. However, despite this, inhibition of platelet function is not maximal at the lower aspirin dosage. Doses of aspirin in excess of 80 mg/d resulted in substantial inhibition of endogenous prostacyclin biosynthesis. Thus, it is unlikely that any dose of aspirin can maximally inhibit thromboxane generation without also reducing endogenous prostacyclin biosynthesis. These results also indicate that recovery of endogenous prostacyclin biosynthesis is delayed following aspirin administration and that the usual effects of aspirin on platelet function ex vivo may be obscured during chronic aspirin administration in man.

Adenosine Diphosphate↗

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↗

PubMed1999

Experimental inhibition of protamine cardiotoxicity by prostacyclin.

Twelve animals (26+/-5 kg) were subjected to the study. In this experimental study, the authors used prostacyclin to inhibit the toxic metabolite release during protamine administration. Animals were divided into two equal groups. Six animals received prostacyclin (the prostacyclin group), and the other six animals did not receive any additional treatment (the control group). All cardiac output and biochemical measurements were evaluated at baseline; before cardiopulmonary bypass; and at 5, 30, and 60 minutes after protamine administration. The measured cardiac index showed that the hearts treated with prostacyclin had satisfactory preservation of left ventricular function. Metabolic and biochemical data showed that the tumor necrosis factor level was raised significantly in the control group (20.75+/-2.2 in the control group and 13.75+/-2.5 pg/mL in the prostacyclin group). Also, E and P selectin levels were elevated in the control group, but this change was less marked in the prostacyclin group. In addition, the intracellular adhesion molecule-1 (ICAM-1) level was significantly higher in the control group than in the prostacyclin group (9.26+/-2.13 in the control group and 5.13+/-1.66 ng/mL in the prostacyclin group). The authors observed that prostacyclin inhibited the toxic mediator release during heparin reversal with protamine. This inhibition is one way of protecting the myocardium reserves from protamine cardiotoxicity.

Animals↗

PubMed1987

Acute and chronic effects of ethanol and its metabolites on vascular production of prostacyclin in rats.

The cutaneous vasodilation produced by ethanol is exaggerated when acetaldehyde levels are increased after aldehyde dehydrogenase inhibition, producing a flushing reaction, the mechanism of which is unknown. The authors investigated whether ethanol and its metabolites affect the vascular release of prostacyclin, a potent vasodilator, and whether such an effect might be modified by chronic alcohol consumption. Aortic rings from rats fed Chow ad libitum or pair-fed liquid diets containing either ethanol (36% of energy) or isocaloric carbohydrate for 4 to 5 weeks were incubated in Krebs-Ringer bicarbonate supplemented with saturating amounts of arachidonate (10-20 microM) in the presence of ethanol (10-100 mM), acetaldehyde (10-100 microM) or acetate (1.25-5 mM). Prostacyclin was measured by the radioimmunoassay of 6-keto-prostaglandin F1 alpha. Acetaldehyde produced a concentration-dependent stimulation of prostacyclin production both in alcohol-fed and control rats, whereas acetate did not. This effect was associated with increased conversion of arachidonate (either exogenous or released with A23187) and of prostaglandin endoperoxide H2 to prostacyclin. Ethanol did not affect prostacyclin release in control rats, but, in aortas from alcohol-fed animals, 50 mM ethanol did stimulate prostacyclin formation. These effects may contribute to the cardiovascular responses associated with high blood acetaldehyde levels in flushers and with high ethanol levels in alcoholics. In conclusion, acetaldehyde is a potent stimulant of vascular prostacyclin production. This effect is due, at least in part, to enhanced activity of prostacyclin synthase. Ethanol acquires such a stimulatory effect on prostacyclin formation after chronic alcohol consumption.

Acetaldehyde↗

PubMed1983

Designing prostacyclin analogues.

A series of prostacyclin analogues were synthesized and investigated for influence on blood pressure in rats, in vivo inhibition of platelet aggregation in rats, and in vitro inhibition of platelet aggregation in human platelet-rich plasma. The common feature of the analogues described is a replacement of C1-C4 of prostacyclin by a carboxyphenylene residue. The following structure-activity relationships were obtained. Only the meta-carboxyphenylene derivatives yield substantial prostacyclin activity. The 2,3,4-trinor-1,5-inter-m-phenylene prostacyclin analogues in contrast to the natural prototype are reasonably stable against hydrolysis of the enolether bond. The corresponding 2,3,4-trinor-1,5-inter-m-phenylene analogues of carbaprostacyclin have a somewhat lower specific activity but are superior in stability at acid pH values. With regard to the stereoisomerism at the delta 5 double bond, the Z-isomers of the oxa-cyclic prostacyclin series and the E-isomers of the carba-cyclic prostacyclin series are substantially more active than their counterparts. As with natural prostacyclin, the OH group at C15 has to be present in S-configuration. The "wrong" isomers do not inhibit prostacyclin-dependent effects. Resistance against 15-hydroxyprostaglandin dehydrogenase is achieved by substitutions at or near C15. Optimum specific activity combined with resistance against all known prostaglandin-activating enzymes is observed in prostacyclin and carbaprostacyclin analogues, in which the terminal n-pentyl residue is replaced by cyclohexyl. Duration of action, i.e. lowering of blood pressure in anaesthesized rats and inhibition of platelet aggregation in anaesthesized rats, was investigated with selected analogues in order to check the consequences of chemical and metabolic stabilization.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗

PubMed1983

Dissociation between hemodynamic and platelet antiaggregant effects of prostacyclin in dogs determined with a rapid platelet isolation technique.

Prostacyclin, a potent vasodilator and inhibitor of platelet aggregation, is being increasingly used in disease states in which platelets may play a pathophysiologic role. A literature review revealed a variable dissociation between the in vitro platelet antiaggregant activity of prostacyclin and both the in vivo hemodynamic and platelet antiaggregant activities. Because widely variable platelet isolation techniques may have contributed to this variability, we investigated the hemodynamic and platelet antiaggregant effects of prostacyclin infusion in the dog, using in vitro techniques limiting the time from blood sampling to aggregometry to 2 1/2 and 10 1/2 min. Using the short technique, we demonstrate complete inhibition of platelet aggregation at a prostacyclin infusion rate that caused only a mild decrease in arterial pressure. In contrast, the longer technique requires an eightfold higher prostacyclin infusion rate to achieve the same degree of antiaggregant activity. The prostacyclin activity apparent half-life was 3 min. Because interspecies differences exist in both the hemodynamic and antiaggregant effects of prostacyclin and in their relationship to each other, we suggest that a closer approximation of in vivo antiaggregant effects may be obtained with in vitro methods that are rapid, thus taking into account the lability of prostacyclin. We conclude that the variable in vitro platelet antiaggregant effects of prostacyclin reported in the literature are due to the variable and longer techniques.

Animals↗

PubMed1984

Prostacyclin production by perturbed bovine aortic endothelial cells in culture.

This study reports that endotoxin (Escherichia coli serotype 026:B6) and 12-O-tetradecanoyl-phorbol-13-acetate stimulate cultured bovine aortic endothelial cells to generate prostacyclin. The prostacyclin concentration of the culture medium was measured indirectly by radioimmunoassay for 6-keto-PGF1 alpha. The amount of prostacyclin generated depended on the concentration of endotoxin or phorbol diester. Prostacyclin generation was not immediate, but occurred slowly after a six-hour lag period. The perturbed cells contracted and showed marked shape changes that correlated temporally with the start of enhanced prostacyclin production. Cytochalasins B and D, vinblastine, and colchicine inhibited prostacyclin production, indicating involvement of the cytoskeleton in the cellular response to endotoxin and phorbol diester. The increase in prostacyclin production was prevented by trifluoperazine, an inhibitor of the Ca++-calmodulin system, which is known to be involved in cytoskeletal function. Generation of prostacyclin was inhibited by cycloheximide and actinomycin D, indicating dependence on protein and ribonucleic acid synthesis. It is postulated that exposure to endotoxin or phorbol diester leads, via a series of reactions that involve RNA and protein synthesis and require intact cytoskeletal function, to the generation of toxic active intermediate(s) that stimulate the enzymes necessary for prostacyclin production.

Animals↗

PubMed1993

Effects of prostacyclin on spinal cord ischemia: an experimental study.

BACKGROUND: Paraplegia after thoracic aortic aneurysm has an incidence of 2.2% to 24%. This study was planned to show the beneficial effects of prostacyclin on spinal cord ischemia. METHODS: Twelve rabbits underwent 30 minutes of aortic occlusion. Six rabbits received prostacyclin, whereas the remaining rabbits did not. Prostacyclin administration was started with a rate of 5 ng/kg/min 5 minutes before aortic occlusion. This dosage was increased to 25 ng/kg/min during aortic occlusion. Prostacyclin administration after aortic occlusion was maintained for a period of 5 minutes. During this period, prostacyclin dosage was 5 ng/kg/min. RESULTS: One rabbit in the prostacyclin group and five rabbits in the control group were paraplegic. Arterial pressure proximal to the clamp was 65 +/- 7 mm Hg before aortic occlusion and 78 +/- 10 mm Hg during aortic occlusion in the control group and 68 +/- 12 mm Hg before aortic occlusion and 65 +/- 6 mm Hg during aortic occlusion in the prostacyclin group. Arterial pressure distal to the clamp was 11 +/- 4 mm Hg during aortic occlusion in the control group and 18 +/- 5 mm Hg during aortic occlusion in the prostacyclin group (p = 0.02). CONCLUSIONS: Intravenous prostacyclin reduced the neurologic injury caused by spinal cord ischemia and reperfusion after 30 minutes of aortic occlusion in the rabbit model.

Animals↗

PubMed1993

Impaired endothelial prostacyclin production of the canine vein graft in a poor distal runoff limb.

BACKGROUND: Because blood flow modulates endothelial prostacyclin production, the extent of this production in autologous vein grafts implanted in poor distal runoff limbs needed to be examined. METHODS: Endothelial prostacyclin production in canine autologous vein grafts was measured in poor distal runoff limbs (poor runoff group) and compared with findings in normal runoff limbs (control group). Vein grafts were perfused in a closed circuit at 3 days and 1, 2, 3, and 4 weeks after implantation; after perfusion for the first 30 minutes in a steady flow (basal prostacyclin production), the grafts were exposed to arachidonic acid (stimulated prostacyclin production) for the following 30 minutes. Prostacyclin, as the metabolite 6-keto-PGF1 alpha, was radioimmunoassayed. RESULTS: Basal and stimulated prostacyclin production increased in both groups during a period of time after implantation. At 2 weeks when endothelialization was complete, prostacyclin production in the poor runoff group was impaired, compared with the findings in the control group, and this difference increased with time. At 4 weeks the stimulated prostacyclin production was 18.91 +/- 4.03 ng/cm2 in the control group and 11.60 +/- 1.67 ng/cm2 in the poor runoff group (p < 0.05). CONCLUSIONS: We propose that the impaired capacity of the vein graft to produce prostacyclin in a poor distal runoff may lead to loss of graft patency in reconstructed arteries.

Animals↗

PubMed1989

Epidermal growth factor stimulation of prostacyclin production by cultured aortic smooth muscle cells: requirement for increased cellular calcium levels.

We have examined the ability of epidermal growth factor (EGF) to regulate prostacyclin production by cultured A10 smooth muscle cells. EGF by itself had no effect on prostacyclin production, but it augmented the response to arg8-vasopressin. An AGF stimulation of prostacyclin production was also observed in the presence of the calcium ionophore A23187; it therefore seemed likely that the key event required for EGF to stimulate prostacyclin production might be an increase in the available cellular Ca2+. Studies with 45Ca2+ showed that vasopressin both mobilised Ca2+ from intracellular stores and increased the influx of extracellular Ca2+ into A10 cells. The increase in prostacyclin production caused by vasopressin and the augmentation by EGF were both abolished by TMB-8, an antagonist of Ca2+ mobilisation, by EGTA, a chelator of Ca2+ ions, or by incubating cultures in the absence of added Ca2+. These results were consistent with a central role for Ca2+ in the responses and showed that both intracellular and extracellular sources of Ca2+ were important for the triggering of prostacyclin production. The increases in prostacyclin production were only marginally affected by nifedipine, and no responses were seen (either in the absence or presence of EGF) when KCl was used to depolarise the cell membrane. These data indicated that uptake of Ca2+ ions via voltage-dependent channels was unlikely to be a major factor in the stimulation of prostanoid production. We conclude that the ability of EGF to stimulate prostacyclin production in A10 smooth muscle cells depends upon a concurrent stimulus that will increase available intracellular Ca2+ levels.

6-Ketoprostaglandin F1 alpha↗

PubMed1997

Effects of oxygen tension and shear stress on human endothelial cell prostacyclin production.

Under in vivo conditions of ischemia and reperfusion, vascular endothelium (EC) experience concurrent changes in oxygen tension, shear stress, and the local concentration of metabolites. These studies explored the combined effects of shear stress and oxygen tension on EC prostacyclin production. EC grown on microcarrier beads were exposed to 120 min of normoxia and basal shear stress by stirring at 20 rpm. After normoxia, EC were exposed to hypoxia (2% 0(2), 20 rpm), ischemia (2%, 0(2), 5 rpm) or sham ischemia (20% 0(2), 5 rpm). Following hypoxia, EC were reoxygenated (20% 0(2), 20 rpm). After ischemia and sham ischemia, EC were reperfused (20% 0(2), 20 rpm). Minimal accumulation of metabolites occurred during normoxia, hypoxia, and reperfusion. All metabolites were allowed to accumulate in the flasks during ischemia and sham ischemia. Prostacyclin levels were measured by ELISA, and prostaglandin H2 synthase levels in cells were analyzed by immunoblotting. An acute decrease in shear stress decreased prostacyclin production. An acute decrease only in oxygen tension did not alter prostacyclin production significantly. The combined acute decrease in both shear stress and oxygen tension significantly stimulated prostacyclin production for 30 min. By 120 min of ischemia and hypoxia, prostacyclin release was significantly less than sham ischemia. Prostacyclin production after 30 min of reoxygenation was significantly less than that of cells subjected to reperfusion. By 120 min of reperfusion and reoxygenation, there was no significant difference in EC prostacyclin synthesis. These findings suggest that temporal and quantitative aspects of EC prostaglandin synthesis are dependent on both oxygen tension and shear stress.

Cell Hypoxia↗