Absence of circulating PGI2 response to bubble-provoking decompression.
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Adult↗
Biomedical subjects
J M Ritter
Publications and source records attributed to J M Ritter.
Prostacyclin synthesis by vascular tissue. Effect of extracellular Ca2+.
Prostacyclin (PGI2) synthesis in vascular tissue is stimulated by free Ca2+. Concentrations in excess of 4 mM result in a sustained release of PGI2, but not other prostanoids, from rat aorta. This effect arises by increased synthesis of PGI2 and not through the inhibition of its metabolism. Physico-chemical examination of serum and plasma extract has indicated that much of the PGI2-stimulating activity reported for human serum derives from the presence of free Ca2+.
Animals↗
Prostacyclin in the circulation of patients with vascular disorders undergoing surgery.
The object of this study was to investigate clinical conditions in which increased production of prostacyclin (PGI2) has been reported. 6-Oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha) is the stable hydrolysis product of PGI2 and was measured in plasma from patients undergoing hepatic or cardiac surgery and in unoperated patients with vascular and hepatic disease, using gas chromatography/mass spectrometry. Blood obtained simultaneously from portal and peripheral veins, during emergency surgery for bleeding oesophageal varices in six patients with cirrhosis of the liver, contained very high concentrations of 6-oxo-PGF1 alpha (range 99-11,485 pg/ml of plasma). 6-Oxo-PGF1 alpha was higher in portal than in peripheral blood in five out of six patients. Six unoperated patients with cirrhosis and oesophageal varices which were not bleeding all had normal peripheral plasma concentrations of 6-oxo-PGF1 alpha less than 2 pg/ml (normal up to 5 pg/ml). Seventeen patients with severe vascular disease had normal basal plasma 6-oxo-PGF1 alpha concentrations (less than 2 pg/ml). Eighteen subjects with atheromatous coronary artery disease underwent aorta-coronary artery grafting, and plasma concentrations of 6-oxo-PGF1 alpha were markedly elevated during surgery (range 55-1207 pg/ml). We conclude that surgery stimulates PGI2 production substantially, and argue that the function of PGI2 may be to limit intravascular extension of thrombus from sites of haemostasis. Inappropriate PGI2 synthesis may contribute to the massive haemorrhage characteristic of oesophageal variceal bleeding.
6-Ketoprostaglandin F1 alpha↗
Effect of vasoactive peptides on prostacyclin synthesis in man.
Bradykinin, angiotensin II, arginine vasopressin (AVP) or des-amino-D-arginine vasopressin (DDAVP) were administered by intravenous infusion to 10 healthy men. The concentration of 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha), the stable hydrolysis product of prostacyclin (PGI2), was measured in plasma using gas chromatography/negative ion chemical ionisation mass spectrometry. Dose-related increases in plasma concentrations of 6-oxo-PGF1 alpha occurred during administration of bradykinin (100-3200 ng kg-1 min-1). The concentrations of 6-oxo-PGF1 alpha rose from baseline values in the range less than 1.0-4.9 pg ml-1 to 24.9-47.6 pg ml-1 at maximum tolerated infusion rates. There were no changes in the concentrations of 6-oxo-PGF1 alpha during administration of angiotensin II, AVP or DDAVP at infusion rates which caused haemodynamic changes.
6-Ketoprostaglandin F1 alpha↗
Therapeutic opportunities in vasoocclusive disease.
There is evidence that aspirin is partially effective in the prophylaxis of various vasoocclusive disorders. This article reviews pharmacologic opportunities for improvement over and above the therapeutic effect of aspirin. It is concluded that several rational possibilities merit consideration, in particular, the use of combinations of drugs that affect the thrombotic process at different points. Such strategies will ultimately require validation by clinical trial.
Arterial Occlusive Diseases↗
Plasma prostacyclin levels in Behçet's disease.
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6-Ketoprostaglandin F1 alpha↗
Teratogenicity of dimethoxyethyl phthalate and its metabolites methoxyethanol and methoxyacetic acid in the rat.
It is hypothesized that the known teratogen di(2-methoxyethyl) phthalate (DMEP) acts by in vivo hydrolysis to 2-methoxyethanol (2-ME), also a known teratogen, which in turn is metabolized to methoxyacetic acid (MAA), the proximate teratogen. Teratological studies were conducted with Wistar rats, with the administration of these three agents on day 12 of gestation. On an equimolar dosage basis, DMEP, 2-ME, and MAA were equally potent, which is consistent with the hypothesis. There was a striking similarity in the defects produced by these agents, mainly hydronephrosis, heart defects, and short limbs and tails. In particular all three agents produced unusual heart defects (dilated ductus arteriosus and dilated aortic arch) not seen with other agents, as well as ventral polydactyly, a rarely seen defect, suggesting teratogenic action by a common mechanism or component; 4-methylpyrazole, an alcohol dehydrogenase inhibitor, provided significant protection against 2-ME. This combination of effects strongly suggests that following the administration of DMEP, 2-ME, or MAA, MAA is the proximate teratogen.
Abnormalities, Drug-Induced↗
Effects of a stable prostaglandin analogue, L-644,122, in healthy and hypertensive men.
L-644,122 is a chemically stable vasodilator prostaglandin analogue. It is a selective renal vasodilator in dogs. The object of the present study was to determine whether it increases effective renal plasma flow (ERPF) in man. L-644,122 was administered intravenously to 4 healthy volunteers and by mouth to 4 mild hypertensives. It did not increase ERPF. Instead it acted as a non-specific vasodilator, lowering diastolic blood pressure and increasing heart rate. An unexpected increase in glomerular filtration rate (19% greater than placebo) after low dose intravenous L-644,122 merits further study.
Administration, Oral↗
Correlation of prostacyclin synthesis by human umbilical artery with status of essential fatty acid.
Prostacyclin production by human umbilical artery rings was measured in a variety of incubation media and related to gestational age, mode of delivery, and birth weight. Prostacyclin production was directly correlated with the status of essential free fatty acid in the tissue as assessed by the ratio of tissue concentrations of arachidonic acid and Mead's acid. The results indicate a possible association of the essential fatty acid status both with intrauterine growth retardation and with fetal vascular prostacyclin production.
5,8,11,14-Eicosatetraynoic Acid↗
Prostanoid synthesis by aortic rings in human blood: selective increase of prostacyclin mediated by a serum factor.
Synthesis of vascular epoprostenol (PGI2) and platelet thromboxane (TX) A2 is influenced by the coagulation cascade in incompletely understood ways. To elucidate this, prostanoids were determined in human blood anticoagulated by different drugs and incubated with and without rat aortic rings. Control incubations were performed in Hanks balanced salt solution. PGI2 and TXA2 synthesis were assessed by radioimmunoassay of their stable hydrolysis products 6-oxo-prostaglandin (PG) F1 alpha and TXB2. Fresh aortic rings incubated in Hanks solution with a thrombin inhibitor (TCK) synthesized similar quantities of 6-oxo-PGF1 alpha in the presence or absence of sodium citrate. In contrast, the intracellular calcium antagonist TMB-8 inhibited 6-oxo-PGF1 alpha synthesis. In contrast to the finding in Hanks solution, sodium citrate inhibited 6-oxo-PGF1 alpha synthesis by fresh aortic rings incubated in blood anticoagulated with TCK. However, TXB2 synthesis was not affected by citrate. Blood incubated alone at 37 degrees C in plain glass tubes generated a small amount of immunoreactive 6-oxo-PGF1 alpha. A thromboxane synthase inhibitor, OKY1581, increased immunoreactive 6-oxo-PGF1 alpha. However, blood anticoagulated with TCK and incubated similarly, generated no detectable 6-oxo-PGF1 alpha either in the presence or absence of OKY1581, showing that 6-oxo-PGF1 alpha synthesis in the previous experiments was dependent on the vascular rings. OKY1581 had little or no effect on 6-oxo-PGF1 alpha synthesis in incubations of fresh aortic rings with blood anticoagulated with TCK, despite inhibition of TXB2 synthesis. However, OKY1581 increased 6-oxo-PGF1 alpha synthesis by rings pretreated with acetylsalicylic acid (ASA) when incubated in blood, presumably by diversion of platelet endoperoxide to vascular PGI2 synthase. Sodium citrate did not influence the increase in 6-oxo-PGF1 alpha synthesis by ASA pretreated aortic rings caused by OKY1581 in whole blood. This implies that the PGI2 stimulating activity of whole blood in the absence of citrate exerts its effect proximal to PGI2 synthase. It is concluded that a low molecular weight serum factor formed during activation of the intrinsic coagulation pathway in blood, modulates PGI2/TXA2 balance by an action on vascular cyclo-oxygenase, possibly by an effect on intracellular calcium.
6-Ketoprostaglandin F1 alpha↗
Prostacyclin synthesis is stimulated by a serum factor formed during coagulation.
Fresh aortic rings incubated in serum produce more 6-oxo-PGF1 alpha, the stable hydrolysis product of prostacyclin, than in plasma or buffer. A method is described of recovering this stimulatory activity from a dialysate of serum, showing that the activity is due to a prostacyclin stimulating factor. This factor is formed during coagulation initiated by the intrinsic pathway but not by the extrinsic pathway or by thrombin. By contrast with a previously described plasma factor, the activity of the prostacyclinstimulating factor in serum is not greater in serum from patients with renal failure than from healthy controls. The stimulating factor is antagonised by heparin, but differs in other ways from previously described platelet derived stimulating factor(s).
6-Ketoprostaglandin F1 alpha↗
Release of prostacyclin in vivo and its role in man.
Concentrations of 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha), the stable hydrolysis product of prostacyclin (PGI2) were determined in venous blood sampled from a forearm vein after dextrose (10% w/v) perfusion and after subsequent distension with physiological saline in seven healthy volunteers. 6-oxo-PGF1 alpha was measured by gas chromatography/negative ion chemical ionisation mass spectrometry. Local release of PGI2 was demonstrated in six volunteers: in three both stimuli were effective and in three only one stimulus was effective. In seven trained athletes studied before and after vigorous exercise baseline plasma concentrations of 6-oxo-PGF1 alpha were less than 1.3-3.2 pg/ml. The concentration increased after exercise in each subject (mean 10.9 pg/ml; range 5.5-18.2 pg/ml). Mild chemical and mechanical stimuli therefore can cause local production of PGI2 from human blood vessels in vivo.
6-Ketoprostaglandin F1 alpha↗
Cardiovascular and platelet effects in man of BW 245C, a stable mimic of epoprostenol (PGI2).
1 BW 245C is a stable hydantoin prostaglandin analogue with a biological action similar to epoprostenol (PGI2). 2 Intravenous BW 245C (1,2 and 4 ng kg-1 min-1) produced a progressive increase in heart rate and pulse pressure in four healthy male volunteers. 3 These changes in heart rate and pulse pressure were accompanied by reduced ex vivo platelet aggregation to submaximal concentrations of ADP. 4 In man, BW 245C has a profile of action and potency similar to PGI2. However, it has a longer duration of action than PGI2.
Adenosine Diphosphate↗
Stimulation of vascular prostacyclin (PGI2) production by human serum.
Prostacyclin (PGI2) synthesis by chopped rings of rat aorta was measured by radioimmunoassay (RIA) of its stable hydrolysis product 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha). 6-oxo-PGF1 alpha production by matched groups of aortic rings incubated at 37 degrees in human citrated plasma (PPP) or serum were compared. Serum was prepared by the addition of calcium chloride to citrated plasma and agitation for 3 hr at 37 degrees; the serum was expressed from the coagulum so formed. At the start of an incubation, immediately after the addition of the aortic rings, no 6-oxo-PGF1 alpha was detectable either in plasma or in serum. As described previously, in plasma 6-oxo-PGF1 alpha rose asymptotically toward a plateau at about 30 min. In serum the rapid initial production was prolonged and the increase in 6-oxo-PGF1 alpha concentration was almost linear for 60 min (r = 0.78, P less than 0.001). Production of 6-oxo-PGF1 alpha in serum at 4, 8, 30 and 60 min exceeded that in plasma by factors of 1.48, 1.67, 3.60 and 5.71 respectively (P less than 0.005 at each time). Similar stimulatory activity was found in serum derived from platelet-rich plasma (PRP-S) and that derived from platelet-poor plasma (PPP-S). It was heat stable (100 degrees for 5 min) but was lost following dialysis against an isotonic balanced salt solution. It was not restored by adding calcium chloride to such dialysed serum, and no stimulatory activity was generated if PPP was agitated at 37 degrees for 3 hr without the addition of calcium chloride. The stimulatory activity was not inhibited by cycloheximide. It is concluded that a small heat-stable molecule is generated during coagulation of plasma that stimulates PGI2 synthesis by rat aorta in vitro. Its mechanism of action does not depend on de novo protein synthesis.
6-Ketoprostaglandin F1 alpha↗
The time course and magnitude of prostacyclin (PGI2) production by rat aortic rings incubated in human plasma.
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Animals↗
Prostanoid synthesis by human umbilical artery.
A discrepancy between published values of PGI2 production by human umbilical artery in vitro measured by platelet bioassay, compared with values of 6-oxo-PGF1 alpha by radioimmunoassay, raised the possibility that another anti-aggregatory prostanoid was produced by this tissue. To test this hypothesis, umbilical artery rings were incubated in buffer and PGI2 determined by platelet bioassay and by a more specific radioimmunoassay based on comparison of 6-oxo-PGF1 alpha in hydrolysed and non-hydrolysed samples. 6-oxo-PGF1 alpha, PGF2 alpha and TXB2 were also measured by gas chromatography negative ion chemical ionisation mass spectrometry. PGI2 concentrations by radioimmunoassay and bioassay were significantly correlated (r = 0.92, p less than 0.01). There was no difference between them, disproving the presence of an additional antiaggregatory substance. PGI2 production determined by bioassay (mean 1.21 ng/mg wet weight/h, range 0.59-1.53 ng/mg/h) differed from previously reported values (range 70-325 ng/mg/h). 6-oxo-PGF1 alpha concentrations were confirmed by gas chromatography negative ion chemical ionisation mass spectrometry. Previous determinations of PGI2 production by this tissue overestimated it by approximately 100 times.
6-Ketoprostaglandin F1 alpha↗
Inhibition of vascular epoprostenol (prostacyclin, PGI2) production in vitro by plasma from healthy subjects and patients with severe renal impairment.
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Adult↗
A documented episode of pulmonary vasoconstriction in systemic sclerosis.
Severe paroxysmal pulmonary hypertension with increased pulmonary vascular resistance precipitated by exposure to cold is postulated as the mechanism causing dyspnea and cardiopulmonary arrest in a patient with systemic sclerosis. Multiple exposures to cold air and a 0 degree C saline infusion resulted in the acute onset of dyspnea and peripheral vasoconstriction. Pressure readings from a Swann-Ganz catheter in place during the saline-induced dyspneic attack showed significant elevation of pulmonary arterial pressure and vascular resistance, suggesting that pulmonary vasospasm caused the attack.
Blood Pressure↗