Prostaglandin F2 Alpha Levels Research Articles

Serum prostaglandin F2 alpha (PGFM) and oxytocin levels correlate with sonographic changes in the cervix in patients with preterm labor.

This is a study on the correlation of maternal serum oxytocin and prostaglandin F2 alpha (PGFM) levels with sonographically measurable changes in the cervix and the internal cervical os in patients with preterm labor. Oxytocin levels significantly correlate (P = 0.03) with the width of the internal os and the PGFM values significantly correlate with the length of the cervix (P = 0.008). An increase in the oxytocin level resulted in a measurable widening of the internal os and an increase in the prostaglandin level resulted in a measurable shortening of the cervix.

Depression of stimulated arachidonate metabolism and superoxide production in rat alveolar macrophages following in vivo exposure to 0.5 PPM NO2

Alveolar macrophages (AM) have been found to suffer significant functional deficits in response to nitrogen dioxide (NO2) exposure. The present investigation examined changes in the activation of AM arachidonate metabolism and superoxide production in response to an environmentally relevant level of NO2. Rats were exposed to 0.5 ppm NO2 for periods of 0.5-10 d and AM were obtained by bronchoalveolar lavage (BAL). NO2 exposure produced complex effects upon both unstimulated and stimulated AM arachidonate metabolism. Unstimulated AM synthesis of leukotriene B4 (LTB4) was depressed rapidly within 1 d of exposure, and depressed again at 5 d. Alveolar macrophage production of thromboxane B2 (TxB2), LTB4, and 5-hydroxyeicosatetraenoate (5-HETE) in response to stimulation with the calcium ionophore, A23187, were acutely depressed within 1 d of exposure; however, generation of these compounds recovered to air-control levels with longer exposure, while 5-HETE was increased at 10 d. In contrast, AM production of LTB4 in response to another stimulus, zymosan-activated rat serum (ZAS), was not depressed until following 5 d of exposure and remained slightly lower than air-control levels at 10 d. Levels of TxB2, LTB4, prostaglandin E2 (PGE2), and prostaglandin F2 alpha (PGF2 alpha) measured in BAL fluid (BALF) were found to be depressed within 4 h of exposure, suggesting an acute decrease in the in vivo pulmonary arachidonate metabolism; however, production of these compounds generally recovered to air-control levels with longer exposure. The AM superoxide production stimulated by phorbol myristate acetate (PMA) was decreased rapidly and continuously throughout the study. Thus, exposure to a low concentration of NO2 acutely depresses activation of AM arachidonate metabolism and superoxide production in response to external stimuli, and may impede defense against pulmonary infection.

Modulating effect of amount and types of dietary fat on ornithine decarboxylase, tyrosine protein kinase and prostaglandins production during colon carcinogenesis in male F344 rats.

Epidemiological and laboratory animal model studies suggest that the effect of dietary fat on colon carcinogenesis depends on the amount and its type. In the present study, we investigated the modulating effect of high-fat diets rich in omega-3, omega-6 and omega-9 fatty acids on liver, colon and small intestine mucosal ornithine decarboxylase (ODC) and tyrosine-specific protein kinase (TPK) activities and plasma, liver and colon mucosal prostaglandin E2 (PGE2) and 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) levels in male F344 rats. At 6 weeks of age, groups of animals were fed the low-fat diet containing 5% corn oil (LFCO), or high-fat diets containing 23.5% corn oil (HFCO), 23.5% olive oil (HFOO) and 20.5% fish oil + 3% corn oil (HFFO). Two weeks later, all animals except the vehicle-treated groups received azoxymethane (AOM) s.c. once weekly for 2 weeks at a dose rate of 15 mg/kg body wt. All animals were killed 5 days later and liver, colon and small intestine mucosa were analyzed for ODC, TPK and PGs and plasma for PGs. Carcinogen treatment enhanced the ODC and TPK activities (P < 0.0001) in the liver and colon of animals, irrespective of dietary treatment. Dietary HFCO compared with LFCO significantly increased the ODC (P < 0.01) and membrane TPK (P < 0.05) activities in the liver and colon of carcinogen-treated animals, whereas the HFOO and HFFO diets significantly (P < 0.002) suppressed the ODC and membrane TPK (P < 0.05) activities in the liver and colon mucosa compared with the HFCO diet. Carcinogen treatment also significantly (P < 0.01) increased the PG levels in plasma, liver and colon. Feeding of the HFFO diet significantly suppressed both the basal levels and ex vivo production of PGE2 and 6-keto PGF1 alpha levels compared with the HFCO diet, whereas the HFOO diet only decreased PGE2 in liver and colon. These results thus demonstrate that high levels of corn oil in the diet increase colon and liver ODC, TPK and PGs whereas high dietary levels of fish oil and olive oil suppress these activities.

Nimesulide in dysmenorrhoea.

Nimesulide does not affect active intrauterine pressure, as measured using microsensors, or the direction and velocity of the propagation of uterine activity, but nevertheless alleviates pain significantly by 30 minutes after oral administration. In dysmenorrhoeic patients, resting pressure is high only in the fundus. Nimesulide reduces the pressure during the maximal but not during the submaximal pain period, with concomitant alleviation of pain. The drug changes the painful state of uterine contracture to painless cyclic contractions. With a single oral dose of 100mg, nimesulide is evenly distributed in female genital tissues (uterine fundus and cervix, oviduct and ovaries), reaching peak concentrations and peak plasma: tissue ratio (0.5) 3 hours after administration. Tissue concentrations range from 0.3 to 1.8 micrograms/g. Two 100mg oral doses of nimesulide administered to dysmenorrhoeic women in a double-blind placebo-controlled cross-over study reduced prostaglandin F2 alpha levels in menstrual blood from 382 to 94 micrograms/L. Double-blind placebo-controlled studies also confirmed that nimesulide relieves pain in dysmenorrhoeic patients.

Lipopolysaccharide priming of alveolar macrophages for enhanced synthesis of prostanoids involves induction of a novel prostaglandin H synthase.

We report here that lipopolysaccharide (LPS) priming of rabbit alveolar macrophages leads to amplified synthesis of prostanoids, at least in part, by induction of a novel prostaglandin H synthase (PGH synthase). Rabbit alveolar macrophages were cultured with or without added LPS derived from Escherichia coli 0111:B4 for 4 h and then stimulated with opsonized zymosan (OPZ). LPS priming of alveolar macrophages resulted in enhanced release of thromboxane (TX) upon stimulation with OPZ, when compared to stimulated non-LPS controls. Addition of exogenous arachidonic acid to LPS-primed alveolar macrophages also resulted in increased production of TX. The LPS-induced increase in TX formation, in response to OPZ or arachidonic acid, was abolished by the addition of actinomycin D or cycloheximide during the priming period. Gas chromatography/mass spectrometry analysis indicated that levels of prostaglandins D2, E2, and F2 alpha, along with TX, were augmented in stimulated LPS-primed alveolar macrophages, implicating PGH synthase in the priming process. PGH synthase enzymatic activity, as determined by addition of arachidonic acid to macrophage sonicates, was markedly enhanced in LPS-primed alveolar macrophages. This correlated with increased PGH synthase levels detected by immunoprecipitation of 35S-labeled proteins and by Western blot analysis. Finally, Northern blot analysis using a cDNA probe to the recently described mitogen-inducible mouse PGH synthase revealed strong induction of approximately 4.3-kilobase mRNA in LPS-primed alveolar macrophages. Taken together, these results reveal that induction of a novel PGH synthase, probably the rabbit homologue of PGH synthase-2, plays a role in the enhanced synthesis of prostanoids by LPS-primed alveolar macrophages.

Changes in decidual stromal cell function associated with labour.

To determine whether decidual cells produce altered levels of prostaglandins after labour. Decidual stromal cells and macrophages were isolated before and after labour, and the production of prostaglandins E2 and F2 alpha measured. Changes in the numbers of cyclooxygenase enzyme positive cells were assessed by immunocytochemistry. Decidual stromal cells obtained after labour produced 30 times more prostaglandins E2 and F2 alpha in culture than cells obtained before labour. The increased production persisted for up to 72 h of culture, and was associated with an increase in the numbers of cyclooxygenase-positive cells from less than 5% to greater than 95%. No changes in macrophage function were observed. Increased levels of prostaglandins E2 and F2 alpha were released from decidual stromal cells after labour, suggesting that these cells may be an important source of prostaglandins in labour.

Eicosanoid production by brain tumours in vivo ? evidence for intracranial compartmentation

Brain tumours produce prostaglandins in vitro; their in vivo production has been studied by determining the levels of prostaglandin F2 alpha, prostaglandin E2, 6-ketoprostaglandin F1 alpha and thromboxane B2 in tumour cyst fluid and ventricular CSF taken from 21 patients with a variety of intracranial tumours. The levels were high in tumour cyst fluid but there was no overall increase in ventricular CSF. Hence, brain tumours do not produce a consistent pattern of abnormality of eicosanoid concentrations in the ventricular CSF that would be useful for diagnosis. If brain tumours produce excess quantities of these prostaglandins in vivo as they do in vitro, these prostaglandins may be rapidly cleared by the cerebral microvasculature unless compartmentalized within a tumour cyst.

Plasma prostanoids in neonates with pulmonary hypertension treated with conventional therapy and with extracorporeal membrane oxygenation

Thromboxane may be a mediator of pulmonary hypertension in the neonate. Acute thromboxane-mediated pulmonary hypertension has been described in sheep receiving extracorporeal membrane oxygenation, which raises concerns about a potential thromboxane-mediated exacerbation of pulmonary hypertension in human neonates with severe pulmonary hypertension who are treated with extracorporeal membrane oxygenation. We measured plasma levels of thromboxane, prostaglandin F2 alpha, and 6-keto-prostaglandin F1 alpha in infants with pulmonary hypertension, some of whom were treated medically and some of whom were treated with extracorporeal membrane oxygenation. Plasma levels of all three prostanoids were elevated in infants with pulmonary hypertension and decreased with time, whether the neonates were treated with extracorporeal membrane oxygenation or with medical management alone. In infants treated with extracorporeal membrane oxygenation, we collected samples simultaneously from preoxygenator sites, postoxygenator sites, and umbilical artery catheter. We could demonstrate no significant difference in plasma prostanoid levels across the oxygenator. In two patients, plasma thromboxane and prostaglandin F2 alpha levels measured shortly after a platelet transfusion were distinctly higher in the umbilical artery catheter than in venous samples.

The Role of Prostanoids in the Production of Acute Acalculous Cholecystitis by Platelet-activating Factor

Gallbladder tissue from patients with acute acalculous cholecystitis contains increased amounts of prostanoids when compared to normal gallbladder tissue. Platelet-activating factor (PAF) is a potent stimulus of eicosanoid formation. It has been implicated as a mediator of acute inflammatory processes and systemic responses to shock. In this study the role of PAF in acute acalculous cholecystitis was evaluated. Anesthetized cats underwent gallbladder perfusion with a physiologic buffer solution containing [14C]polyethylene glycol as a nonabsorbable tracer to quantitate mucosal water absorption. Platelet-activating factor was infused into the hepatic artery for 2 hours. Control experiments were performed when vehicle alone was infused. Experiments also were performed when indomethacin was administered intravenously and when indomethacin and PAF were administered. Gallbladder mucosal absorption/secretion and perfusate and tissue prostaglandin E (PGE) and 6 keto prostaglandin F1 alpha (6-keto PGF1 alpha) levels were evaluated. Gallbladder inflammation was evaluated by beta-glucuronidase and myeloperoxidase tissue concentrations and by a histologic scoring system. Platelet-activating factor eliminated gallbladder absorption and produced net fluid secretion associated with dose-related increases in perfusate PGE concentrations and gallbladder tissue PGE and 6 keto PGF1 alpha levels when compared to control values. Platelet-activating factor produced significant inflammation in the gallbladder with increases in the histologic score of inflammation and tissue lysosomal enzyme activities. Indomethacin significantly decreased the fluid secretion, prostanoid levels, and inflammation produced by PAF. The results suggest that PAF may induce acute gallbladder inflammation associated with systemic stress through a prostanoid-mediated mechanism.

Prostacyclin and prostaglandin E2 mediate reduction of increased mean arterial pressure during cardiopulmonary bypass by aspiration of shed pulmonary venous blood

Increased mean arterial pressure during the aortic crossclamp period while on cardiopulmonary bypass was usually treated by us with hypotensive drugs. We noticed, however, that aspirating shed excess pulmonary venous blood from the open pleural cavities causes an immediate reduction in mean arterial pressure, obviating the need for any further pharmaceutical intervention. In this study we investigated the relationship between the reduction in mean arterial pressure and the levels of prostacyclin and prostaglandin E2 in the peripheral and pulmonary venous blood. Ten men undergoing coronary bypass operations had 21 episodes of increased mean arterial pressure (106.9 +/- 11.4 mm Hg) during aortic crossclamping, which was reduced to 67.4 +/- 11.4 mm Hg (p less than 0.001) only by aspirating a mean of 490 ml (range 150 to 1100 ml) of pulmonary venous blood from the pleurae back into the circulation. Mean peripheral prostacyclin level, measured as 6-keto-prostaglandin F1 alpha, and prostaglandin E2 level, both measured by radioimmunoassay technique, were significantly lower at peak mean arterial pressure (419 +/- 180 and 59.5 +/- 21.2 pg/ml) than at lowest mean arterial pressure (632 +/- 271 and 96.7 +/- 52.4 pg/ml for 6-keto-prostaglandin F1 alpha and prostaglandin E2, respectively; p less than 0.001). Prostaglandin F1 alpha and prostaglandin E2 levels in the aspirated pulmonary venous blood were 2309 +/- 3098 pg/ml and 749 +/- 909 pg/ml, respectively. The hypotensive effect of shed pulmonary venous blood that is aspirated back from the pleurae into the circulation seems to be mediated by the high levels of prostacyclin and prostaglandin E2, both powerful vasodilators.

Effects of Epostane on Ovarian Levels of Progesterone, 17β-Estradiol, Prostaglandin E2, and Prostaglandin F2α during Ovulation in the Gonadotropin-Primed Immature Rat*

The antiovulatory action of epostane, an inhibitor of 3 beta-hydroxysteroid dehydrogenase activity and progesterone synthesis, was studied in the immature rat. The ovulatory process was induced in 25-day-old rats by injecting them with hCG (10 IU, sc) 2 days after the animals had been primed with PMSG (10 IU). Epostane was administered at different times between 20 h before and 11 h after hCG. Maximum inhibition of ovulation occurred when the drug was given at 3 h after hCG. Epostane inhibited ovulation in a dose-dependent manner when administered in doses ranging from 1.0-50 mg/rat, while exogenous doses of progesterone restored the ovulation rate. A dose of 3.1 mg epostane/rat 3 h after hCG reduced ovarian progesterone levels within 15 min, but the production of this steroid rebounded within 2 h and approached normal levels by 12 h after hCG, i.e. when the follicles began to rupture in control animals. 17 beta-Estradiol synthesis was inhibited just as rapidly, but it remained suppressed for up to 12 h after hCG administration. The ovarian levels of prostaglandins E2 and F2 alpha decreased approximately 30% within 2 h after the administration of epostane, but such a moderate reduction in the synthesis of ovarian prostanoids is usually not sufficient to block ovulation. The results show that epostane has a rapid, but transient, effect on ovarian progesterone synthesis. The temporary decline in the local progesterone level is apparently sufficient to interfere with the normal sequence of metabolic events that lead to the rupture of follicles.

Levels of 15‐Ketodihydroprostaglandin F2α During Experimental Toxoplasma gondii Infection in Non‐Pregnant Ewe Lambs

In order to study the relation between prostaglandin F2 alpha levels and fever during Toxoplasma gondii infection, six non-pregnant ewe lambs were exposed orally to T. gondii oocysts and an additional four animals were used as non-inoculated controls. Rectal temperature was measured daily during four weeks and plasma samples were analysed for the content of 15-ketodihydroprostaglandin F2 alpha. As compared to controls, the inoculated animals had significantly elevated rectal temperatures on days 4-16 after infection, but no concomitant changes in prostaglandin F2 alpha metabolite levels were recorded.

Effect of Experimental Subarachnoid Hemorrhage on CSF Eicosanoids in the Rat

A simple and inexpensive experimental model of subarachnoid hemorrhage (SAH) was developed in the rat. Based on accumulating data indicating the important role of arachidonic acid metabolites in the etiology of delayed cerebral vasospasm, we investigated changes induced by SAH on cerebrospinal fluid (CSF) levels of prostaglandin E2 (PGE2), F2 alpha (PGF2 alpha), and thromboxane B2 (TXB2). SAH was produced by the cisternal injection of blood via percutaneous suboccipital puncture. SAH rats (n = 200) were injected with 300 microliters of fresh autologous arterial blood; Control rats (n = 100) received the same volume of mock CSF. In 60 additional animals, no injections were made. To follow the changes induced by SAH on both the spectrum and time course of CSF eicosanoids, cisternal CSF samples were collected under basal conditions, 6, 12, and 36 after cisternal injection. PGE2, PGF2 alpha, and TXB2 were assayed in aliquots of CSF obtained by pooling samples from each experimental group. Eicosanoids were assayed using radioimmunoassay techniques. Arterial spasm was verified in parallel groups of SAH and control rats by comparison of the angiographic diameters of the basilar arteries (BA) and middle cerebral arteries (MCA) to that of the stapedial artery. CSF levels of all three eicosanoids were significantly higher in the SAH groups compared to both noninjected and mock-CSF injected control rats. These increases in concentrations of eicosanoids were accompanied by a decrease in the mean vascular diameter (77.5-82.0% of control) on day 2 following cisternal injection. We conclude that marked elevations of spasmogenic eicosanoids in the CSF are associated with experimental SAH.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of low-dose marine oils on intimal hyperplasia in autologous vein grafts

The effects of low-dose cod-liver oil on intimal hyperplasia of vein grafts were examined in 45 adult mongrel dogs undergoing peripheral arterial reconstruction. Fifteen animals served as the control group, 15 animals were fed a fish-oil supplement containing 240 mg of eicosapentaenoic acid daily, and a further 15 animals received 480 mg of eicosapentaenoic acid daily. Segments of undistended external jugular vein were anastomosed to bilaterally divided femoral arteries. The grafts were harvested at 6 weeks and intimal thickness was measured with a computerized interactive image analyzing system. Serum cholesterol level, prothrombin time, partial thromboplastin time, bleeding time, and platelet counts were measured before the operation and at 2, 4, and 6 weeks after the operation. Plasma levels of thromboxane B2 and prostaglandin F1 alpha and serum levels of eicosapentaenoic acid were measured before and 4 weeks after the operation. Serum cholesterol level increased similarly and significantly in all animals. Serum levels of eicosapentaenoic acid rose proportionately with the oral ingestion of fish oil but did not affect coagulation parameters. Plasma thromboxane B2 and prostaglandin F1 alpha were not significantly affected by the ingestion of marine oils. Intimal thickness was 39 +/- 5 microns in the control dogs. Ingestion of 240 mg of eicosapentaenoic acid reduced intimal thickness to 24 +/- 3 microns at 6 weeks (p less than 0.01). Increasing the dose by a factor of 2 did not decrease intimal thickness further, the intima being 23 +/- 2 microns (p less than 0.005). Our data indicate that small doses of fish oil will reduce intimal proliferation in autologous vein grafts and that marine oils may exert their beneficial effects on intimal hyperplasia by a mechanism other than their known effects on prostanoid metabolism.

Possible role of prostaglandins in the regulation of mouse myoblasts

A differentiation-defective mouse myoblast subclone (DD-1), cells of which do not fuse into myotubes nor synthesize muscle-specific proteins, was employed to help define the role of eicosanoids in mouse myoblast differentiation. We observed by hplc, tlc, and radioimmunoassay that the DD-1 cells release strikingly higher levels of cyclooxygenase pathway products prostaglandin E2 and F2 alpha into the culture medium than the parental non-differentiation-defective cells (DZ). In contrast, the levels of 15-hydroxyeicosatetraenoic acid (15-HETE), a lipoxygenase product, and a putatively identified second lipoxygenase product (LLP) did not differ greatly in the two cell types. The DD-1 cells also have strikingly higher levels of cyclooxygenase activity than the parental cells as determined by intact and broken cell assays. Additional fusion-defective clones were isolated on the basis of their flattened appearance and ability to grow in "mitogen-poor" medium and these cells also released strikingly higher levels of prostaglandins E2 and F2 alpha into the growth medium. The "turn on" of the cyclooxygenase pathway in the DD-1 cells and other fusion-defective cells is consistent with the hypothesis that the products of this pathway contribute to the inability of myoblasts to fuse with one another. This hypothesis is supported by the observation that there is a dose-dependent decrease in fusion of DZ cells when PGE2 is added to commitment medium.

Evidence for prostanoid biosynthesis as a biochemical feature of certain subclasses of non-small cell carcinomas of the lung as determined in established cell lines derived from human lung tumors : Hubbard WC, Alley MC, Gray GN, Green KC, McLemore TL, Boyd MR. Program Development Research Group, Division of Cancer Treatment, National Cancer Institute, Frederick Cancer Research Facility, Frederick, MD 21701-1013.

Detectable levels (greater than or equal to 0.2 pmol/10(6) cells) of one or more prostanoid species resultant to calcium ionophore A23187-induced biosynthesis from endogenous arachidonic acid were distributed in 28 cell lines derived from different histological classes of lung tumors as follows: large cell undifferentiated carcinoma (3 of 3 cell lines); adenosquamous carcinoma (1 of 2 cell lines); squamous cell carcinoma (0 of 2 cell lines); adenocarcinoma (9 of 10 cell lines); bronchioloalveolar cell carcinoma (2 of 2 cell lines); and small cell carcinoma (1 of 9 cell lines). Using the mean levels of 9 alpha,11 beta-prostaglandin F2, prostaglandin F2 alpha, prostaglandin D2, prostaglandin E2, thromboxane B2 and 6-keto-prostaglandin F1 alpha as an index of prostaglandin H (PGH) synthase activity, the distribution in cell lines representative of the different histological classes of human lung tumors exhibiting PGH synthase activity exceeding mean values greater than or equal to 2 pmol/10(6) cells was as follows: large cell undifferentiated carcinoma (3 of 3 cell lines), adenosquamous carcinoma (1 of 2 cell lines), adenocarcinoma (8 of 10) cell lines), bronchioloalveolar cell carcinoma (2 of 2 cell lines) and small cell carcinoma (0 of 9 cell lines). Three different prostanoid species accumulated to mean levels greater than or equal to 2 pmol/10(6) cells. Prostaglandin E2 levels exceeded 2 pmol/10(6) cells in 14 of the 16 cell lines in which this prostanoid accumulated to detectable levels. Cumulative levels of prostaglandin F2 alpha exceeded 2 pmol/10(6) cells in 9 of the 15 cell lines in which prostaglandin F2 alpha reached detectable levels. Detectable levels of thromboxane B2 were observed in five cell lines with thromboxane B2 accumulation exceeding 2 pmol/10(6) cells in two of the five cell lines. 9 alpha,11 beta-prostaglandin F2 and 6-keto-prostaglandin F1 alpha accumulated to detectable levels in the culture medium of one cell line, while prostaglandin D2 accumulation to detectable levels was observed in two cell lines. Stimulation of cultured human lung tumor cells exhibiting PGH synthase activity greater than or equal to 2 pmol/10(6) cells in the presence of 10(-5) M exogenous arachidonic acid resulted in a 2- to 4-fold increase in the accumulation of individual prostanoids, while the inclusion of a 10(-5) M exogenous concentration of arachidonic acid failed to stimulate detectable prostanoid production in human lung tumor cells in which PGH synthase activity was not previously expressed.(ABSTRACT TRUNCATED AT 400 WORDS)

Accumulation of Arachidonic Acid Cyclo‐ and Lipoxygenase Products in Rat Brain During Ischemia and Reperfusion: Effects of Treatment with GM1‐Lactone

The aim of our study was to investigate the changes of various biochemical parameters (concentrations of lactate, free arachidonate, cyclo- and lipoxygenase products) in rat brain after ischemia and reperfusion and the effects of pretreatment with the ganglioside derivative GM1-lactone on the same parameters. Ischemia was induced by reversible occlusion of common carotid arteries for 20 min, which included a final 5 min of respiration of 5% oxygen in nitrogen. Reperfusion was obtained by removing the occlusion. Pre-ischemic conditions were obtained on sham-operated animals. Animals were killed by microwave irradiation of their heads. Brain levels of lactate and of free arachidonate were markedly increased after ischemia and returned to normal values at 5 min of reperfusion. Levels of the cyclooxygenase metabolites prostaglandin F2 alpha, 6-keto-prostaglandin F1 alpha, and thromboxane B2 were increased after ischemia, whereas levels of the lipoxygenase metabolite leukotriene C4 (LTC4) did not change. After reperfusion, a very marked increase of the cyclooxygenase products occurred but not of LTC4. Treatment with GM1-lactone prevented the elevation of cyclo- and lipoxygenase metabolites especially during reperfusion, with limited effects on lactate and free arachidonate levels.

Prostacyclin mediates antiaggregatory and hypotensive actions of endothelin in anaesthetized beagle dogs

The effects of endothelin on blood pressure and in vivo aggregation of platelets were studied in anaesthetized beagle dogs. Intravenous administration of endothelin (0.03-0.3 nmol kg-1) resulted in a dose-dependent transient hypotension followed by a long-lasting hypertension and inhibition of platelet aggregation. These changes were accompanied by dose-dependent elevation of plasma 6-keto prostaglandin F1 alpha levels. Pretreatment of the animals with acetylsalicylic acid significantly attenuated both the vascular and antiaggregatory responses to endothelin. These data provide evidence for in vivo release of prostacyclin by endothelin in anaesthetized dogs.

Prevention of chronic cerebral vasospasm in dogs with ibuprofen and high-dose methylprednisolone.

Severe chronic cerebral vasospasm was produced in dog basilar arteries by two injections, 2 days apart, of autologous blood into the cisterna magna of 25 dogs. Treatment with ibuprofen (n = 8) or high-dose methylprednisolone (n = 8) after the first injection of blood prevented or reduced angiographic vasospasm. Cerebrospinal fluid concentrations of prostaglandin E2, prostaglandin F2 alpha, 6-ketoprostaglandin F1 alpha (a metabolite of prostacyclin), and thromboxane B2 (a metabolite of thromboxane A2) were measured in both treated and untreated (n = 7) dogs. In untreated dogs, the level of prostaglandin E2 increased 94-fold by Day 8 after the first injection of blood and was strongly and positively correlated with the degree of angiographic vasospasm. Treatment with ibuprofen and high-dose methylprednisolone prevented or significantly reduced this increase in prostaglandin E2 concentration. Smaller increases in cerebrospinal fluid concentrations of thromboxane B2 and 6-ketoprostaglandin F1 alpha occurred after experimental subarachnoid hemorrhage; the magnitude of these increases was also reduced by ibuprofen or high-dose methylprednisolone treatment. In contrast, prostaglandin F2 alpha levels were not significantly altered during the study. These data show that enhanced prostaglandin E2 synthesis occurs during experimental subarachnoid hemorrhage, and the by-products generated in its synthesis may play a role in the pathogenesis of cerebral vasospasm.

Arachidonic acid metabolites produced by platelet-depleted human blood monocytes: a possible role in thrombogenesis.

The arachidonic acid metabolites produced by human peripheral blood monocytes were studied to determine which metabolites could have a role in thrombogenesis. Monocytes were found to be free of platelets by scanning electron microscopy and by measurement of 12-HETE. Human peripheral blood monocytes produce thromboxane as their major metabolite. Thromboxane levels reached a plateau at 12-16 hours of culture. Monocytes produced relatively little prostaglandin E2 or F2. In contrast to our control platelet preparation, neither A23187 (1-10 microM) nor exogenous arachidonic acid (0-40 microM) caused an increase in monocyte thromboxane B2. On the other hand, lipopolysaccharide (20 micrograms per ml), collagen (2.5 mg per 10(7) cells), and thrombin (5-10 units per ml) caused a two- to fivefold increase in monocyte thromboxane B2 in most donors but had no effect on prostaglandin F1 alpha levels. Blockage of thromboxane synthase by 1-benzylimidazole abolished thromboxane B2 production but did not increase prostaglandin F1 alpha. Finally, aspirin-treated platelets from a volunteer donor, which were refractory to 30 microM arachidonate, could be aggregated by isolated blood monocytes. Our data indicate that monocytes are capable of producing thromboxane in large amounts. The regulation of this increase, however, appears to be quite different from platelets. We postulate that monocytes may have a role in hemostasis by virtue of their ability to adhere at sites of vascular injury and release thromboxane, which may enhance platelet aggregation and thrombus formation.