6-ketoprostaglandin-f1-alpha and Vascular-Diseases

Replacement of antithrombin has proved to be effective for treating disseminated intravascular coagulation. The administration of antithrombin is also useful for preventing organ failure in animals challenged with endotoxin or bacteria, and it increases the survival rate of such animals. Since inhibition of coagulation abnormalities by heparin failed to prevent organ failure in animals challenged with bacteria, antithrombin might exert therapeutic effects independently of its anticoagulant effect. These therapeutic mechanisms of antithrombin have been explored by using animal models of septicemia. Antithrombin prevents pulmonary vascular injury by inhibiting leukocyte activation in rats challenged with endotoxin. A higher dose of antithrombin was required to prevent pulmonary vascular injury than was required to inhibit disseminated intravascular coagulation. This preventive effect of antithrombin is mediated by the promotion of endothelial release of prostacyclin, an inhibitor of leukocyte activation. An interaction between antithrombin and heparin-like glycosaminoglycans on the endothelial cell surface appears to be important for this effect. Heparin inhibits such therapeutic effects of antithrombin by preventing it from interacting with the cell surface heparin-like glycosaminoglycans. Since activated leukocytes are of critical importance in patients with sepsis-associated organ failure, this anti-inflammatory activity of antithrombin may explain why it can prevent organ failure as well as coagulation abnormalities in patients with sepsis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antithrombin III; Endotoxins; Epoprostenol; Heparin; Humans; Lung; Neutrophil Activation; Rats; Vascular Diseases

The body's ability to produce prostacyclin and thromboxane by blood vessels and platelets may be important in hemostatic and thrombotic disorders and in blood pressure regulation. There are limitations to the information that can be derived from measurement of the active substances or metabolites in plasma and urine. Assays for thromboxane and prostacyclin in bleeding time blood reflect production in response to a single standardized vascular injury, and show considerable promise in furthering our understanding of the production of these chemicals in vivo. These assays may improve the assessment of risk of developing thrombotic disorders and improve the ability to monitor treatment. Studies to date have focused largely on the influences of various doses of aspirin on the production of prostacyclin and thromboxane in bleeding time blood, but also suggest that smokers are high thromboxane producers. In addition, individuals who exhibit type A behavior, a behavior pattern characterized by a relatively high level of ambitiousness, hostility, and competitive drive and a chronic sense of urgency appear to be low prostacyclin producers. Diets enriched in sunflower oil were found to diminish thromboxane production, while diets high in canola oil enhanced prostacyclin formation.

Topics: 6-Ketoprostaglandin F1 alpha; Bleeding Time; Humans; Platelet Function Tests; Thromboxane B2; Vascular Diseases

The 'systemic inflammatory response syndrome' (SIRS) may represent the underlying cause of complications after bone marrow transplantation (BMT). This study was conducted to determine whether blocking the etiologic factors of SIRS could improve the complications of BMT. Sixteen consecutive patients with unrelated donors were allocated alternately to two groups. Seven patients received 1.8 g/day of eicosapentaenoic acid (EPA) orally from 3 weeks before to about 180 days after transplantation, while nine patients did not. These two groups were compared with respect to complications, survival, and various cytokines and factors causing vascular endothelial damage. All seven patients receiving EPA survived and only two had grade III graft-versus-host disease (GVHD). Among the nine patients not receiving EPA, three had grade III or IV GVHD. In addition, thrombotic microangiopathy developed in four patients and cytomegalovirus disease occurred in four. Five patients died in this group. The levels of leukotriene B(4), thromboxane A(2), and prostaglandin I(2) were significantly lower in patients receiving EPA than in those not receiving it (all P < 0.01). Cytokines such as tumor necrosis factor-alpha, interferon-gamma, and interleukin-10 were also significantly decreased by EPA (P < 0.05), as were factors causing vascular endothelial damage such as thrombomodulin and plasminogen activator inhibitor-1 (P < 0.05). The survival rate was significantly higher in the group given EPA (P < 0.01). EPA significantly reduced the complications of BMT, indicating that these complications may be manifestations of the systemic inflammatory response syndrome.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Adult; Anemia, Aplastic; Bone Marrow Transplantation; Cytokines; Cytomegalovirus Infections; Eicosapentaenoic Acid; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Interferon-gamma; Interleukins; Leukemia; Life Tables; Lung Diseases, Interstitial; Male; Survival Analysis; Systemic Inflammatory Response Syndrome; Transplantation, Homologous; Tumor Necrosis Factor-alpha; Vascular Diseases

Prostacyclin prevents pulmonary vascular injury and shock by inhibiting increases in lung tissue levels of TNF in rats administered endotoxin. We previously reported that NO derived from eNOS increases endothelial production of prostacyclin. Because neutrophil elastase has been shown to decrease endothelial production of prostacyclin by inhibiting NOS activity, we examined whether neutrophil elastase inhibitors reduce pulmonary vascular injury and hypotension by inhibiting the decrease in pulmonary endothelial production of prostacyclin in rats administered endotoxin. Animals were pretreated with sivelestat or L-658,758, neutrophil elastase inhibitors, before endotoxin administration. Lung tissue levels of 6-keto-prostaglandin F1alpha were markedly increased after endotoxin administration, followed by a rapid decrease to baseline levels. Sivelestat and L-658,758 inhibited these decreases as well as inhibiting increases in lung tissue levels of TNF and lung wet-to-dry weight ratios in animals administered endotoxin. These inhibitors also reduced hypotension and inhibited increases in lung tissue levels of mRNA of the inducible form of NOS in animals administered endotoxin. The effects of neutrophil elastase inhibitors were completely reversed by pretreatment with nitro-L-arginine methyl ester, an inhibitor of NOS, or indomethacin, a nonspecific cyclooxygenase inhibitor. These observations suggested that neutrophil elastase might decrease the pulmonary endothelial production of prostacyclin by inhibiting endothelial NO production, thereby contributing to the development of pulmonary vascular injury and shock through increases in lung tissue levels of TNF in rats administered endotoxin.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cephalosporins; Endotoxins; Enzyme Inhibitors; Leukocyte Elastase; Lung; Lung Diseases; Male; Nitric Oxide; Rats; Shock, Septic; Tumor Necrosis Factor-alpha; Vascular Diseases

Raynaud's phenomenon has been suggested as a predisposing factor for pulmonary vasospasm which may lead to pulmonary hypertension, but the occurrence of cold stimulus-induced pulmonary vasospasm has been inconsistent. Such inconsistent pulmonary vascular responses may be caused by differences in the production of endogenous vasodilators and vasoconstrictors among patients. Fourteen patients with Raynaud's phenomenon associated with mixed connective tissue disease (n=10) or systemic sclerosis (n=4) participated in the study. Right heart catheterization was performed before and after a cold pressor test, immersing a hand in cold water (15 degrees C) for 5 min. Plasma levels of 6-keto prostaglandin (PG)F1alpha, thromboxane (TX)B2 and endothelin (ET)-1 in the mixed venous blood were measured. Mean pulmonary artery pressure increased after the cold pressor test in five of 14 patients, and the patients were divided into those with pulmonary vasospasm (responders) and those without vasospasm (nonresponders). After the cold pressor test, levels of 6-keto PGF1alpha increased significantly in nonresponders (p<0.01) and decreased significantly in responders (p<0.05). The ratios of 6-keto PGF1alpha to TXB2 significantly increased in nonresponders (p<0.01) but not in responders and the difference between responders and nonresponders after the cold pressor test was also statistically significant (p<0.05). No significant change in plasma ET-1 levels occurred in either responders or nonresponders. The results suggest that an impaired production of prostaglandin I2 and an imbalance between prostaglandin I2 and thromboxane A2 are associated with the occurrence of pulmonary vasospasm induced by Raynaud's phenomenon.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Cold Temperature; Endothelin-1; Female; Hemodynamics; Humans; Male; Middle Aged; Pulmonary Artery; Pulmonary Veins; Raynaud Disease; Respiratory Function Tests; Spasm; Thromboxane B2; Vascular Diseases

Plasma levels of 6-keto-prostaglandin F1 alpha (6kPGF1 alpha) and thromboxane (Tx) B2 have been assessed in sickle cell disease (SCD) with discrepant results. Inasmuch as direct measurement of plasma prostanoids is fraught with the problem of interfering substances, we assessed plasma 6kPGF1 alpha and TxB2 levels in patients with SCD by RIA after extraction of eicosanoids and separation by HPLC. We demonstrate that the 6kPGF1 alpha and TxB2 levels in children with SCD in steady state as well as in vaso-occlusive crisis (VOC) are significantly lower when compared with those from age-matched controls. The VOC plasma 6kPGF1 alpha and TxB2 levels were, however, significantly elevated when compared with those from children in steady state. Changes similar to those noted with unpaired plasma samples were also observed when paired steady state and VOC plasmas from the same patients were assessed. The ratio of TxB2 to 6kPGF1 alpha was, however, significantly elevated in patients with SCD in crisis when compared with eicosanoid ratios obtained during steady state. In an attempt to understand whether the abnormality in 6kPGF1 alpha was due to an impairment in endothelial cell prostacyclin-regenerating ability, we compared the ability of plasma from controls and children with SCD to activate arachidonic acid (AA) release and prostacyclin production by [14C]AA-prelabeled bovine aortic endothelial cells. Our results suggest that the decreased 6kPGF1 alpha levels in plasma from children with SCD was not due to an effect on substrate AA release but rather a modulatory effect of sickle plasma components on endothelial cell cyclooxygenase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Anemia, Sickle Cell; Animals; Arachidonic Acid; Case-Control Studies; Cattle; Cells, Cultured; Child; Child, Preschool; Chromatography, High Pressure Liquid; Constriction, Pathologic; Endothelium, Vascular; Epoprostenol; Humans; Thromboxane B2; Vascular Diseases; Vasoconstrictor Agents; Vasodilator Agents

Thromboxane A2 is a potent vasoconstrictor and a stimulus of platelet aggregation, which may contribute to hypercoagulability. The prostacyclin, prostaglandin I2, has exactly the opposite effect. Measurement of the major urinary metabolites, 11-dehydro-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha (prostaglandin F1 alpha) by radioimmunoassay can accurately reflect in vivo the biosynthesis of thromboxane A2 and prostaglandin I2, respectively. Group 1 consisted of 60 patients less than 50 years old. The mean urinary 11-dehydro-thromboxane B2 level of 3 patients with arteriogenic impotence was significantly greater than that of the 57 control volunteers: 2.66 +/- 0.65 versus 1.74 +/- 0.56 (plus or minus standard deviation) ng./mg. creatinine (p = 0.008). The prostaglandin F1 alpha levels for the patients and controls were 32.74 +/- 8.45 and 37.58 +/- 16.55 ng./mg. creatinine, respectively, which was not significantly different (p greater than 0.05). Group 2 consisted of 96 patients 50 years old or older. The 11-dehydro-thromboxane B2 concentration in the urine was 1.83 +/- 0.58, 2.54 +/- 1.12 and 1.91 +/- 0.73 ng./mg. creatinine in the 47 normal control volunteers, 20 patients with arteriogenic impotence and 29 with arteriogenic impotence plus intracavernous injection of 20 micrograms prostaglandin E1, respectively. The arteriogenic impotence group showed the significantly highest level among the 3 groups (p = 0.0025). Also, the urinary prostaglandin F1 alpha levels in these patients were 45.71 +/- 36.3, 57.71 +/- 35.53 and 59.30 +/- 45.08 ng./mg. creatinine, respectively, which was not significantly different (p greater than 0.05). For the 13 patients with arteriogenic impotence (group 3) we compared the urinary 11-dehydro-thromboxane B2 and prostaglandin F1 alpha levels before and after intracavernous injection of prostaglandin E1 by using a paired t test. The results showed that the change in 11-dehydro-thromboxane B2 levels was 2.78 +/- 1.09 versus 1.99 +/- 0.75 ng./mg. creatinine, which was significantly different (p = 0.005), whereas that for prostaglandin F1 alpha was 62.30 +/- 40.41 versus 58.86 +/- 44.26 ng./mg. creatinine, with no significant difference (p greater than 0.05). Our findings suggest that urinary 11-dehydro-thromboxane B2 may have an important role in the diagnosis and treatment of arteriogenic impotence.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Blood Flow Velocity; Erectile Dysfunction; Humans; Male; Middle Aged; Penile Erection; Penis; Thromboxane B2; Vascular Diseases

Topics: 6-Ketoprostaglandin F1 alpha; Anemia, Sickle Cell; Epoprostenol; Humans; Vascular Diseases

The production of 6-keto-prostaglandin F1 alpha, a stable metabolite of the vasodilator prostacyclin (PGI2), by fragments of the thoracic aorta of rats made diabetic by streptozotocin, was evaluated by radio-immunological assay. The level of production was found to be statistically higher (p less than or equal to 0.01) in the group treated with Coenzyme A (CoA) than in the placebo group. The authors suggest that the mode of action of CoA 1000 much greater than in microcirculatory pathology could involve an increased production of vasodilator prostacyclin.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Animals; Aorta, Abdominal; Coenzyme A; Diabetes Mellitus, Experimental; Epoprostenol; Female; Humans; Male; Microcirculation; Radioimmunoassay; Rats; Rats, Inbred Strains; Vascular Diseases

The levels of 6-keto-PGF1 alpha and TXB2 were determined by the RIA method in Blackfoot disease which is an endemic disease of the peripheral vascular system found in the southwest coast of Taiwan. The level of TXB2 was normal, but that of 6-keto-PGF2 alpha concentration was 30% lower than the normal. The activity of 15-hydroxyprostaglandin dehydrogenase was higher in patients' blood plasma than in the normal. Patient's vascular endothelium was also found to have lower prostacyclin synthase activity. These results suggest that the reduced prostacyclin production in vascular endothelium contributes to the pathogenesis of Blackfoot disease.

Topics: 6-Ketoprostaglandin F1 alpha; Arteries; Cytochrome P-450 Enzyme System; Endothelium, Vascular; Epoprostenol; Humans; Hydroxyprostaglandin Dehydrogenases; Intramolecular Oxidoreductases; Isomerases; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Thromboxane B2; Vascular Diseases

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.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Cardiopulmonary Bypass; Coronary Disease; Epoprostenol; Esophageal and Gastric Varices; Humans; Hypertension, Portal; Middle Aged; Vascular Diseases

To evaluate the role of arachidonate metabolites in regulating pulmonary vascular tone, we performed multiple studies on a 17-month-old girl with idiopathic pulmonary hypertension, systemic arterial hypoxemia (due to ventilation-perfusion mismatching), and an elevated thromboxane A2 (TXA2) to prostacyclin (PGI2) ratio due to increased TXA2 (measured as their stable metabolites, TXB2 and 6-keto-PGF1 alpha, respectively). Intravenous infusions of PGI2 reduced mean pulmonary arterial pressure (from 80 to 47 mmHg), increased cardiac output (from 3.43 to 3.97 L/min), increased systemic arterial oxygen saturation (from 60 to 72 percent), and decreased the TXB2 to 6-keto-PGF1 alpha ratio (from 5.9 to 0.2); mean systemic arterial pressure was unchanged. Pharmacologically decreasing the TXB2 to 6-keto-PGF1 alpha ratio with administration of nifedipine or diltiazem also reduced pulmonary hypertension and increased systemic arterial oxygen saturation in this patient. Nifedipine and diltiazem decreased the ratio by decreasing TXB2. Prostacyclin decreased the ratio by increasing 6-keto-PGF1 alpha. These studies support the hypothesis that the balance between TXA2 and PGI2 is an important influence on pulmonary vascular tone.

Topics: 6-Ketoprostaglandin F1 alpha; Aging; Arachidonic Acid; Arachidonic Acids; Blood Pressure; Diltiazem; Epoprostenol; Female; Hemodynamics; Humans; Infant; Nifedipine; Pulmonary Artery; Pulmonary Circulation; Thromboxane B2; Vascular Diseases; Vasodilation

Pure acetylcholine esterase from Electrophorus Electricus has been covalently coupled to different prostaglandins or thromboxanes. The corresponding conjugates have been tested using microtiter plates with 96 wells coated with a second antibody. The minimal detectable concentrations were 10 pg/ml. We suggest that this procedure which has been extended to non icosanoid molecules may serve as a general technique for enzyme immunoassay.

Topics: 6-Ketoprostaglandin F1 alpha; Arachidonic Acid; Arachidonic Acids; Child, Preschool; Chromatography, Gas; Dinoprost; Dinoprostone; Humans; Hydroxyeicosatetraenoic Acids; Immunoenzyme Techniques; Infant, Newborn; Mass Spectrometry; Prostaglandins; Prostaglandins E; Prostaglandins F; Thromboxane B2; Thromboxanes; Vascular Diseases