dinoprost and Shock--Septic

Prostaglandin F2alpha (PGF2alpha), a foremost stable vasoactive cyclooxygenase (COX)-catalyzed prostaglandin, regulates a number of key physiological functions such as luteolysis, ovarian function, luteal maintenance of pregnancy, and parturition as a constitutive part of ongoing reproductive processes of the body. It has recently been implicated in the regulation of intricate pathophysiological processes, such as acute and chronic inflammation, cardiovascular and rheumatic diseases. Since the discovery of a second isoform of COXs, it has been shown that PGF2alpha can be formed in vivo from arachidonic acid through both isoforms of COXs, namely cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Being synthesized in various parts of the body, it metabolizes instantly to a number of rather inactive metabolites mainly in the lungs, liver, kidney, and efficiently excretes into the urine. 15-Keto-dihydro-PGF2alpha, a major stable metabolite of PGF2alpha that reflects in vivo PGF2alpha biosynthesis, is found in larger quantities than its parent compound in the circulation and urine in basal physiological conditions, with short-lived pulses during luteolysis, induced termination of pregnancy and parturition, and is increased in tissues and various body fluids during acute, sub-chronic, and severe chronic inflammation. Further, the close relationship of PGF2alpha with a number of risk factors for atherosclerosis indicates its major role in inflammation pathology. This review addresses multiple aspects of PGF2alpha in addition to its emerging role in physiology to inflammation.

Topics: Animals; Atherosclerosis; Body Fluids; Carbon Tetrachloride Poisoning; Carotid Arteries; Cyclooxygenase 1; Cyclooxygenase 2; Diabetes Complications; Dinoprost; Female; Humans; Inflammation; Linoleic Acids, Conjugated; Luteolysis; Myocardial Reperfusion Injury; Obesity; Pregnancy; Risk Factors; Shock, Septic; Smoking

The aim of this study was to determine the effects of enrofloxacin (ENR), flunixin meglumine (FM) and dexamethasone (DEX) on antioxidant status and organ damage markers in experimentally-induced endotoxemia. Rats were divided into three groups. To induce endotoxemia, lipopolysaccharide (LPS) was injected into all groups, including the positive control. The two other groups received the following drugs (simultaneously with LPS): ENR + FM + low-dose DEX and ENR + FM + high-dose DEX. After the treatments, blood samples were collected at 0, 1, 2, 4, 6, 8, 12, 24 and 48 h. Oxidative stress parameters were determined by ELISA, while serum organ damage markers were measured by autoanalyser. LSP increased (p < 0.05) malondialdehyde, 13,14-dihydro-15-keto-prostaglandin F(2 alpha) and nitric oxide, while LPS reduced vitamin C. These changes were especially inhibited (p < 0.05) by ENR + FM + high-dose DEX. LPS increased organ damages markers. Cardiac and hepatic damage was not completely inhibited by any treatment, whereas renal damage was inhibited by two treatments. This study suggested that ENR + FM + high-dose DEX is most effective in the LPS-caused oxidative stress and organ damages.

Topics: Animals; Ascorbic Acid; Autoanalysis; Biomarkers; Clonixin; Dexamethasone; Dinoprost; Disease Models, Animal; Drug Therapy, Combination; Enrofloxacin; Enzyme-Linked Immunosorbent Assay; Female; Fluoroquinolones; Heart Diseases; Kidney Diseases; Lipopolysaccharides; Liver Diseases; Male; Malondialdehyde; Multiple Organ Failure; Nitric Oxide; Oxidative Stress; Rats; Rats, Sprague-Dawley; Shock, Septic; Superoxide Dismutase; Time Factors

To test the hypothesis whether pure oxygen ventilation is equally safe and beneficial in fully developed fecal peritonitis-induced septic shock as hyperoxia initiated at the induction of sepsis.. Prospective, randomized, controlled, experimental study with repeated measures.. Animal research laboratory at a university medical school.. Twenty anesthetized, mechanically ventilated, and instrumented pigs.. Twelve hours after induction of fecal peritonitis by inoculation of autologous feces, swine, which were resuscitated with hydroxyethyl starch and norepinephrine to maintain mean arterial pressure at baseline values, were ventilated randomly with an Fio2 required to keep Sao2 >90% (controls: n = 10) or Fio2 1.0 (hyperoxia, n = 10) during the next 12 hrs.. Despite similar hemodynamic support (hydroxyethyl starch and norepinephrine doses), systemic and regional macrocirculatory and oxygen transport parameters, hyperoxia attenuated pulmonary hypertension, improved gut microcirculation (ileal mucosal laser Doppler flowmetry) and portal venous acidosis, prevented the deterioration in creatinine clearance (controls 61 (44;112), hyperoxia: 96 (88;110) mL.min(-1), p = .074), and attenuated the increase in blood tumor necrosis factor-alpha concentrations (p = .045 and p = .112 vs. controls at 18 hrs and 24 hrs, respectively). Lung and liver histology (hematoxyline eosine staining) were comparable in the two groups, but hyperoxia reduced apoptosis (Tunel test) in the liver (4 (3;8) vs. 2 (1;5) apoptotic cells/field, p = .069) and the lung (36 (31;46) vs. 15 (13;17) apoptotic cells/field, p < .001). Parameters of lung function, tissue antioxidant activity, blood oxidative and nitrosative stress (nitrate + nitrite, 8-isoprostane levels; deoxyribonucleic acid (DNA) damage measured using the comet assay) were not further affected during hyperoxia.. When compared with the previous report on hyperoxia initiated simultaneously with induction of sepsis, i.e., using a pretreatment approach, pure oxygen ventilation started when porcine fecal peritonitis-induced septic shock was fully developed proved to be equally safe with respect to lung function and oxidative stress, but exerted only moderate beneficial effects.

Topics: Animals; Apoptosis; Biomarkers; Comet Assay; Dinoprost; DNA Damage; Nitrates; Nitrites; Oxidative Stress; Oxygen Inhalation Therapy; Prospective Studies; Pulmonary Circulation; Pulmonary Gas Exchange; Random Allocation; Respiration, Artificial; Safety; Shock, Septic; Swine; Tumor Necrosis Factor-alpha

Prostaglandins are profoundly involved in endotoxaemic shock. Twenty pigs were given endotoxin at various doses (0.063-16 microg kg(-1) h(-1)). Three non-endotoxaemic pigs served as controls. Two eicosanoids were measured in plasma (8-iso-PGF(2alpha), a free radical-mediated lipid peroxidation product, and 15-keto-dihydro-PGF(2alpha) a major metabolite of COX activity) and evaluated against the pathophysiological responses that occur during endotoxaemic shock. Endotoxin mediates an increase in both 8-iso-PGF(2alpha) and 15-keto-dihydro-PGF(2alpha). An increase in the endotoxin dose induced significant log-linear responses in 8-iso-PGF(2alpha) and 15-keto-dihydro-PGF(2alpha). Oxidative injury correlated to the TNF-alpha, IL-6, reductions in cardiac performance and to oxygen delivery and utilisation. COX-mediated inflammatory responses correlated to TNF-alpha, IL-6 and to reductions in arterial oxygen tension. Thus, oxidative injury and COX-mediated inflammation play a central role in the manifestation of endotoxaemic shock. Furthermore, formation of these eicosanoids on endotoxin-mediated alterations in pulmonary hypertension, oxygen delivery and oxygen utilisation seems to be independent of the administered endotoxin dose.

Topics: Animals; Dinoprost; Heart; Inflammation; Oxidative Stress; Shock, Septic; Sus scrofa; Swine

This study addressed the possible role of cyclooxygenase (COX) and its products in the rebound response to inhaled nitric oxide (INO). Anesthetized, mechanically ventilated piglets were exposed to endotoxin alone, endotoxin combined with INO, or endotoxin with INO plus the COX inhibitor diclofenac (3 mg/kg iv) (n = 8 piglets/group). A control group of healthy pigs (n = 6) was also studied. Measurements were made of blood gases, hemodynamic parameters, lung tissue COX expression, and plasma concentrations of thromboxane B(2) (TxB(2)), PGF(2alpha), and 6-keto-PGF(1alpha). Endotoxin increased lung inducible COX (COX-2) expression and circulating prostanoids concentrations. Inhalation of NO during endotoxemia increased the constitutive COX (COX-1) expression, and the circulating TxB(2) and PGF(2alpha) increased further after INO withdrawal. The combination of COX inhibitor with INO blocked all these changes and eliminated the rebound reaction to INO withdrawal, which otherwise was seen in endotoxemic piglets given INO only. We conclude that the rebound response to INO discontinuation is related to COX products.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Inhalation; Animals; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; Isoenzymes; Lung; Nitric Oxide; Osmolar Concentration; Prostaglandin-Endoperoxide Synthases; Shock, Septic; Swine; Thromboxane B2

To evaluate the early myocardial biochemical inflammatory response with the microdialysis technique during porcine endotoxemia and to simultaneously monitor systemic hemodynamics.. Prospective, randomized, placebo-controlled trial with parallel groups.. Animal research laboratory at the University Hospital of Uppsala, Sweden.. Thirteen piglets aged 12-14 wks receiving general anesthesia.. After thoracotomy and the insertion of microdialysis probes in standardized locations in the left ventricle of the heart and in the quadriceps muscle, seven pigs received a continuous infusion of endotoxin, initiating a severe endotoxemic shock. Six pigs received saline instead of endotoxin.. Endotoxemia caused a rapid and pronounced elevation of a metabolite obtained from prostaglandin degradation, 15-keto-dihydro-PGF(2alpha), in myocardial microdialysate fluid being specific of cyclooxygenase (COX)-mediated inflammation (p <.001 vs. saline-infused controls). Simultaneously, we observed a decrease in left ventricular stroke work index in the endotoxemic pigs (p <.01 vs. saline-infused controls). Endotoxemia did not alter 15-keto-dihydro-PGF(2alpha) levels in quadriceps muscle. Endotoxemia caused increases in taurine, hypoxanthine, and magnesium in myocardial microdialysate (p <.05 vs. saline-infused controls), whereas the contents of pyruvate, lactate, inosine, adenosine, and calcium were not significantly changed.. Endotoxemia induced a myocardial COX-mediated inflammation without signs of ischemia. In parallel, a depletion of myocardial energy substrates and a deterioration in myocardial performance were seen.

Topics: Analysis of Variance; Animals; Dinoprost; Endotoxemia; Female; Hemodynamics; Inflammation; Male; Microdialysis; Myocardium; Prostaglandin-Endoperoxide Synthases; Random Allocation; Shock, Septic; Swine

Retinols seem to be of clinical importance in ameliorating the clinical consequences of septic shock. These beneficial effects of retinols are suggested to be due to an antioxidant property. The present study was undertaken in order to confirm or rule out such an effect of retinol palmitate (RP) in experimental septic shock by measuring F2-isoprostanes and a major prostaglandin F2 alpha metabolite as indicators of oxidative injury and inflammatory response, respectively.. Fourteen anaesthetised pigs were randomly given an injection of RP (2.300 IU x kg-1) or the corresponding volume of vehicle. All pigs received a continuous infusion of E. coli endotoxin (10 micrograms x kg-1 x h-1). Blood samples were analysed for lipid peroxidation products (8-iso-PGF2 alpha), indicating free radical induced oxidative injury and 15-keto-dihydro-PGF2 alpha indicating cyclooxygenase-mediated inflammatory response).. Significantly elevated levels of 8-iso-PGF2 alpha were seen at 3, 5 and 6 hours of endotoxaemia in the vehicle + endotoxin group as compared to RP + endotoxin group. Endotoxin induced cyclooxygenase-mediated inflammatory response was not affected by RP.. This study is the first one to show that RP counteracts oxidative injury rather than inflammatory response in experimental septic shock. These results may be of importance for the understanding of some beneficial effects of RP during endotoxaemia (i.e. improved systemic haemodynamics and reduced serum levels of endotoxin). Our results may explain the therapeutic effects of nutrients rich in caroten/retinols used in some clinical studies.

Topics: Analysis of Variance; Animals; Antioxidants; Dinoprost; Disease Models, Animal; Diterpenes; Endotoxins; Escherichia coli Infections; F2-Isoprostanes; Female; Inflammation; Lipid Peroxidation; Male; Oxidative Stress; Radioimmunoassay; Random Allocation; Retinyl Esters; Shock, Septic; Swine; Vitamin A

Human septic shock can be replicated in the endotoxaemic pig. Endotoxaemia causes a multitude of events, including reduced PaO(2) and increased lipid peroxidation. This study was designed to evaluate the possible effects of a commonly used anaesthetic drug with known antioxidant properties (propofol) during porcine endotoxaemia.. Ten pigs were anaesthetised and given a 6 h E. coli endotoxin infusion. The animals received, randomly, a supplementary continuous infusion of propofol emulsion (containing 0.005% EDTA) or the corresponding volume of vehicle (controls). Pathophysiologic responses were determined. Non-enzymatic (by measuring plasma 8-iso-PGF(2 alpha) and enzymatic (by measuring plasma 15-keto-dihydro-PGF(2 alpha)) lipid peroxidations were evaluated. Plasma levels of the endogenous antioxidants alpha- and gamma-tocopherols, were also analysed.. Endotoxaemia increased plasma levels of 8-iso-PGF(2 alpha) (1st-4th h) and 15-keto-dihydro-PGF(2 alpha) (1st-4th h) significantly more in controls than in the propofol+endotoxin group. PaO(2) was significantly less affected by endotoxin in the propofol treated animals (2nd-4th h). Mean arterial pressure (4th-6th h) and systemic vascular resistance (6th h) were reduced significantly more by endotoxin among the propofol-treated animals. Vitamin E (alpha-tocopherol) increased in all animals, significantly more in the propofol+endotoxin group (1/2-6th h) than in the control group.. Propofol reduced endotoxin-induced free radical mediated and cyclooxygenase catalysed lipid peroxidation significantly. The implication is that propofol counteracts endotoxin-induced deterioration of PaO(2).

Topics: Anesthetics, Intravenous; Animals; Dinoprost; Endotoxemia; Escherichia coli Infections; F2-Isoprostanes; Inflammation; Lipid Peroxidation; Oxidative Stress; Propofol; Radioimmunoassay; Shock, Septic; Swine; Vitamin E

Lipid peroxidation and antioxidant balance in the body is a crucial factor in the pathophysiology of various diseases. This study investigates the circulatory alpha-tocopherol levels and its relationship with 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), a non-enzymatic and, 15-keto-13,14-dihydro-PGF2alpha (15-K-DH-PGF2alpha), a cyclooxygenase catalysed oxidation product of arachidonic acid in experimental septic shock in pigs. A steady decrease in alpha-tocopherol levels in plasma was observed in both survivor and non-survivor animals. A simultaneous increase of oxidative injury indicator, plasma 8-iso-PGF2alpha was seen in both groups but with a different fashion. 8-Iso-PGF2alpha levels increased steadily in the animals that died during the experiment. An early and rapid increase of plasma 15-K-DH-PGF2alpha, an inflammatory response indicator, was also observed in all animals. There was a significant difference in the kinetics of decrement of alpha-tocopherol levels and a concomitant increase in 15-K-DH-PGF2alpha levels among the non-survivors. Thus, a successive disappearance of circulatory vitamin E in conjunction with the surge of plasma isoprostanes and prostaglandins impairs the oxidant-antioxidant balance in favour of the former and may possibly have an effect on the survivality during experimental porcine septicaemia.

Topics: Animals; Arachidonic Acid; Dinoprost; Endotoxemia; F2-Isoprostanes; Female; Lipid Peroxidation; Male; Oxidative Stress; Prostaglandin-Endoperoxide Synthases; Shock, Septic; Swine; Vasoconstrictor Agents; Vitamin E

This study investigates the plasma levels of 8-iso-PGF2alpha, a non-enzymatic, and 15-K-DH-PGF2alpha, a cyclooxygenase catalyzed oxidation product of arachidonic acid in an experimental porcine endotoxemic shock model. A significant (P < 0.001) and rapid appearance and disappearance of PGF2alpha metabolite after endotoxin infusion was very similar in both non-survival and survival groups indicating an acute progression and recession of inflammation. When oxidative injury was assessed by measuring free 8-iso-PGF2alpha the levels in plasma increased significantly up to 2 h and remained at this level until death among the non-survivors. This was apparently different from the survivors where the 8-iso-PGF2alpha levels increased to its height at 1 h, then decreased to the basal levels after 5 h. Thus, free radical and cyclooxygenase catalyzed oxidation of arachidonic acid occurs during endotoxemia. Free radical dependent oxidative injury following endotoxin induced inflammation may be the major cause of organ failure and increased mortality.

Topics: Animals; Arachidonic Acid; Biomarkers; Dinoprost; Endotoxemia; Escherichia coli Infections; F2-Isoprostanes; Female; Inflammation; Male; Oxidative Stress; Radioimmunoassay; Shock, Septic; Survival Analysis; Swine; Time Factors

To investigate the vascular smooth muscle dysfunction of septic shock, in vitro isometric responses to phenylephrine (PE) and acetylcholine (ACh) were evaluated in aortic rings, with and without endothelium (+/-E), removed from male Wistar rats 1.5, 3 and 6 h after intravenous (i.v.) administration of 5 mg/ kg lipopolysaccharide (LPS) or vehicle. A reduction in maximum contraction (+/-E) and sensitivity (-E) to PE were identified at 6 but not at 1.5 or 3 h. Maximum relaxation to ACh (+E) was not affected by LPS treatment but sensitivity was increased at 1.5 and 3 h. Having identified 6 h as the time at which the most pronounced changes were observed, further studies at this interval found that maximum contraction to potassium chloride (+/-E), prostaglandin F2 alpha (+E) and detomidine (-E) and relaxation to salbutamol (-E) were less in aortic rings from endotoxaemic rats. Sensitivity to KCl (+/-E), PGF2 alpha (-E) and detomidine (-E) was also reduced. Relaxation to sodium nitroprusside and atrial natriuretic peptide was not changed. These results suggest that attenuated pressor responses to a variety of vasoactive agents may be expected in patients 6 h after systemic exposure to endotoxin and that this vasoplegia may influence the vascular side-effects of therapeutic agents.

Topics: Acetylcholine; Adrenergic alpha-Agonists; Adrenergic beta-Agonists; Albuterol; Analysis of Variance; Animals; Aorta, Thoracic; Atrial Natriuretic Factor; Dinoprost; Dose-Response Relationship, Drug; Endothelium, Vascular; Imidazoles; Injections, Intravenous; Isometric Contraction; Lipopolysaccharides; Male; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Nitroprusside; Phenylephrine; Potassium Chloride; Rats; Rats, Wistar; Shock, Septic; Vasodilator Agents

The influence of nitric oxide (NO) on vascular responses to transmural stimulation (TNS) of noradrenergic nerves was studied in isolated rings of rat iliac arteries. TNS produced frequency-dependent contractions in all vessels. The NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) significantly enhanced TNS responses in intact vessels, but not in those in which the endothelium had been removed. However, in endothelium-denuded rings incubated for 8 hours, L-NMMA increased the contractions induced by nerve stimulation, an effect which was prevented by treatment with dexamethasone or cycloheximide, and enhanced by incubation with lipopolysaccharide and gamma-interferon. Addition of L-arginine reversed the effect of L-NMMA in intact rings; however, it significantly decreased below control values TNS-induced contractions in vessels without endothelium. The results indicate that a) the arterial response to noradrenergic nerve stimulation is modulated by NO originating either in endothelial cells or in smooth muscle cells after induction of NO synthase activity, and b) once NO synthase is induced, the limiting step in NO production is the availability of the substrate L-arginine. An overproduction of vascular NO in the presence of endotoxin or other inflammatory stimuli may prevent the vascular response to sympathetic stimuli and contribute to the vasodilation observed in inflammation or endotoxic shock.

Topics: Acetylcholine; Animals; Arginine; Cycloheximide; Dexamethasone; Dinoprost; Endothelium, Vascular; Endotoxins; Iliac Artery; In Vitro Techniques; Interferon-gamma; Isometric Contraction; Male; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Nitric Oxide; omega-N-Methylarginine; Phentolamine; Prazosin; Rats; Rats, Inbred Strains; Shock, Septic

Endotoxic shock is characterized by a variety of hemodynamic disturbances which result in tissue hypoperfusion. There is some evidence for endothelial damage caused by endotoxin. The present study addressed the hypothesis that vascular responsiveness to endothelial-dependent vasodilators is altered in endotoxic shock. Dose-response relationships for an endothelial-dependent vasodilator, acetylcholine, and an endothelial-independent vasodilator, adenosine, were determined in guinea pig aortic rings. Rings were examined from either control (untreated) animals or from animals given Escherichia coli endotoxin (4 mg/kg, i.p.) 16 hr prior to functional studies. Dose-response relationships to adenosine were similar in aortic rings from control and shocked animals. However, response to acetylcholine were attenuated by 30% (P less than .05) in the shocked group. To distinguish between a direct, acute effect of endotoxin versus effects produced by systemic changes that occur during shock, rings were isolated from untreated animals and incubated with endotoxin in vitro for 30 min prior to and during dose-response measurements. Incubation with endotoxin caused no change in aortic responses to adenosine or acetylcholine. Electron microscopy revealed a separation of the endothelium from the internal elastic lamina and an increase in inter-endothelial gaps in rings isolated from shocked animals. These structural changes were not observed in rings from untreated animals or in rings incubated with endotoxin in vitro. We conclude that endothelial-dependent vasodilation is attenuated during endotoxic shock. The functional changes are correlated with ultrastructural alterations of the endothelium.

Topics: Acetylcholine; Adenosine; Animals; Aorta, Thoracic; Dinoprost; Endothelium, Vascular; Endotoxins; Escherichia coli; Guinea Pigs; Male; Microscopy, Electron; Shock, Septic; Vasodilation

The role of prostaglandin F2 alpha (PGF2 alpha) in embryonic loss following induced endotoxemia was studied in mares that were 21 to 44 days pregnant. Thirteen pregnant mares were treated with a nonsteroidal anti-inflammatory drug, flunixin meglumine, to inhibit the synthesis of PGF2 alpha caused by Salmonella typhimurium endotoxin given IV. Flunixin meglumine was administered either before injection of the endotoxin (group 1, -10 min; n = 7), or after endotoxin injection into the mares (group 2, 1 hour, n = 3; group 3, 2 hours, n = 3); 12 pregnant mares (group 4) were given only S typhimurium endotoxin. In group 4, the secretion of PGF2 alpha, as determined by plasma 15-keto-13,14-dihydro-PGF2 alpha concentrations, was biphasic, initially peaking at 30 minutes followed by a second, larger peak approximately 105 minutes after the endotoxin was given IV. When flunixin meglumine was administered at -10 minutes, synthesis of PGF2 alpha was inhibited for several hours, after administration of flunixin meglumine at 1 hour, the second secretory surge of PGF2 alpha was blocked, and administration of the drug at 2 hours did not substantially modify the secretion of PGF2 alpha. Plasma progesterone concentrations were unchanged after endotoxin injections were given in group 1. In group 2, progesterone values decreased less than 2 ng/ml and remained low for several days. In group 3 and group 4, progesterone concentrations decreased to values less than 0.5 ng/ml by 48 hours after endotoxin injections were given.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Abortion, Veterinary; Animals; Clonixin; Dinoprost; Endotoxins; Female; Fetal Death; Horses; Injections, Intravenous; Pregnancy; Progesterone; Salmonella typhimurium; Shock, Septic; Time Factors

The role of decreased luteal activity in embryonic loss after induced endotoxemia was studied in mares 21 to 35 days pregnant. Fourteen pregnant mares were treated daily with 44 mg of altrenogest to compensate for the loss of endogenous progesterone secretion caused by prostaglandin F2 alpha (PGF2 alpha) synthesis and release following intravenous administration of Salmonella typhimurium endotoxin. Altrenogest was administered daily from the day of endotoxin injection until day 40 of gestation (group 1; n = 7), until day 70 (group 2; n = 5), or until day 50 (group 3; n = 2). In all mares, secretion of PGF2 alpha, as determined by the plasma 15-keto-13,14-dihydro-PGF2 alpha concentrations, followed a biphasic pattern, with an initial peak at 30 minutes followed by a second, larger peak at 105 minutes after endotoxin injection. Plasma progesterone concentrations decreased in all mares to values less than 1 ng/ml within 24 hours after endotoxin injection. In group 1, progesterone concentrations for all mares were less than 1 ng/ml until the final day of altrenogest treatment. In 6 of 7 mares in group 1, the fetuses died within 4 days after the end of treatment, with progesterone concentrations less than 1 ng/ml at that time. In the mare that remained pregnant after the end of treatment, plasma progesterone concentration was 1.6 ng/ml on day 41 and increased to 4.4 ng/ml on day 44. In group 2, all mares remained pregnant, even though plasma progesterone concentrations were less than 1 ng/ml in 4 of 5 mares from the day after endotoxin injection until after the end of altrenogest treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Dinoprost; Endotoxins; Evaluation Studies as Topic; Female; Fetal Death; Horse Diseases; Horses; Pregnancy; Pregnancy Maintenance; Progesterone; Salmonella typhimurium; Shock, Septic; Trenbolone Acetate

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Creatinine; Dinoprost; Epoprostenol; Hemodynamics; Kidney; Male; Prostaglandins; Renal Circulation; Shock, Septic; Swine; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cells, Cultured; Dinoprost; Female; Macrophages; Mice; Peritoneal Cavity; Shock, Septic; Solanaceous Alkaloids; Thromboxane B2

Murine toxin of Yersinia pestis when injected in the rat tail vein (LD50) caused pronounced alterations in PGE1 and PGF2 alpha content in different tissues (lung, heart, spleen, liver, kidney, small intestine) and blood. Heat-inactivated toxin has been shown to have the same effects as the intact toxin preparation. The changes in PG content are, probably, due to the lipopolysaccharide component of both preparations. The differences in metabolic effects between Yersinia pestis endotoxin and lipopolysaccharides of other Gram-negative bacteria are discussed.

Topics: Alprostadil; Animals; Bacterial Toxins; Dinoprost; Plague; Prostaglandins F; Rats; Rats, Inbred Strains; Shock, Septic; Time Factors; Tissue Distribution; Yersinia pestis

Epinephrine and norepinephrine adrenal levels were depleted in Escherichia coli endotoxin-treated (10 mg/kg) male Wistar rats from 504 +/- 203 to 119 +/- 77 ng/mg in control and from 200 +/- 97 to 123 +/- 66 ng/mg wet wt, respectively. However dopamine increased from 4.2 +/- 1.9 to 14.9 +/- 3.4 ng/mg. After endotoxin administration, norepinephrine content in peripheral organs, heart 1.27 +/- 0.19 ng/mg, spleen 1.52 +/- 0.59 ng/mg, liver 0.15 +/- 0.05 ng/mg, and kidney 0.24 +/- 0.09 ng/mg wet wt. decreased by 34, 36, 47, and 18%, respectively. Indomethacin treatment kept the catecholamine levels constant in endotoxic rats, but naloxone had no effect. PGF2 alpha tissue levels (12.0 +/- 10.1 pg/mg protein in spleen and 1.85 +/- 0.6 pg/mg protein in liver) were increased twofold by endotoxin treatment: PGE2 content in spleen and liver 0.5 +/- 0.2 pg/mg protein and 2.3 +/- 1.9 pg/mg protein, respectively, increased by only 27 and 26%. In the kidneys of endotoxin-treated animals, PGF2 alpha and PGE2 levels were lower than in control. Indomethacin treatment decreased PGF2 alpha and PGE2 and increased the norepinephrine content in the same organs. It is suggested that prostaglandins play a participative role in the control of norepinephrine tissue levels in endotoxemia.

Topics: Adrenal Glands; Animals; Catecholamines; Dinoprost; Dinoprostone; Dopamine; Endotoxins; Epinephrine; Escherichia coli; Kidney; Liver; Male; Myocardium; Norepinephrine; Prostaglandins; Prostaglandins E; Prostaglandins F; Rats; Rats, Inbred Strains; Shock, Septic; Spleen

15 out of 68 patients with severe sepsis were examined in an early stage of shock and analyzed for objective hemodynamic and functional shock criteria. These data were correlated to endogenous plasma concentrations of the vasoactive arachidonate derivatives: prostaglandin F2 alpha (PGF2 alpha), thromboxane A2 (TXA2) and prostacyclin (PGI2). Marked differences in invasively measured data of cardiac, pulmonary and renal functions divided clinically otherwise comparable patients into group I and II. Group I was characterized by a hypodynamic response as compared to group II which was hyperdynamic. In spite of similar levels of PGF2 alpha (570 +/- 80 vs. 560 +/- 103 pg/ml) in both groups indicating a comparable state of arachidonate turnover, opposing profiles with regard to the TXA2/PGI2 ratio as measured from their stable degradation products were found (TXB2 [I]: a 740 +/- 184; TXB2 [II]: 280 +/- 75; 6-k-PGF1 alpha [I]: 260 +/- 117; 6-k-PGF1 alpha [II]: 940 +/- 190 pg/ml). It is concluded that early sepsis in man leads to variable profiles of endogenously released prostaglandins and thromboxane in which the predominance of PGI2 over TXA2 is associated with better cardiovascular performance and organ functions, and vice versa.

Topics: Adolescent; Adult; Aged; Creatinine; Dinoprost; Epoprostenol; Female; Hemodynamics; Humans; Kidney; Lung; Male; Middle Aged; Multiple Organ Failure; Prostaglandins F; Retrospective Studies; Shock, Septic; Thromboxane A2

We studied the effects of a selective leukotriene (LT) antagonist (FPL 57231, 2 mg kg-1 min-1) on the acute cardiopulmonary changes observed in feline endotoxin shock. LTC4 and LTD4 (0.1-3.0 micrograms kg-1) given intravenously had little or no activity on pulmonary arterial pressure (PAP), dynamic lung compliance (Cdyn), and airways resistance (Raw). They did, however, produce a systemic hypertension, which was significantly attenuated during the FPL 57231 infusion. E. coli endotoxin (2 mg kg-1) administration resulted in decreases in systemic arterial blood pressure and Cdyn, together with increases in both PAP and Raw. During infusion of FPL 57231, all these endotoxin-induced cardiopulmonary changes were attenuated. Radioimmunoassay of blood samples taken from cats given FPL 57231 showed that levels of 6-keto prosta-glandin F1 alpha and thromboxane B2 were not significantly increased by endotoxin, as would normally be expected in cats administered endotoxin. FPL 57231 was also found to antagonise the pulmonary effects of the thromboxanemimetic U46619 and of prostaglandin F2 alpha. These results indicate that it is unlikely that the leukotrienes are involved as important mediators of the acute phase of endotoxin shock in cats.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 6-Ketoprostaglandin F1 alpha; Airway Resistance; Animals; Blood Pressure; Cats; Chromones; Dinoprost; Endotoxins; Escherichia coli; Evaluation Studies as Topic; Hypertension, Pulmonary; Infusions, Intravenous; Lung Compliance; Male; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Prostaglandins F; Pulmonary Circulation; Shock, Septic; SRS-A; Thromboxane B2

An evaluation was made of 106 surgical patients with Gram-negative septic shock, both for clinical criteria as well as the biochemical mediators endotoxin, prostaglandin F2 alpha, prostaglandin I2 (prostacyclin), and thromboxane. These data were correlated to various defined shock phases, functional data of vital organs, and clinical outcome. Patients underwent invasive organ function monitoring and the usual laboratory tests of intensive care. Prostaglandins and thromboxane were measured radioimmunologically, endotoxin by the limulus amebocyte lysate test. Endotoxin proved to be a more accurate predictor of severe sepsis than did positive blood cultures. Endotoxin as well as prostaglandins and thromboxane are predominantly released in early shock phases, appearing in plasma concentrations, which correlate with the severity of organ failure. Sepsis-induced respiratory failure coincides with a deterioration of pulmonary prostaglandin inactivation, which contributes to the release mechanism. High systemic prostacyclin activity benefits the patients' organ functions and clinical outcomes, while a predominance of thromboxane seems to effect the opposite. Transpulmonary-thromboxane gradients correlate significantly with pulmonary hypertension in the early phases of septic shock.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Adolescent; Adult; Aged; Dinoprost; Endotoxins; Epoprostenol; Humans; Middle Aged; Peritonitis; Prostaglandins; Prostaglandins F; Respiratory Insufficiency; Shock, Septic; Surgical Wound Infection; Thromboxanes

Short-term (0 to 30 minutes) physiologic responses of neonatal lambs infused with a trichloroacetic extract of a type III (strain 878) group B streptococcus (878-TCA) were studied. Bolus injections of 878-TCA were associated with pulmonary hypertension, peripheral arterial hypoxemia, and reductions in circulating white blood cell and platelet counts. These events were associated with a rise in plasma levels of prostaglandins F2 alpha and E and could be prevented by proper treatment with ibuprofen. Continuous infusions of 878-TCA were associated with a dose-dependent rise in systemic and pulmonary arterial pressures and a fall in arterial PO2. During infusion, inhibition of prostaglandin synthesis resulted in a return toward preinfusion values. The authors conclude that venous infusions of extracts of 878-TCA induce significant pulmonary and systemic arterial vascular perturbations in the neonatal lamb and that some of these alterations are associated with the release of prostaglandins or other arachidonic acid metabolites.

Topics: Animals; Animals, Newborn; Cell Extracts; Dinoprost; Female; Hypertension; Ibuprofen; Infusions, Parenteral; Injections; Leukocyte Count; Lung; Male; Oxygen; Platelet Count; Prostaglandins; Prostaglandins E; Prostaglandins F; Pulmonary Artery; Sheep; Shock, Septic; Streptococcus agalactiae; Trichloroacetic Acid

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Animals; Child; Child, Preschool; Dinoprost; Dogs; Epoprostenol; Female; Humans; Infant; Male; Prostaglandins E; Prostaglandins F; Shock, Septic; Solanaceous Alkaloids; Vasodilator Agents

In anesthetized piglets the intravenous injection of a lethal dose of endotoxin, 0.5 mg/kg, resulted in a progressively evolving deterioration of the cardiovascular system (hypotension, decrease in cardiac output), in an increase in pulmonary vascular resistance and in the death of all animals within 210 min following endotoxin administration. Endotoxin induced a significant increase in immunoreactive (i) i-6-oxo-PGF1 alpha, i-TXB2, and i-15-oxo-13,14-dihydro-PGF2 alpha levels in peripheral plasma. Pretreatment with the PG-synthesis inhibitor, flurbiprofen, abolished the profound rise in PG-levels, whereas cardiovascular performance was more sustained. The results suggest the involvement of several prostanoids during the evolution of endotoxic shock in the piglet.

Topics: Animals; Dinoprost; Epoprostenol; Female; Flurbiprofen; Hemodynamics; Propionates; Prostaglandin Antagonists; Prostaglandins; Prostaglandins F; Shock, Septic; Swine; Thromboxane A2; Vascular Resistance

Pasteurella hemolytica endotoxin (12 micrograms/kg) was infused intravenously into ewes over 500 min. Blood was sampled for 60 min before the infusion and at intervals during the infusion and for 1500 min postinfusion. The control values for plasma TxB2, 6-keto-PGF1 alpha, PGF2 alpha, and serotonin were 283 +/- 53 pg/ml (mean +/- standard error of mean), 281 +/- 14 pg/ml, 199 +/- 27 pg/ml, and 56.8 +/- 2.0 ng/ml, respectively. The plasma concentrations of TxB2, 6-keto-PGF1 alpha, PGF2 alpha, and serotonin significantly increased to a maximum at 50 min of infusion to 359%, 344%, 313%, and 201% of the control, respectively. PGF2 alpha and TxB2 returned to control levels at 300 min during infusion and 6-keto-PGF1 alpha at 60 min postinfusion and serotonin at 100 min of infusion. Serotonin concentration decreased significantly at 450 min of infusion to 73% of control and returned to control level at 1500 min postinfusion. No significant changes were found in the plasma levels of PGE, histamine, and ACE activity. We conclude that release of TxA2, PGI2, PGF2 alpha, and serotonin may contribute to pathophysiology induced by P. hemolytica endotoxin in sheep.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprost; Endotoxins; Female; Histamine; Pasteurella; Prostaglandins; Prostaglandins F; Serotonin; Sheep; Shock, Septic; Thromboxane A2; Thromboxane B2; Time Factors

Topics: Adolescent; Animals; Child; Child, Preschool; Dinoprost; Dogs; Escherichia coli; Humans; Infant; Meningitis, Meningococcal; Prostaglandins E; Prostaglandins F; Shock, Septic

Nine surgical patients underwent haemodynamic and respiratory monitoring during the course of severe sepsis. Endogenous PGF2 alpha levels in mixed venous and arterial plasma were measured. Results indicate pulmonary net release of PGF2 alpha, since arterial levels (1252 +/- 119 pg/ml) are significantly higher than mixed venous ones (824 +/- 89 pg/ml) in full-pronounced hyperdynamic septic shock. By contrast, the inactive metabolite KH2PGF2 alpha was found in lowest concentrations during shock (368 +/- 72 pg/ml) which suggests impaired pulmonary degradation. It is concluded that circulating PGF2 alpha is a marker of stimulated prostaglandin production in severe human sepsis.

Topics: Adolescent; Adult; Dinoprost; Female; Hemodynamics; Humans; Male; Middle Aged; Platelet Count; Prostaglandins F; Respiratory Function Tests; Shock, Septic

3 collectives of a total of 22 surgical patients demonstrate massive release of vasoactive prostanoids accompanying clinical septic shock. PGF2 alpha serves as an example for impaired pulmonary prostaglandin metabolism under this condition. Moreover, divergent profiles consisting of PGF2 alpha, thromboxane and prostacyclin can be attributed to divergent shock parameters revealing that the thromboxane/prostacyclin-ratio might be of crucial significance on whether the prostanoid profile exerts toxic or rather beneficial effects. This is demonstrated clinically by means of renal function. The clinical hypotheses are subsequently evaluated in a porcine endotoxic shock model: Comparable stimulation of endogenous prostanoids is detected. The beneficial effects of prostacyclin are concluded from objective hemodynamic and functional data of lung and kidney.

Topics: Adult; Animals; Creatinine; Dinoprost; Disease Models, Animal; Hemodynamics; Humans; Prostaglandins; Prostaglandins F; Pulmonary Wedge Pressure; Shock, Septic; Swine

During endotoxemia there is increased synthesis of arachidonic-acid-derived metabolites. We investigated the potential deleterious role of the proaggregatory vasoconstrictor, thromboxane A2, an arachidonic acid metabolite, in the endotoxic shocked rat. Plasma levels of thromboxane B2, the stable metabolite of thromboxane A2, 6-keto-PGF1 alpha, the stable metabolite of PGI2, and PGE were measured via radioimmunoassay. We also investigated the therapeutic efficacy of the fatty acid cyclo-oxygenase imidazole and 7(1-imidazolyl)-heptanoic acid (7-IHA), in endotoxic shocked rats. Thirty minutes after intravenous (IV) administration of Salmonella enteritidis endotoxin (20 mg/kg), plasma immunoreactive thromboxane B2 (TxB2) was increased from nondetectable levels (less than 200 pg/ml) in normal nonshocked rats to 2207 +/- 282 pg/ml (N = 16). The 6-keto-PGF1 alpha level was increased from nondetectable levels to 840 +/- 59 pg/ml (N = 8), and prostaglandin E rose from 146 +/- 33 to 2160 +/- 606 pg/ml (N = 5). Ibuprofen (3.75 mg/kg) or indomethacin (10 mg/kg) administered IV 30 min prior to endotoxin (20 mg/kg) improved the survival rate to 81% (N = 15, P less than 0.001) and 78% (N = 17, P less than 0.001), respectively, compared to the 24-hr survival of 8% (N = 26) in the vehicle-treated rats. Ibuprofen also inhibited the endotoxin-induced elevation of TxB2, 6-keto-PGF1 alpha, and fibrinogen/fibrin degradation products. Imidazole (30 mg/kg) or 7-IHA (30 mg/kg), IV, 30 min prior to endotoxin improved survival 65% (N = 11) and 81% (N = 15), respectively. These drugs also inhibited endotoxin-induced elevations in TxB2 and fibrinogen/fibrin degradation products, but did not inhibit endotoxin-induced elevations in plasma PGE. These results are consistent with the suggestion that TxA2 plays a role in the pathogenesis of endotoxic shock.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprost; Disseminated Intravascular Coagulation; Fibrin Fibrinogen Degradation Products; Ibuprofen; Indomethacin; Male; Muridae; Prostaglandins E; Prostaglandins F; Shock, Septic; Thromboxane A2; Thromboxanes

Baboons treated with lidocaine (2 mg/kg/hr) after shock from endotoxin were compared to untreated controls in an LD70 E coli endotoxin (4 mg/kg) model. Survival, systemic and pulmonary arterial pressures, cardiac output, white blood cell and platelet counts, blood gases and arterial and mixed venous PGE and PGF 2 alpha levels were determined. Baboons receiving lidocaine had a better (P less than 0.05) survival at 72 hours than the controls. Circulatory function was improved with lidocaine; however, white blood cell and platelet counts, blood gases, and the prostaglandin release were similar in both groups. The mechanism by which lidocaine improves survival in baboon endotoxin shock appears to be unrelated to its effects on white blood cells, platelets, or the prostaglandin release.

Topics: Animals; Blood Pressure; Cardiac Output; Dinoprost; Endotoxins; Heart Rate; Lidocaine; Male; Papio; Prostaglandins E; Prostaglandins F; Shock, Septic