Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anisodamine, an anticholinergic drug, is widely used in China for treatment of infants with septic shock and has been reported to inhibit thromboxane synthesis in cultured cells. Thromboxane A2 plays an important role in the early pulmonary hypertension in sepsis; however, the role of thromboxane A2 later in sepsis is unclear. We tested the hypothesis that thromboxane A2 synthesis inhibition with dazmegrel, and cholinergic blockade with anisodamine, would attenuate the later phase of pulmonary hypertension induced by 4 h of group B streptococcus (GBS) infusion. 1 mg/kg of dazmegrel reversed the pulmonary hypertension and slightly increased cardiac output; these hemodynamic improvements persisted for 30-60 min. Plasma thromboxane B2 levels returned toward pre-GBS baseline values after dazmegrel treatment. Thus, thromboxane A2 is still a major mediator of pulmonary hypertension in piglets after 4 h of continuous GBS infusion. 0.5 mg/kg of anisodamine had no significant hemodynamic effect. 2 and 4 mg/kg of anisodamine each caused transient, dose-related decreases in systemic artery pressure; cardiac output also fell after the highest anisodamine dose. Pulmonary hypertension was not alleviated by anisodamine. All hemodynamic changes induced by anisodamine were short-lived and returned to preanisodamine values within 10 min. Anisodamine did not ameliorate thromboxane-mediated pulmonary hypertension in this animal model, and therefore may not inhibit thromboxane synthesis in vivo. The results of this study do not support the use of anticholinergic therapy to improve hemodynamics in GBS sepsis, but do suggest that thromboxane synthesis inhibition may be a clinically useful therapy in advanced GBS sepsis.
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PMID:Delayed thromboxane synthesis inhibition, but not cholinergic blockade, reverses group B streptococcus-induced pulmonary hypertension. 130 45

Isoproterenol, dobutamine, dopamine, and nitroprusside are four vasoactive drugs used to decrease pulmonary arterial pressure and increase cardiac output in newborns, infants, and children with sepsis. Thromboxane A2 likely produces some of the hemodynamic changes in sepsis, and U46619, a thromboxane A2 mimetic, produces similar changes in lambs. We studied the hemodynamic effects of these four vasoactive drugs in 10 spontaneously breathing newborn lambs during an infusion of U46619. After baseline hemodynamic measurements, U46619 (1-2 micrograms/kg/min) was infused to increase pulmonary arterial pressure and to decrease cardiac output. Then, either isoproterenol (0.05-1.0 micrograms/kg/min), dobutamine (5-20 micrograms/kg/min), dopamine (3-30 micrograms/kg/min), or nitroprusside (0.5-10.0 micrograms/kg/min) was infused. Every 10 min, measurements were repeated and the dose increased. U46619 significantly increased pulmonary arterial pressure by 182% and decreased cardiac output by 25% (p less than 0.05). Isoproterenol decreased pulmonary arterial pressure by 30% (p less than 0.05) and increased cardiac output by 25% (p less than 0.05) at low doses, and increased cardiac output by 115% at the maximum dose (p less than 0.05). Dobutamine decreased pulmonary arterial pressure by 11% (p less than 0.05) at low doses, and increased cardiac output by 28% (p less than 0.05) at low doses, and increased cardiac output by 71% at the maximum dose (p less than 0.05). Dopamine did not decrease pulmonary arterial pressure or increase cardiac output. Nitroprusside decreased pulmonary arterial pressure by 11% at the maximum dose (p less than 0.05). Isoproterenol and dobutamine may be more useful than dopamine and nitroprusside in the management of pulmonary hypertension and decreased cardiac output during sepsis.
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PMID:Effects of vasoactive drugs on thromboxane A2 mimetic-induced pulmonary hypertension in newborn lambs. 201 53

This study determined whether a sepsis-associated increase in cyclooxygenase products altered the pulmonary vascular response to the thromboxane A2 mimic, 9,11-dideoxy-11a,9a-epoxymethano-prostaglandin F2 alpha (U46619). Rats were anesthetized (50 mg/kg of sodium pentobarbital i.p.), and sepsis was induced by cecal ligation and puncture. Four hours later, pulmonary effluent immunoreactive thromboxane (iTXB2) levels were significantly increased (156.8%) and pulmonary vascular reactivity to U46619 (50-200 ng) was significantly (P less than .05) decreased compared to lungs from nonseptic controls. This decreased vascular reactivity was not seen in lungs from cecally ligated rats challenged with angiotensin II (5-200 ng). Sham surgery did not alter pulmonary iTXB2 synthesis nor did it result in a depressed vascular response to U46619. Rats pretreated with ibuprofen (15 mg/kg i.v.) did not show the sepsis-associated increase in iTXB2 levels nor was a decrease in pulmonary vascular reactivity to U46619 observed. These data indicate that a sepsis-associated increase in TXA2 and/or other cyclooxygenase products can alter the pulmonary vascular response to the TXA2 mimic, U46619.
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PMID:Bacterial sepsis-induced decrease in lung vascular reactivity to 9,11-dideoxy-11a9a-epoxymethano-prostaglandin F2 alpha (U46619) in the rat. 211 80

The role of the various cyclo-oxygenase products of arachidonic acid metabolism in the production of the pathologic, physiologic, hemodynamic, and metabolic derangements of sepsis has been reviewed and there is a wide variation in different species and with different models of sepsis. The relationship of these potential mediators cannot be definitely determined. There is much circumstantial evidence that would incriminate the various arachidonic metabolites in the production of the sepsis manifestations; however, we must keep in mind that this may only be "guilt by association." Clearly, the available evidence does suggest that there is some role played by TXA2 and PGI2 in the physiologic and hemodynamic manifestations of sepsis, but the exact role remains undetermined.
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PMID:Prostaglandins, cyclo-oxygenase inhibitors, and thromboxane synthetase inhibitors in the pathogenesis of multiple systems organ failure. 249 47

Thromboxane A2 may play a major role in circulatory shock. In some species, thromboxane synthetase inhibitors have a beneficial effect on shock induced by endotoxin, trauma, sepsis and administration of arachidonate. In some shock models, however, results with thromboxane synthetase inhibitors have been conflicting. The effect of UK-38,485, a selective thromboxane inhibitor, was evaluated in ponies injected with endotoxin intraperitoneally. Four groups of ponies were used to compare the effects of endotoxin alone, UK-38,485 alone, treatment with UK-38,485 before endotoxin challenge and treatment with UK-38,485 after endotoxin challenge. Haematological, metabolic, eicosanoid and clinical responses in each group were evaluated. The results indicated that UK-38,485 is an effective inhibitor of thromboxane A2 generation following endotoxin challenge. Prostacyclin values were elevated compared with baseline in ponies administered UK-38,485 and endotoxin. However, prostacyclin values were not significantly different from those of ponies receiving endotoxin alone. Furthermore, UK-38,485 failed to attenuate the haematological, metabolic and clinical manifestations commonly seen in the pony after endotoxin challenge.
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PMID:Effects of a specific thromboxane synthetase inhibitor in equine endotoxaemia. 331 81

Thromboxane A2 has been implicated as a mediator of cardiorespiratory dysfunction in sepsis. This study evaluated whether or not thromboxane A2 was necessary or sufficient for these adverse effects to occur during bacteremia. Fourteen adult swine under barbiturate anesthesia and breathing room air were monitored with arterial and pulmonary artery catheters. Animals were studied for 4 hours in three groups: group I, graded infusion of 10(9)/ml Aeromonas hydrophila; group II, Aeromonas hydrophila infusion plus SQ 29,548 (thromboxane A2 antagonist); and group III, U46619 (thromboxane A2 agonist) infusion in normal swine to pulmonary artery pressures observed in group I. Hemodynamic parameters, arterial and mixed venous blood gases, and plasma thromboxane B2 and prostaglandin 6-keto-F1 were measured. At sacrifice after 4 hours, wet-to-dry lung weights were calculated. Results indicated that thromboxane A2 was necessary and sufficient for the development of pulmonary hypertension and impaired alveolar-capillary oxygen diffusion in graded bacteremia. It was necessary but not sufficient for increased lung water to occur and sufficient but not necessary for decreased cardiac index and stroke volume index. Thromboxane A2 was neither sufficient nor necessary to the pathophysiology of systemic hypotension during graded bacteremia. Plasma prostaglandin 6-keto-F1 levels were increased in hypotensive animals with sepsis, suggesting its involvement in hypotension during sepsis.
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PMID:Thromboxane A2 mediates hemodynamic and respiratory dysfunction in graded bacteremia. 352 3

The early phase of endotoxin-induced acute hemodynamic disturbances and hypoxemia is mediated by various factors, including eicosanoids and tumor necrosis factor-alpha (TNF alpha). Thromboxane A2 is the major mediator of the early pulmonary hypertension associated with endotoxemia, but the mechanisms underlying the prolonged hemodynamic disturbances observed in ongoing endotoxemia are not well understood. The authors used a chronically instrumental young piglet model to determine the roles of several eicosanoids and of TNF alpha in the prolonged endotoxin-induced pulmonary hypertension and other cardiovascular derangements. Animals were given 40 micrograms/kg endotoxin intravenously per hour for 30 minutes, followed by 20 micrograms/kg per hour. In all animals, persistent pulmonary hypertension, lowered cardiac output, any hypoxemia developed during endotoxin infusion. After 3 hours of endotoxin infusion, randomly ordered infusions of 1 mg/kg dazmegrel (a thromboxane A2 synthesis inhibitor), 5mg/kg nordihydroguaiaretic acid (a 5-lipoxygenase inhibitor), and 20 mg/kg pentoxifylline (A TNF alpha inhibitor) were given intravenously at 30-to-60-minute intervals. Dazmegrel and pentoxifylline lowered pulmonary arterial pressure and resistance and raised arterial oxygen tension. Cardiac output increased significantly after pentoxifylline. These hemodynamic effects persisted for 30-60 minutes, despite continued endotoxin infusion. The elevated plasma concentrations of thromboxane B2 and TNF alpha returned toward preendotoxin baseline values after dazmegrel and pentoxifylline treatment, respectively. No beneficial effects were noted after administration of nordihydroguaiaretic acid. Based on these results, both thromboxane A2 and TNF alpha, but not 5-lipoxygenase products, play active roles in prolonged endotoxin-induced pulmonary hypertension and hypoxemia in young piglets. Combined thromboxane A2 and TNF alpha blockade may be clinically useful in treatment of advanced sepsis in neonates.
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PMID:Delayed thromboxane or tumor necrosis factor-alpha, but not leukotriene inhibition, attenuates prolonged pulmonary hypertension in endotoxemia. 766 5

The study deals with an animal model for the problems of surgical intensive care patients. Following repeated applications of E. coli endotoxin WO 111:B4 under standard conditions, specific hemodynamic and biochemical (TNF, TXA2, PGI2, IL-6, PAF) and morphological (endothelium of the lung) alterations were detected. ARDS patterns induced by the sepsis were analyzed by high-frequency measurement of pressure and flow (385 measurements per breathing cycle). The role of the intestine in sepsis was investigated by ion-selective monitoring of surface potassium activity comparing mucosa and serosa. Every injection of endotoxin was followed by a selective increase of the potassium activity revealing relative ischemia induced by the endotoxin. The profile of the potassium levels on the surface correlates both with the cardiac output and with the prostacyclin levels. The continuous narrowing of the difference between mucosa and serosa, potassium during the period of investigation can be regarded as evidence for pathologic change in permeability fostering the septic course.
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PMID:[Septic shock and multiple organ failure in surgical intensive care. An animal experiment model on the analysis of pulmonary and intestinal dysfunction]. 769 Jan 6

To examine the roles of thromboxane A2 and prostaglandin I2, which are arachidonic acid metabolites found in patients with sepsis, we measured the serum levels of their respective stable metabolites, thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) in 22 patients with sepsis. Results were analyzed in relation to patients' survival. The levels of both TXB2 and 6-keto-PGF1 alpha were significantly higher in patients who died than in those who survived, thus reflecting the severity of the patients' illness. There was a significant correlation between the levels of TXB2 and 6-keto-PGF1 alpha. These findings suggest that TXA2 and PGI2 are chemical mediators involved in the severity of clinical sepsis.
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PMID:Relationship between thromboxane B2 and 6-keto-prostaglandin F1 alpha in sepsis. 800 79

Early-onset neonatal group B beta-hemolytic streptococcus (GBS) infection exhibits pathophysiologic characteristics of a toxic shock syndrome, in which a cascade of inflammatory mediators are involved. Thromboxane A2 (TXA2) is thought to play an important role as a mediator of the pulmonary response to GBS toxin, because high lung lymph concentrations of a TXA2 metabolite have been observed after GBS toxin injections in sheep. The aim of this study was to evaluate the effects of a selective antagonist of the TXA2-prostaglandin endoperoxide receptor (SQ 29,548). Six unanesthetized young lambs, each serving as its own control, were given SQ 29,548 or vehicle control followed by GBS toxin challenge. Hemodynamic and lung function (lung mechanics, lung volume, ventilation) responses were followed for 5 h. When compared with the control studies, treatment with SQ 29,548 significantly altered the response to GBS toxin. SQ 29,548 reduced the increase in pulmonary and systemic vascular resistance, improved cardiac output and stroke volume, improved dynamic lung compliance but not airway resistance, and improved oxygenation. The attenuating effect of SQ 29,548 was most pronounced during the first phase of toxin response (15-90 min after toxin infusion), but significant treatment effects were also seen during the second phase (120-300 min after toxin infusion). This study demonstrates that TXA2 is an important mediator of the response to GBS toxin and is responsible for hemodynamic and lung function changes. Thromboxane receptor blockade may offer a potential therapeutic approach to infants with severe early-onset GBS sepsis.
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PMID:Thromboxane receptor blockade (SQ 29,548) in group B streptococcal toxin challenge in young lambs. 806 40


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