Changes in platelet aggregation, TXB2 and 6-keto-PGF1 alpha in surgical shock

Platelet aggregation rate (PAR), plasma concentration of TXB2 and 6-Keto-PGF1 alpha were measured in 26 patients with shock (hypovolumic shock 10 and septic shock 16) and 10 controls. PAR, plasma TXB2 and 6-Keto-PGF1 alpha were increased during shock, with TXB2 increased more significantly than 6-Keto-PGF1 alpha, accordingly the TXB2/6-Keto-PGF1 alpha ratio were raised during shock, especially in the septic cases. PAR, plasma TXB2 and 6-Keto-PGF1 alpha will decrease while shock become subsiding, and elevate while shock become irreversible. As a rule, the change of PAR is parallel with the concentration of plasma TXB2. The speed of platelet aggregation and plasma TXB2 concentration were higher in eleven mortal cases.     

6-keto-PGF1 alpha levels and prostacyclin therapy in 2 adult patients with hemolytic-uremic syndrome

Evidence supports the hypothesis that plasma prostacyclin activity is deficient in hemolytic-uremic syndrome (HUS). We studied 2 adult patients with HUS. Plasma levels of 6-keto-PGF1 alpha, the stable metabolite of prostacyclin, were measured by radioimmunoassay. Both patients were found to have elevated 6-keto-PGF1 alpha levels. These findings are in contradiction with the prostacyclin deficiency hypothesis and with earlier reports of low or undetectable plasma levels of this metabolite. The patients were treated with IV prostacyclin after a single plasma exchange. The first patient, admitted with advanced renal failure, obtained a rapid remission but renal function did not recover; the second patient, admitted with a less pronounced degree of renal failure, reacted slowly to therapy but renal function partially recovered. We believe that, if any benefit is to be expected from prostacyclin therapy in HUS, it should be started early in the course of the disease.     

Influence of pressure, flow rate, and pulsatility on release of 6-keto-PGF1 alpha and thromboxane B2 in ex vivo-perfused canine veins

The influence of pressure, flow, and pulsatility on the release of prostacyclin (measured as 6-keto-PGF1 alpha) and thromboxane (measured as TxB2) was assessed in canine jugular veins perfused ex vivo with Hanks' balanced salt solution for five consecutive 15-minute periods. Control segments were perfused at 7 mm Hg with nonpulsatile flow at a rate of 90 ml/min, whereas experimental segments were perfused with pulsatile flow as well as nonpulsatile flow at pressures of 50 or 100 mm Hg and flow rates of 60 or 130 ml/min. Prostacyclin release from control segments during the first 15-minute period was 49.5 +/- 7.4 pg/mm2/15 min, which declined to 13.9 +/- 2.5 pg/mm2/15 min after 60 minutes (p less than 0.002). Arachidonic acid stimulation during the last 15-minute perfusion period increased the release to 56.1 +/- 9.4 pg/mm2/15 min (p less than 0.002). Thromboxane release from control segments was initially 4.4 +/- 1.2 pg/mm2/15 min, which declined to 0.8 +/- 0.2 pg/mm2/15 min after 60 minutes (p less than 0.002), and subsequently increased with arachidonic acid stimulation to 1.3 +/- 0.1 pg/mm2/15 min (p less than 0.01). In contrast to control perfusion conditions, changes in nonpulsatile flow rates did not affect prostacyclin release, whereas thromboxane release was lower when perfused at 60 ml/min. Pressures of 50 and 100 mm Hg increased the initial release of prostacyclin. Similarly, pulsatile flow enhanced prostacyclin release at both low and high pressures, being more pronounced with the latter.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma level and effects of thromboxane A2 and 6-keto-PGF1 alpha in patients with acute obstructive suppurative cholangitis

The changes of the plasma thromboxane B2 (TXB2) and 6-keto-PGF1 alpha, the stable metabolites of TXA2 and PGI2, respectively and their effects on platelet counts, platelet aggregation and hypotension were studied in patients with AOSC. The results showed that the plasma TXB2, 6-keto-PGF1 alpha and 6-keto-PGF1 alpha/TXB2 ratios in these patients were markedly increased, however, the platelet counts markedly decreased and platelet aggregation inhibited significantly. After operation, they recovered to normal gradually. There were negative correlation between TXB2 with platelet count and 6-keto-PGF1 alpha with platelet aggregation, as well as both TXB2 and 6-keto-PGF1 alpha with blood pressure. TXA2 was an important factor which lead to platelet decrement and take part in the pathological course of disseminated intravascular coagulation (DIC) and multiple organ failure (MOF), but PGI2 might play an important role in improving microcirculation and preventing DIC and MOF through the inhibition of platelet aggregation.     

Changes in arterial thromboxane B2 and 6-keto-prostaglandin-F1 alpha levels in cirrhotic and non-cirrhotic patients after hepatectomy

Following hepatectomy, arterial concentrations of thromboxane B2(TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), which are stable metabolites of thromboxane A2(TXA2) and prostaglandin I2(PGI2), were measured by radioimmunoassay in 17 cirrhotic and 9 non-cirrhotic patients to assess the role of TXB2 and PGI2 in patients with liver dysfunction during hepatectomy. In both cirrhotic and non-cirrhotic patients, arterial TXB2 and 6-keto-PGF1 alpha levels significantly increased during hepatectomy and decreased to preoperative levels at the 1st postoperative day (1-POD). The TXB2/6-keto-PGF1 alpha ratio significantly decreased during hepatectomy and at 1-POD. There were no significant differences in changes of TXB2 and PGI2 levels between cirrhotic and non-cirrhotic patients. In cirrhotic patients with poor hepatic reserve, whose ICG K values were less than 0.08, arterial 6-keto-PGF1 alpha levels were significantly higher and the ratio were significantly lower than in cirrhotic patients with good hepatic reserve and non-cirrhotic patients before and after operation. Based on these results, it is concluded that the TXA2/PGI2 ratio becomes low after hepatectomy and the ratio is lower in cirrhotic patients with poor hepatic reserve.     

Effect of dietary fish oil on plasma thromboxane B2 and 6-keto-prostaglandin F1 alpha levels in septic rats

Increased mortality from sepsis is associated with high levels of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (PGF1 alpha). Linoleic acid, an n-6 essential fatty acid, is the usual precursor of TXB2 and PGF1 alpha, while fish oil is rich in n-3 essential fatty acid, the precursor of less active moieties. Rats were fed chow, an essential fatty acid-deficient diet, or an essential fatty acid-deficient diet supplemented with linoleic acid or fish oil for 2 weeks. The animals then underwent a sham operation or cecal ligation and puncture to induce sepsis. Six hours later, blood was obtained for analysis. The chow and linoleic acid diets produced significant (twofold to fivefold) increases in levels of both TXB2 and PGF1 alpha after sepsis. The essential fatty acid-deficient diet and fish oil diet protected against increases in levels of TXB2 or PGF1 alpha during sepsis. Dietary restriction of linoleic acid or fish oil supplementation may play an important role in altering the inflammatory mediator response to sepsis.     

Increased plasma PGE2, 6-keto-PGF1 alpha, and 12-HETE levels following experimental concussive brain injury

Previous investigations have shown that brain prostaglandin levels are transiently elevated following experimental fluid percussion brain injury. Associated with these increased prostaglandin levels there is free radical production and abnormalities in cerebral arteriolar function. The purpose of this study was to determine whether experimental fluid percussion brain injury in cats is associated with increased systemic levels of prostaglandins and the lipoxygenase product, 12-HETE. Blood samples were collected before and at various periods of time after 2.7 atm of fluid percussion brain injury was produced in adult cats. Prostaglandin and 12-HETE analysis was performed by radioimmunoassay after extraction of the plasma samples. The control levels for 6-keto-PGF1 alpha, PGE2, and 12-HETE were 477 +/- 42, 2,372 +/- 431, and 13,328 +/- 1,769 pg/ml, respectively. Following injury all three eicosanoids reached peak plasma levels by 1-5 min after injury. The percentile increases for all eicosanoids were similar and increased from 70 to 110%. The increases were sustained at up to 30 min postinjury and by 1 h after injury were at control levels. As in previous studies, hypertension following injury was maximal by 1 min postinjury and blood pressure had returned to near normal levels by 5 min postinjury. These studies demonstrate prolonged systemic increases in eicosanoids following injury. Since free radical production and vascular damage occur concomitantly with eicosanoid production, the prolonged increases in these products suggest that there is an attainable therapeutic window following injury during which administration of free radical scavengers may decrease radical damage and reduce the consequences of injury.     

Experimental traumatic brain injury elevates brain prostaglandin E2 and thromboxane B2 levels in rats

Prostaglandin E2 (PGE2) and thromboxane B2 (TxB2) levels were measured in rats following experimental traumatic brain injury. Rats (n = 36) were prepared for fluid percussion brain injury under pentobarbital anesthesia. Twenty-four hours later, rats were lightly anesthetized using methoxyflurane, injured (2.3 atm), and killed 5 or 15 min later. Twelve of the rats died before and are not included in the analyses. The following groups were used for data analysis: group I (n = 6) were sham-injured rats prepared for injury but not injured: group II (n = 6) were injured and killed 5 min later; group III (n = 12) were injured and killed 15 min posttrauma. Thirty seconds prior to sacrifice by decapitation into liquid nitrogen, all rats were injected with indomethacin (3 mg/kg, intravenously [IV]) to prevent postmortem PG synthesis. After sacrifice, brains were removed, weighed, and homogenized in a small quantity of phosphate buffer with indomethacin (50 micrograms/ml). PGE2 and TxB2 levels were determined using double-label radioimmunoassays. Posttraumatic convulsions were observed in 5 of 12 rats in group III and these rats were analyzed separately. PGE2 and TxB2 levels increased significantly (p less than 0.05) in both hemisphere and brainstem 5 min posttrauma. Fifteen minutes after injury, both PGE2 and TxB2 levels remained elevated but the levels were lower than at 5 min in the rats that did not exhibit posttraumatic seizures. This decrease in PG levels at 15 min was not observed in the rats that had seizures after injury and both PGE2 and TxB2 levels remained high in hemispheres and brainstem. Thus, fluid percussion brain injury results in substantial elevations in PGE2 and TxB2 levels and posttraumatic seizures exacerbate the observed increases.     

活血化瘀中药对激素性股骨头坏死血浆TXB2与6-keto-PGF1α影响的实验研究

目的：探讨活血化瘀法在激素性股骨头坏死的治疗作用。方法：用内毒素加激素注射造成兔股骨头坏死，测定其血浆TXB2和6-keto-PGF1α的动态变化，以此作为血瘀证的观察指标。结果：光镜观察示模型组股骨头骨小梁变细、空骨陷窝增加，成骨细胞数量减少，并出现TXB2与6-keto-PGF1α比值失平衡，这些表现随着时间的推移逐渐加重；而用复方生脉成骨胶囊治疗能逆转股骨头坏死，保护血管内皮，恢复TXB2与6-keto-PGF1α的平衡。结论：激素性股骨头坏死与血瘀证之间有密切关系，用活血化瘀中药可防止股骨头坏死的发展。     

Renal hemodynamics and urinary excretion of 6-keto-prostaglandin F1 alpha and thromboxane B2 in newly diagnosed type I diabetic patients

We have studied the functional importance of renal eicosanoids in renal hemodynamics of seven newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients by treatment with two structurally unrelated inhibitors of cyclooxygenase (i.e., piroxicam and sulindac). Glomerular filtration rate (GFR), renal plasma flow (RPF), daily urinary excretion of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha, the stable hydrolysis product of prostacyclin), and thromboxane B2 (TXB2, the stable hydrolysis product of thromboxane A2) were measured before, during, and after piroxicam (all patients) or sulindac (3 patients) treatment. Urinary excretion of 6-keto-PGF1 alpha was significantly increased (P less than .01) in diabetic patients compared with seven healthy subjects, whereas urinary excretion of TXB2 was unchanged. The baseline value of GFR was significantly (P less than .01) higher in diabetic compared with normal volunteers, whereas baseline RPF was comparable in both groups. Piroxicam (20 mg/day) reduced urinary excretion of 6-keto-PGF1 alpha and TXB2 by 65.7 +/- 26 and 64.6 +/- 33%, respectively. These biochemical changes were temporally associated with the approximately 19% decrease in GFR (P less than .01). A week after discontinuation of the drug, GFR and urinary excretion of 6-keto-PGF1 alpha were still significantly (P less than .05) reduced, whereas urinary excretion of TXB2 returned to control values. In contrast, urinary excretion of eicosanoids and renal function were not affected by sulindac (0.4 g/day) treatment. No functional changes were detected in healthy subjects despite a similar suppression of renal cyclooxygenase activity when they were treated with piroxicam.(ABSTRACT TRUNCATED AT 250 WORDS)     

Aprotinin decreases release of 6-keto-prostaglandin F1 alpha and increases release of thromboxane B2 in cultured human umbilical vein endothelial cells.

Use of the proteinase inhibitor aprotinin significantly improves hemostasis and reduces bleeding after operations in which extracorporeal circulation is used. The mechanism of action, however, has been only partially clarified. In this work we investigated whether aprotinin influenced the production and release of the eicosanoids prostacyclin, measured as the stable metabolite 6-keto-prostaglandin F1 alpha, and thromboxane A2, measured as the stable metabolite thromboxane B2, from endothelial cells. Human umbilical vein endothelial cells were incubated with different concentrations of aprotinin (5.5, 20, 55, and 100 mumol/L). The levels of 6-keto-prostaglandin F1 alpha and thromboxane B2 were measured at baseline and after thrombin stimulation. A concentration-dependent effect of aprotinin on 6-keto-prostaglandin F1 alpha synthesis was demonstrated. After incubation with 100 mumol/L of aprotinin, a 90% reduction in 6-keto-prostaglandin F1 alpha production was seen (31.69 versus 307.44 picograms per million cells; p less than 0.001). Conversely, thromboxane B2 production showed a 345% increase after incubation with aprotinin (287.80 versus 83.82 picograms per million cells; p less than 0.0001). Since 6-keto-prostaglandin F1 alpha inhibits and thromboxane B2 strongly enhances platelet aggregation, it appears that one mechanism of the clinically observed effectiveness of aprotinin lies in the altered ratio of 6-keto-prostaglandin F1 alpha: thromboxane B2 in endothelial cells, which leads to enhanced platelet aggregation and improved vessel sealing.     

Effect of experimental cardiopulmonary bypass on systemic and transcardiac thromboxane B2 levels

Systemic and cardiac metabolism of thromboxane was studied in a canine model (n = 13) of standard cardiopulmonary bypass and surgical cardioplegia. Sterile techniques were applied and no donor blood was used. Systemic samples (thoracic aorta) and transcardiac gradients (coronary sinus - aortic root) were obtained (1) 5 minutes after cannulation, (2) 20 minutes after the onset of partial bypass, (3) 5 seconds after the first administration of cardioplegic solution (CP-1), and (4) 5 seconds after the second administration of cardioplegic solution (CP-2). Cardioplegic doses were administered 30 minutes apart and consisted of 500 ml of hypothermic (8 degrees C), hyperkalemic (25 mEq potassium chloride) solution infused into the aortic root at 60 to 70 mm Hg. Thromboxane B2 was determined by a double-antibody radioimmunoassay (picograms per milliliter +/- standard error of the mean). Onset of partial bypass was followed by a significant rise in systemic arterial thromboxane B2 levels: after cannulation, 115 +/- 21 pg/ml; after the onset of partial bypass, 596 +/- 141 pg/ml; p less than 0.01). Significant transcardiac thromboxane B2 gradients were found during the first and second cardioplegic washouts (CP-1: aortic root 73 +/- 12 pg/ml, coronary sinus 306 +/- 86 pg/ml, p less than 0.01; CP-2: aortic root 65 +/- 11 pg/ml, coronary sinus 355 +/- 98 pg/ml, p less than 0.01). Transcardiac gradients of 6-keto-prostaglandin F1 alpha and thromboxane B2 were obtained at CP-1 and CP-2. Gradients of 6-keto-prostaglandin F1 alpha were not different from thromboxane B2 gradients during CP-1 but were significantly higher than thromboxane B2 gradients during CP-2. In a subgroup of five dogs, transcardiac thromboxane B2, lactate, and platelet gradients were measured simultaneously. Cardiac thromboxane B2 generation was found only in the presence of cardiac lactate production. Transcardiac platelet gradients were significantly higher at CP-1 (13,900 +/- 3,000/mm3) than at CP-2 (4,000 +/- 1,230/mm3) (p less than 0.05), whereas thromboxane B2 gradients were similar at CP-1 and CP-2. Our study demonstrates that thromboxane B2 is released into the coronary circulation during surgical cardioplegic arrest with anaerobiosis.     

A study on the effects of cyclo-oxygenase and thromboxane synthetase inhibitors on right atrial prostacyclin and thromboxane A2 levels

The right atrial tissues obtained at the time of coronary bypass surgery were studied for release of prostacyclin and thromboxane. Human, right atrial tissues are capable of producing thromboxane A₂ (TXA₂) in addition to prostacyclin. Indomethacin and Aspirin by inhibiting generation of cyclic endoperoxides inhibited synthesis of both prostacyclin and TXA₂ In contrast a thromboxane synthethase inhibitor U63557A selectively inhibited TXA₂ without significant effects on prostacyclin synthesis. The study points to the superiority of thromboxane synthetase inhibitor U63557A over Aspirin or Indomethacin and represents an important approach to platelet inhibition by selectively inhibiting thromboxane synthesis without affecting the synthesis of prostacycline.     

健康成年人性活动后血栓素B2和6-酮-前列腺素F1α的变化

目的观察健康成年人性活动后血栓素B(2TXB2)和6-酮-前列腺素F1α(6-K-PGF1α)水平的变化。方法受试者为35例健康成年人,分男女2组,男性组18例,女性组17例。受试者在惯常的条件下进行性活动,采集其性活动前基线状态及性活动高潮期后10min内、30min、60min的肘静脉血,以放免法检测血浆TXB2和6-K-PGF1α水平,计算TXB2/6-K-PGF1α值,性活动后TXB2、6-K-PGF1α及TXB2/6-K-PGF1α梯度变化与性别组间对比采用重复测量数据的方差分析。结果男性组和女性组性活动后各时段血浆TXB2水平和6-K-PGF1α水平与基线状态比较均无显著性变化;男女性别组间各时段血浆TXB2水平和6-K-PGF1α水平也无显著性差异。男性组性活动后各时段血浆TXB2/6-K-PGF1α值与基线状态比较均无显著性变化,女性组只在性高潮后30minTXB2/6-K-PGF1α值较基线状态显著性下降(4.832.1vs07.303.)3;1女性组在性高潮后60minTXB2/6-K-PGF1α值显著低于男性组(5.362.3v4s7.804.)1,8其余三个时段男女性别组间无显著性变化。结论健康成年人性活动后血浆TXB2和6-K-PGF1α水平的梯度变化均不明显。     

1,6—二磷酸果糖对犬内毒素休克血流动力学的影响

１２只犬随机分为两组：内毒素休克组（ＥＴ），内毒素休克治疗组（ＦＤＰ组）。麻醉后机械通气，分别插入动脉导管及 Ｓｗａｎ－Ｇａｎｚ漂浮导管并联接于 ＢＳＭ－８３０１Ｊ／Ｋ生理记录仪。外周静脉注射灭活大肠杆菌（２．７×１０１２／ｋｇ）。３０、９０分钟后ＦＤＰ经外周静脉输入３７５ｍｇ／ｋｇ。ＥＴ组输入等容量平衡盐液。注射ＥＴ前、后１至８小时测血流动力学及心功能指标。结果。注射ＥＴ前两组各项指标间无明显差异，注射后ＣＩ、ＭＡＰ、ＰＡＭＰ、ＰＣＷＰ、ＳＶＩ、ＬＳＷＩ明显低于注射前，且ＥＴ组呈进行性下降，而ＦＤＰ组则逐渐回升至正常水平。８小时死亡率ＦＤＰ组明显低于ＥＴ组。这说明ＦＤＰ通过改善心功能、恢复血流动力学对ＥＴ休克有较好疗效，能显著延长ＥＴ休克犬存活时间。