低氧,山莨菪碱对肺内小动脉平滑肌细胞产生血栓素A2和前列环素的影响

本工作观察了急性重度低氧及山莨菪碱（anisodamine,Am）对分离培养家兔肺内小动脉平滑肌细胞（PASMCS）培养液中TXB2和6-酮-PGF1a含量及它们的比值的影响。结果是：重度低氧明显增加PASMCS培养液中TXB2和6-酮-PGF1a含量及它们的比值。常氧和低氧条件下,终浓度为2.5×10－5×mol／L的山莨菪碱显著降低TXB2的含量,但6-酮-PGF1a的含量无变化。这提示：急性重度低氧可能通过增加PASMCS产生和释放TXA2和PGI2及它们的比值而致肺血管收缩,山莨菪碱可能通过抑制PASMCs产生ThA2和降低ThB2与PGI2的比值逆转低氧所致的肺血管收缩效应。     

埃他卡林对压力超负荷大鼠心室重构和血浆中PGI2的影响

目的：观察埃他卡林（IPT）对压力超负荷大鼠心室重构的影响,探讨其保护作用与血浆中前列环素（PGI2）的关系。方法：SD大鼠经腹主动脉缩窄6周后诱导压力超负荷高血压模型,随机分为5组（n=9）：①假手术组;②模型组;③IPT 3mg／kg组（IPT 3）;④吲哚美辛2mg/kg（Indo2）组;⑤IPT 3mg／kg＋吲哚美辛2mg／kg（IPT 3＋Indo2）组。RM-6000八导生理记录仪记录血流动力学改变,称量计算心脏重量指数,HE染色和iassort’s染色观察心肌组织病理学改变,比色法检测心肌组织羟脯氨酸含量,放免法检测血浆中PGI2含量。结果：腹主动脉缩窄6周后,与假手术组相比,模型组大鼠出现了明显的高血流动力学状态和心室重构,血浆中PGI2含量也明显降低。而IPT 3mg／kg实验治疗6周可明显改善上述变化。单用吲哚美辛可进一步恶化大鼠的高血流动力学状态和心室重构,合用肼可明显改善高血流动力学状态和心肌纤维化,明显抑制血浆中PGI2含量的降低。结论：IPT可明显逆转腹主动脉缩窄／压力超负荷大鼠的心室重构,其机制可能与胛作用于内皮细胞上的KATP通道,恢复内皮细胞的分泌功能增加PGI2的合成和分泌密切相关。     

低氧对培养的不同内径的肺动脉平滑肌细胞增殖的影响

目的和方法：分离培养三种不同内径的肺动脉平滑肌细胞（PASMCs）,用^3H－TdR掺入速率和细胞计数作为细胞增殖的指标,观察低氧对其增殖作用的影响。结果：低氧对三种不同内径的PASMCs（内径分别为＞1000μm、500－800μm、300-400μm）增殖促进作用显著不同,其^3H－TdR掺入速率和细胞计数分别增加23.5％和11.1％、60.0％和33.8％、141.4％和52.0％,选择对低氧最敏感的PASMCs（内径为300－400μm）,进一步探讨低氧促PASMCs增殖作用的细胞机制：钙拮抗剂verapail、蛋白激酶C抑制剂staurosporine(Stau)和细胞Na-H交换抑制剂amiloride可显著降低低氧情况下PASMCs^3H－TdR掺入速率和细胞计数。结论：低氧对三种不同内径的PASMCs增殖促进作用显著不同; Ca^2 、蛋白激酶C和Na^2 －H^ 交换的激活,可能是低氧促PASMCs增殖的重要胞内信息转导机制。     

RNA干扰沉默低氧诱导因子-1α对低氧下大鼠肺动脉平滑肌细胞增殖的影响

本研究应用基因克隆技术,将合成的发卡样特异性低氧诱导因子-1α（hypoxia inducible factor-1alpha,HIF-1α）干扰寡核苷酸（siRNA）序列插入真核表达载体中,构建出特异性HIF-1α基因RNA干扰（RNAi）真核表达载体。采用组织块种植法,原代培养大鼠肺动脉平滑肌细胞（pulmonary artery smooth muscle cells,PASMCs）,将构建出的特异性HIF-1αRNAi真核表达载体转染到PASMCs;分别在常氧和低氧下进行细胞培养,采用RT-PCR检测PASMCsHIF-1αmRNA表达水平,用MTT和流式细胞仪检测细胞增殖水平,探讨低氧条件下HIF-1αRNAi真核表达载体对PASMCs增殖的影响。结果表明,低氧培养48h后,正常PASMCs和转染了HIF-1αsiRNA阴性表达载体的细胞增殖显著,HIF-1αmRNA表达水平也显著升高;而转染了HIF-1αsiRNA阳性表达质粒的细胞增殖不显著,HIF-1αmRNA表达水平较低。结果提示：HIF-1αRNAi真核表达载体能显著干扰培养的PASMCsHIF-1αmRNA表达,同时抑制低氧环境下PASMCs的增殖。     

白藜芦醇通过调控HIF-1α/NOX4/ROS通路抑制低氧诱导的大鼠肺动脉平滑肌细胞氧化应激与增殖

本文旨在明确白藜芦醇对低氧诱导的肺动脉平滑肌细胞(pulmonary artery smooth muscle cells, PASMCs)氧化应激与增殖的作用及分子机制。体外分离培养原代大鼠PASMCs,采用不同浓度的白藜芦醇(10、20和40μmol/L)或NADPH氧化酶(NADPH oxidases, NOXs)抑制剂VAS2870 (10μmol/L)预处理0.5 h,然后将细胞置于常氧(21%O_2, 5%CO_2)或低氧(2%O_2, 5%CO_2)中培养24h。采用CCK-8法和增殖细胞核抗原(proliferatingcellnuclearantigen,PCNA)的表达水平检测细胞增殖,用DCFH-DA测定细胞内活性氧(reactive oxygen species, ROS)的生成,用real-time RT-PCR和Western blot检测NOX1、NOX4和低氧诱导因子-1α(hypoxia inducible factor 1α, HIF-1α)的表达水平,通过小干扰RNAs (small interference RNAs, siRNAs)特异性沉默Hif-1α和Nox4后确定相关信号通路。结果显示,白藜芦醇和VAS2870均能显著抑制低氧诱导的大鼠PASMCs细胞增殖和ROS生成,同时白藜芦醇还能有效阻止低氧诱导的HIF-1α蛋白的聚集和NOX4的表达上调,而对NOX1没有明显的影响。沉默Hif-1α或Nox4后,低氧诱导的大鼠PASMCs细胞增殖和ROS累积均显著降低,且能被白藜芦醇进一步抑制。上述结果提示,白藜芦醇可能通过阻断HIF-1α/NOX4/ROS信号通路抑制低氧诱导的大鼠PASMCs氧化应激和增殖。     

塞来昔布对慢性低O_2高CO_2大鼠肺动脉高压的影响及其机制研究

目的：探讨塞来昔布对慢性低O2高CO2大鼠肺动脉高压的作用。方法：将SD大鼠分为正常对照组,慢性低O2高CO2组,慢性低O2高CO2＋塞来昔布组。用电镜、放免等方法,观察各组大鼠肺动脉平均压、颈动脉平均压、肺细小动脉显微结构、血浆和肺匀浆血栓素B2（TXB2）及6-酮-前列腺素F1α（6-keto-PGF1α）含量的变化。结果：①慢性低O2高CO2组平均肺动脉压（mPAP）比正常组显著升高,塞来昔布组的mPAP比慢性低O2高CO2组显著升高,3组间平均颈动脉压（mCAP）比较差异无显著性。②慢性低O2高CO2组与正常对照组相比血浆和肺匀浆TXB2浓度、TXB2/6-keto-PGF1α比值显著增高,6-keto-PGF1α浓度显著下降;塞来昔布组与慢性低O2高CO2组相比血浆和肺匀浆TXB2浓度无明显变化、TXB2/6-keto-PGF1α显著升高,6-keto-PGF1α显著下降。③光镜下慢性低O2高CO2组与正常组相比,肺细小动脉管壁面积/管总面积（WA/TA）和肺细小动脉中膜厚度（PAMT）均显著增高。塞来昔布组与慢性低O2高CO2组相比WA/TA和PAMT显著增高。④电镜下慢性低O2高CO2组大鼠肺细小动脉内皮细胞吞饮小泡增多,血管壁增厚,中膜平滑肌细胞增生,纤维细胞增多,肺泡II型上皮细胞微绒毛脱落;塞来昔布组中膜平滑肌细胞增大、增多,胞浆肌丝丰富,平滑肌细胞间隙增宽,肺泡隔胶原纤维增生明显。结论：塞来昔布可能有加重慢性低O2高CO2性肺动脉高压和肺血管结构重建倾向,过度抑制COX-2,使TXA2/PGI2比值升高可能是其作用机制之一。     

低氧促进大鼠肺动脉平滑肌细胞Periostin表达及其信号转导机制

观察低氧对大鼠肺动脉平滑肌细胞（pulmonary artery smooth muscle cells,PASMCs）Periostin表达的影响及其相关信号转导机制。胶原酶I法原代培养PASMCs,经低氧（5％O2）分别处理PASMCs2,6,12,24h后,RT-PCR和Western blot法检测Periostin mRNA和蛋白表达。加入PI3K/Akt通路特异性抑制剂LY294002（10μmol／L）进行干预,Western blot分析比较不同条件下低氧处理24h后大鼠PASMCs中Periostin和Akt／P-Akt的蛋白表达。结果表日月,与常氧组比较,低氧处理6h组、12h组和24h纽Periostin mRNA和蛋白的表达均显著上升（P〈0．05,P〈0．01）,低氧处理后的PASMCs中Periostin mRNA和蛋白的表达逐渐升高：低氧处理2h组无显著差异（P〉0．05）。用LY294002对PASMCs处理,并低氧24h后,Periostin的表达被显著抑制（P〈0．01）,细胞P-Akt的表达下调（P〈0．05）,总Akt的蛋白表达没有明显差异（P〉0．05）。推测低氧可诱导大鼠PASMCs中Periostin mRNA和蛋白的表达上调。低氧可能通过激活P13K/Akt通路促进Akt的磷酸化,进而使Periostin在PASMCs中过表达,提示Periostin在低氧性PASMCs增殖过程中可能起着重要作用。     

15-KETE对慢性缺氧大鼠肺动脉平滑肌细胞钾离子通道的作用

目的观察15-酮基二十碳四烯酸（15-ketoeicosatetraenoic acid,15-KETE）对缺氧大鼠肺动脉平滑肌细胞（pulmonary arterial smooth cells,PASMCs）膜电压门控钾离子通道的活性的影响。方法将12只雄性SD大鼠随机分成对照组和缺氧组,每组6只。采用急性酶分离法（胶原酶Ⅰ型和弹性酶）获得SD大鼠单个PASMCs,应用全细胞膜片钳记录方法,研究15-KETE对两组大鼠膜电位（Em）、膜电容（Cm）、电压门控钾电流（IKv）的影响。结果 （1）慢性缺氧使大鼠PASMCs的Em显著去极化（P〈0.05,n=6）,明显地抑制了大鼠PASMCs的IKv（P〈0.01,n=6）,对大鼠PASMCs的Cm无影响;（2）较高浓度的15-KETE（1×10^-7 mol/L、1×10^-6 mol/L）可使慢性缺氧大鼠PASMCs去极化;（3）15-KETE（1×10^-8 mol/L～1×10^-6 mol/L）可浓度依赖性地抑制慢性缺氧大鼠PASMCs的IKv;（4）较高浓度15-KETE（1×10^-7 mol/L、1×10^-6 mol/L）对缺氧PASMCs IKV的平均阻抑率显著高于常氧PASMCs。结论缺氧未改变15-KETE引大鼠PASMCs去极化及浓度依赖抑止IKv的特性,且缺氧可能改变了PASMCs对15-KETE的敏感性。     

NF- kB 对低氧大鼠肺动脉平滑肌细胞ET- 1 表达的影响

目的：探讨核因子kB（NF—kB）对低氧大鼠肺动脉平滑肌细胞（PAMSC）内皮素-1（endothelin—1,ET—1）表达的影响。方法：分离培养大鼠肺动脉平滑肌细胞,分别在常氧和低氧条件下培养48小时。ELISA检测培养上清中ET—1含量,RT—PCR检测ET-1 mRNA表达。在培养液中加入NF—kB抑制剂PDTC,检测PASMCs ET—1表达的变化。Western blotting检测PASMCs IkB表达变化。结果：低氧培养能够诱导PASMCs表达ET—1。NF—kB抑制剂能够减少由于低氧引起的ET—1释放,IkB在低氧情况下表达明显减少。结论：ET-1低氧情况下在PAMCS表达明显增加。可能参与低氧所引起的肺动脉的病理过程。低氧所引起的ET—1表达增加可能通过NF—kB信号通路。     

低氧条件下大鼠肺动脉平滑肌细胞中活性氧与低氧诱导因子-1α和细胞增殖的关系

在低氧条件下,观察大鼠肺动脉平滑肌细胞（pulmonary arterial smooth muscle cells,PASMCs）中活性氧（reactive oxygen species,ROS）的变化,探讨ROS的变化是否通过调控低氧诱导因子-4α（hypoxia-inducible factor 1α, HIF-1α）的表达影响PASMCs的增殖。采用组织块法原代培养大鼠PASMCs,分成3组：常氧组（21％O2,24h）,低氧组（5％O2,24h）,低氧＋Mn-TBAP组（5％O2,24h,Mn-TBAP是一种ROS清除剂）。用激光共聚焦显微镜荧光染色法检测细胞内ROS的变化;用RT-PCR和免疫组织化学方法分别测定HIF-1α mRNA和蛋白的表达;用MTT法检测细胞增殖程度。结果显示：（1）低氧组PASMCs内ROS水平明显高于常氧组（P〈0．05）,低氧＋Mn-TBAP组ROS水平明显低于低氧组（P〈0．05）,但仍高于常氧组（P〈0．05）;（2）低氧组及低氧＋Mn-TBAP组的HIF-1α mRNA和蛋白表达均高于常氧组（P〈0．05）,且低氧组表达高于低氧＋Mn-TBAP组（P〈0．05）;（3）低氧组细胞增殖明显高于常氧组和低氧＋Mn-TBAP组（P〈0．05）,低氧＋Mn-TBAP组细胞增殖高于常氧组（P〈0．05）。结果表明：在低氧条件下大鼠PASMCs中ROS水平明显升高,RROS的变化能够调节HIF-1α的表达,进而影响平滑肌细胞的增殖,提示ROS可能在肺动脉高压的发病机制和低氧信号转导中具有重要作用。     

Failure of acute hypoxia to alter pulmonary prostaglandin metabolism in dogs

We studied the effects of acute hypoxia (Fi02 = 0.09-0.11, 20 min.) on transpulmonary plasma prostaglandin (PG) concentrations in ten anesthetized, paralyzed, artificially ventilated dogs. Concentrations of 6-keto-PGF1 alpha, TxB2, PGE2, PGF2 alpha, and 13,14-dihydro-15-keto-PGF2 alpha were measured from the pulmonary artery and abdominal aorta using radioimmunoassay. In an additional six dogs, the effects of arachidonic acid (AA) infusions (100 mcg/kg/min) during normoxia and acute hypoxia were determined. Compared to normoxic conditions, acute hypoxia increased pulmonary artery pressure (p less than 0.05), decreased both the arterial oxygen tension (PaO2) and the alveolar-to-arterial oxygen tension gradient (A-aDO2) (p less than 0.05), but did not affect transpulmonary plasma PG concentrations. AA infusions significantly (p less than 0.05) increased 6-keto-PGF1 alpha independent of FiO2. Acute hypoxia failed to elicit a pulmonary pressor response in the AA-treated animals although PaO2 and A-aDO2 decreased (p less than 0.05). These data in healthy dogs suggest that (1) acute hypoxia does not alter net pulmonary PG metabolism, (2) prostacyclin synthesis is stimulated by increased plasma AA concentrations and (3) this effect may block normal pressor responses to hypoxic stimuli.     

Measurement of 6-keto-PGF1 alpha and thromboxane B2 levels in critically ill surgical patients

Systemic arterial and mixed venous plasma concentrations of 6-keto-PGF1 alpha and TxB2 were measured by radioimmunoassay in 63 critically ill patients with major trauma (n = 20) or sepsis (n = 43). Patients undergoing elective catheterization procedures served as controls (n = 10). Arterial and mixed venous 6-keto-PGF1 alpha and TxB2 levels were significantly elevated in patients with recent major trauma or active sepsis. The 6-keto-PGF1 alpha levels were found to be significantly elevated in the non-survivors and in patients with hepatic failure. The presence of severe pulmonary failure was not associated with increased levels of either 6-keto-PGF1 alpha or TxB2. Comparison of arterial and mixed plasma samples did not demonstrate increased pulmonary release of either compound. Increased eicosanoid production may account, in part, for the local vascular and humoral responses to tissue injury or infection.     

The effect of hypoxia on rat splanchnic prostanoid output

The effect of hypoxia on isolated perfused rat mesenteric basal venous prostanoid output was studied. Male rat splanchnic vasculature was removed without (SV) or with its end organ (SV + SI) and perfused with Krebs' buffer with a pO2 of 460 or 60 mm torr. Basal splanchnic venous effluent was assayed for 6-keto-PGF1 alpha, TxB2 and PGE by radioimmunoassay at 30, 60, 120 and 180 min of perfusion. Basal output of SV 6-keto-PGF1 alpha was five and ten fold higher than for PGE and TxB2 respectively and comprised 36% or greater of SV + SI 6-keto-PGF1 alpha output. SV PGE and TxB2 output comprised less than 19 and 12% respectively of SV + SI output. Hypoxia decreased SV + SI PG output, 6-keto-PGF1 alpha being most affected. Hypoxia did not alter SV 6-keto-PGF1 alpha output indicating the SI as the anatomic location most influenced by hypoxia. The relative amounts of distribution of PGE or TxB2 output were not altered by hypoxia. These data suggest that there are two distinct areas of splanchnic prostanoid output, the SV and the SI. Decreased 6-keto-PGF1 alpha output might alter splanchnic blood flow at two levels, the splanchnic vasculature, and/or within the bowel wall.     

Thromboxane A2 and prostacyclin do not modulate pulmonary hemodynamics during exercise in sheep

The purpose of this study was to determine the role of thromboxane and prostacyclin in modulating pulmonary hemodynamics during maximal cardiopulmonary stress in the healthy lung. We studied 11 yearling sheep in paired studies during progressive maximal treadmill exercise with and without meclofenamate (n = 5), ibuprofen (n = 6), or UK38485 (n = 2). We also studied five sheep during hypoxia and hypoxic exercise, and six sheep during prolonged steady-state treadmill exercise for 45-60 min with and without drug treatment. We measured the metabolites of thromboxane A2 (thromboxane B2, TxB2) and prostacyclin (6-ketoprostaglandin F1 alpha, 6-keto-PGF1 alpha) in blood plasma and lung lymph in each protocol. We found that progressive exercise significantly reduced pulmonary vascular resistance but that cyclooxygenase or thromboxane synthesis blockade did not alter the change. Plasma TxB2 rose minimally but significantly during maximal exercise, but 6-keto-PGF1 alpha did not change. During continuous hypoxia, exercise reduced pulmonary vascular resistance nearly to base-line levels, but the degree of reduction was also unchanged by drug treatment. There were also no significant changes in lymph or plasma TxB2 or 6-keto-PGF1 alpha during 45-60 min of continuous moderate exercise. We conclude that neither TxB2 nor prostacyclin modulate pulmonary hemodynamics in the normal lung during maximal exercise, prolonged moderate exercise, or exercise-induced reductions in vascular resistance during hypoxia.     

The carbochromene derivative AD6 reduces the TxB2/6-keto-PGF1 alpha ratio in cerebral cortex during hypoxia and recovery and leukotriene synthesis in brain tissue, in the rat

Pretreatments of rats with the Carbochromene derivative AD6 (4 mg/kg i.p., 2 h before sacrifice) resulted in elevation of brain levels of 6-keto-PGF1 alpha in cerebral cortex under physiological conditions, had no effect on levels of TxB2 and 6-Keto-PGF1 alpha at 30 min of hypoxia (respiration of 5% O2 in N2) and prevented the accumulation of TxB2 occurring in brain at 5 min of recovery after hypoxia. In addition, the accumulation of LTC4 and B4 in brain slices incubated in the presence of the Ca++ ionophore A23187 and arachidonic acid, was reduced in samples obtained from pretreated rats. The drug, thus, had favourable effects on the 6-keto-PGF1 alpha/TxB2 ratio in normal conditions, as well as in conditions of altered oxygen supply. In addition it reduced the formation of compounds, the leukotrienes, which may exert pro-inflammatory activities on the cerebral microcirculation.     

Failure of acute hypoxia to alter pulmonary prostaglandin metabolism in dogs

We studied the effects of acute hypoxia (Fi02=0.09–0.11, 20 min,.) on transpulmonary plasma prostaglandin (PG) concentrations in ten anaesthetized, paralyzed, artificially ventilated dogs. Concentrations of 6-keto-PGF1α, TxB2, PGE2, PGF2α, and 13, 13-dihydro-15-keto-PGF2α were measured from the pulmonary artery and abdominal aorta using radioimmunoassay. In an additional six dogs, the effects of arachidonic acid (AA) infusions (100 mg/kg/min) during normoxia and acute hypoxia were determined. Compared to normoxic conditions, acute hypoxia increased pulmonary artery pressure (p<0.0), decreased both the arterial oxygen tension (Pa02) and the alveolar-to-arterial oxygen tension gradient (A-aD02) (p <0.05), but did not affect transpulmonary plasma PG concentrations. AA infusions significantly (p <0.05) increased 6-keto-PGF1α independent of Fi02. Acute hypoxia failed to elicit a pulmonary pressor response in the AA-treated animals although Pa02 and A-aD02 decreased (p<0.5). These data in healthy dogs suggest that (1) acute hypoxia does not alter net pulmonary PG metabolism, (2) prostacyclin synthesis is stimulated by increased plasma AA concentrations and (3) this effect may block normal pressor responses to hypoxic stimuli.     

Prostaglandins and thromboxane outflow from the perfused mesenteric vascular bed in spontaneously hypertensive rats

To clarify the metabolism of PGE2, prostacyclin (PGI2) and thromboxane A2 (TxA2) in small vessels in spontaneously hypertensive rats (SHR), we removed superior mesenteric vascular beds from 10 week old SHR and age matched normotensive controls (WKY). The mesenteric artery was perfused with Krebs-Henseleit buffer and samples of effluent collected every 15 minutes during 3 hours perfusion for analysis of PGE2, 6-keto-PGF1 alpha (a stable metabolite of PGI2) and TxB2 (a stable metabolite of TxA2) by specific radioimmunoassays. Levels of all three arachidonic acid (AA) metabolites, PGE2, 6-keto-PGF1 alpha and TxB2, in the mesenteric effluent were significantly reduced in SHR as compared to WKY. TxB2 was detected in all samples throughout the perfusion. 6-keto-PGF1 alpha/PGE2 ratios and TxB2/PGE2 ratios were significantly increased in SHR. 6-keto-PGF1 alpha/TxB2 ratios in the first four samples were significantly decreased in SHR as compared to WKY. These data suggest that there may be reduced availability of PG precusor AA and unbalanced synthesis of PGs in small vessels in SHR. Both may have relevance to the development of hypertension in the animals.     

Eicosanoid balance and perfusion redistribution of oleic acid-induced acute lung injury.

We have proposed that endogenous prostacyclin opposes the vasoconstriction responsible for redistribution of regional pulmonary blood flow (rPBF) away from areas of increased regional lung water concentration (rLWC) in canine oleic acid- (OA) induced acute lung injury (D. P. Schuster and J. Haller. J. Appl. Physiol. 69: 353-361, 1990). To test this hypothesis, we related regional lung tissue concentrations of 6-ketoprostaglandin (PG) F1 alpha and thromboxane (Tx) B2 in tissue samples obtained 2.5 h after administration of OA (0.08 ml/kg iv) to rPBF and rLWC measured by positron emission tomography. After OA only (n = 16), rLWC increased in dependent lung regions. Some animals responded to increased rLWC by redistribution of rPBF away from the most edematous regions (OA-R, n = 6), whereas others did not (OA-NR, n = 10). In another six animals, meclofenamate was administered after OA (OA-meclo). After OA, tissue concentrations of 6-keto-PGF1 alpha were greater than TxB2 in all groups, but concentrations of 6-keto-PGF1 alpha were not different between OA-R and OA-NR animals. TxB2 was increased in the dependent regions of animals in both OA-R and OA-NR groups compared with controls (no OA, n = 4, P < 0.05). The tissue TxB2/6-keto-PGF1 alpha ratio was smaller in controls and OA-NR in which no perfusion redistribution occurred than in OA-R and OA-meclo in which it did occur. This TxB2/6-keto-PGF1 alpha ratio correlated significantly with the magnitude of perfusion redistribution.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma thromboxane B2 levels and thromboxane B2 production by platelets are increased in patients during spinal and epidural anesthesia

Concentrations of thromboxane (Tx) B2 in plasma and its production by platelets were measured in 20 spinal and 10 epidural anesthesia patients scheduled for small operations in the lower extremities. The main metabolite of prostacyclin, 6-keto-PGF1 alpha and prostaglandin (PG) E2 in plasma were also determined. Plasma TxB2 and TxB2 production by platelets increased during both spinal and epidural anesthesia. Plasma TxB2 levels also remained elevated 1 h after anesthesia. The plasma concentrations of 6-keto-PGF1 alpha and PGE2 did not change during spinal or epidural anesthesia. In in vitro studies, only low concentrations of lidocaine (0.5-1.0 micrograms/ml) and bupivacaine (0.5-3.0 micrograms/ml) increased platelet TxB2 production. In platelet rich plasma, neither lidocaine nor bupivacaine in concentrations of 0.5-3.0 micrograms/ml caused constant changes in ADP-induced platelet aggregation, but they inhibited it in toxic concentrations (12 micrograms/ml). The results suggest that the increased TxB2 plasma levels and platelet TxB2 production during regional anesthesia are not caused by local anesthetics itself but by other factors, e.g. tissue trauma. In clinically found concentrations, local anesthetics do not cause any constant changes in platelet aggregation.     

Effects of thromboxane synthase inhibition on air emboli lung injury in sheep

We tested the effects of OKY-046, a thromboxane synthase inhibitor, on lung injury induced by 2 h of pulmonary air infusion (1.23 ml/min) in the pulmonary artery of unanesthetized sheep with chronic lung lymph fistula so as to assess the role of thromboxane A2 (TxA2) in the lung injury. We measured pulmonary hemodynamic parameters and the lung fluid balance. The concentrations of thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) in plasma and lung lymph were determined by radioimmunoassay. Air infusion caused sustained pulmonary hypertension and an increase in pulmonary vascular permeability. The levels of TxB2 and 6-keto-PGF1 alpha in both plasma and lung lymph were significantly elevated during the air infusion. TxB2 concentration in plasma obtained from the left atrium was higher than that from the pulmonary artery at 15 min of air infusion. When sheep were pretreated with OKY-046 (10 mg/kg iv) prior to the air infusion, increases in TxB2 were prevented. The pulmonary arterial pressure, however, increased similarly to that of untreated sheep (1.8 X base line). The increase in lung lymph flow was significantly suppressed during the air infusion. Our data suggest that the pulmonary hypertension observed during air embolism is not caused by TxA2.