前列腺素E1对脑死亡大鼠供肝微循环的保护作用

背景:脑死亡供者维护对于改善脑死亡供者器官质量具有重要意义,前列腺素E1被广泛使用于临床肝移植领域,但有关前列腺素E1对脑死亡供者的作用未见报道.目的:通过建立稳定的大鼠渐进性脑死亡模型,观察前列腺素E1对脑死亡供肝微循环的保护作用.方法:SD大鼠按随机数字表法分为3组,脑死亡组及前列腺素E1组建立渐进性脑死亡大鼠模型,前列腺素E1组于脑死亡诱导后,经尾静脉微输液泵通道以0.05 Pg/(kg·min)速度持续性泵入前列腺素E1注射液.各组在脑死亡诱导后的2,4 h分别采血及获取肝脏标本.自动生化仪检测肝酶学指标天冬氨酸转氨酶、丙氨酸转氨酶活性,放射免疫分析法测定血清透明质酸质量浓度,日立H-600型透射电镜观察肝血窦超微结构变化.结果与结论:脑死亡诱导2 h后,大鼠肝功能出现不同程度异常:诱导脑死亡4 h后,脑死亡大鼠的肝功能损伤进一步加重,前列腺素E,组较脑死亡组有明显改善(P<0.05).脑死亡诱导2 h后,透明质酸质量浓度升高提示肝脏微循环障碍;诱导脑死亡4 h后,脑死亡组大鼠的透明质酸质量浓度进一步升高,前列腺素E1组较脑死亡组有明显改善(P<0.05).脑死亡后透射电镜显示肝细胞及肝窦内皮细胞的超微结构受损,Kupffer细胞活化,前列腺素E1可减轻大鼠肝脏超微结构的损伤并抑制Kulpffer细胞活化.提示前列腺素E1能改善脑死亡大鼠的肝功能及肝脏微循环,抑制肝脏Kufpper细胞的活化可能是其作用机制之一.     

Systemic administration of prostaglandin E1 produces hypothermic effects in unanesthetized rats.

The effects of intraperitoneal administration of prostaglandin E1 (PGE1) on thermoregulatory responses were assessed in unanesthetized rats at ambient temperatures (Ta) of 8, 22 and 29 degrees C. The body temperatures, metabolic rate, respiratory evaporative heat loss and vasomotor activity in response to PGE1 were observed. Intraperitoneal administration of PGE1 produced dose-dependent hypothermia at Ta's of both 8 and 22 degrees C. The PGE1 hypothermia was due to both the decreased metabolic rate and the cutaneous vasodilation. However, at a Ta of 29 degrees C, intraperitoneal administration of PGE1 produced no changes in rectal temperature, since the thermoregulatory responses were not affected by PGE1 application at this Ta. The data indicate that peripheral administration of PGE1 decreases metabolic heat production and increases heat loss, which leads to hypothermia in rats, in contrast to hyperthermia seen after central administration.     

Sympathoadrenomedullary system mediation of the prostaglandin E2-induced central inhibition of gastric acid output in rats

Mechanisms related to the gastric antisecretory action of i.c.v.-administered prostaglandins (PGs) were investigated in urethane-anesthetized rats with gastric fistula. The gastric acid output was enhanced by electrical stimulation of the left cervical vagus nerve after cutting the bilateral cervical vagus nerves. Intracerebroventricular administered PGE2 (0.05-0.5 microgram/animal) dose-dependently inhibited the vagally stimulated acid output whereas the same doses of PGE2 administered i.v. were without effect. The inhibitory effect of PGE2 (0.1 microgram/animal, i.c.v.) was more potent than the effects of the same doses of PGD2 and PGF2 alpha (PGE2 greater than PGD2 greater than PGF2 alpha). PGE2 (0.1 microgram/animal)-induced inhibition of the gastric acid output was abolished by splanchnicectomy, cutting the preganglionic splanchnic nerves under diaphragm, or by combined pretreatment with adrenalectomy and 6-hydroxydopamine (50 mg/kg i.v., 3 days before). This PGE2-induced inhibition was also abolished by pretreatment with phentolamine (5 mg/kg i.m.), but not by propranolol (5 mg/kg i.m.). These observations suggest that the i.c.v.-administered PGs, in particular PGE2, induces a central excitation of the sympathoadrenomedullary outflow and that the resultant activation of gastric alpha adrenoceptors inhibits the vagally stimulated gastric acid output.     

前列腺素E_1对脑死亡大鼠供肝微循环的保护作用

背景：脑死亡供者维护对于改善脑死亡供者器官质量具有重要意义,前列腺素E1被广泛使用于临床肝移植领域,但有关前列腺素E1对脑死亡供者的作用未见报道。目的：通过建立稳定的大鼠渐进性脑死亡模型,观察前列腺素E1对脑死亡供肝微循环的保护作用。方法：SD大鼠按随机数字表法分为3组,脑死亡组及前列腺素E1组建立渐进性脑死亡大鼠模型,前列腺素E1组于脑死亡诱导后,经尾静脉微输液泵通道以0.05μg/（kg·min）速度持续性泵入前列腺素E1注射液。各组在脑死亡诱导后的2,4h分别采血及获取肝脏标本。自动生化仪检测肝酶学指标天冬氨酸转氨酶、丙氨酸转氨酶活性,放射免疫分析法测定血清透明质酸质量浓度,日立H-600型透射电镜观察肝血窦超微结构变化。结果与结论：脑死亡诱导2h后,大鼠肝功能出现不同程度异常;诱导脑死亡4h后,脑死亡大鼠的肝功能损伤进一步加重,前列腺素E1组较脑死亡组有明显改善（P〈0.05）。脑死亡诱导2h后,透明质酸质量浓度升高提示肝脏微循环障碍;诱导脑死亡4h后,脑死亡组大鼠的透明质酸质量浓度进一步升高,前列腺素E1组较脑死亡组有明显改善（P〈0.05）。脑死亡后透射电镜显示肝细胞及肝窦内皮细胞的超微结构受损,Kupffer细胞活化,前列腺素E1可减轻大鼠肝脏超微结构的损伤并抑制Kupffer细胞活化。提示前列腺素E1能改善脑死亡大鼠的肝功能及肝脏微循环,抑制肝脏Kufpper细胞的活化可能是其作用机制之一。     

Spinal EP receptors mediating prostaglandin E2-induced mechanical hyperalgesia, thermal hyperalgesia, and touch-evoked allodynia in rats.

Intrathecal administration of prostaglandin E(2) (PGE(2)) produces mechanical hyperalgesia, thermal hyperalgesia, and touch-evoked allodynia in rats. Experiments were conducted to examine the effects of intrathecal administration of relatively selective PGE(2) receptor (EP receptor) agonists to establish which spinal EP receptors mediate these behavioral effects of spinally administered PGE(2). Administration of either sulprostone (EP(3) receptor agonist) or PGE(1) alcohol (EP(4) receptor agonist) produced marked mechanical and thermal hyperalgesia and touch-evoked allodynia. Neither 17-phenyl trinor PGE(2) (EP(1) receptor agonist) nor butaprost (EP(2) receptor agonist) produced any significant changes in behavioral response thresholds to mechanical or thermal stimuli. However, 17-phenyl trinor PGE(2) (EP(1) receptor agonist) did produce marked touch-evoked allodynia. These data suggest that in rats activation of spinal EP(3) and EP(4) receptors by PGE(2) is important for development of both mechanical and thermal hyperalgesia as well as for touch-evoked allodynia. PGE(2)-induced allodynia also appears to involve activation of spinal EP(1) receptors.     

前列腺素E1对急性胰腺炎血液流变性的影响

目的：探讨前列腺素E1对急性胰腺炎血液流变性的影响。方法：应用国产前列腺素E1——前列地尔结合传统治疗方法治疗急性胰腺炎36例，设立传统治疗组对照共36例，检测两组血液流变性指标的变化。结果：前列腺素E1组治疗前、后血液流变学指标比较，结果显示PGE4，组用药后除纤维蛋白原外，全血粘度、全血还原粘度、血浆粘度、红细胞压积、红细胞聚集指数均降低，用药前后差异有显著性(P＜0．05或P＜0．01)。与对照组治疗后比较，急性水肿性胰腺炎组全血粘度、全血还原粘度、血浆粘度、红细胞聚集指数的降低有显著差异(P＜0．05或P＜0．01)。结论：前列腺素E1能有效改善症状，降低血液粘度，改善微循环。     

Effects of intravenous and intraventricular prostaglandin E1 on thermoregulatory responses in rabbits

The thermal responses produced by both systemic and central administration of prostaglandin E1 (PGE1) at the three different ambient temperatures (Ta) of 2, 22 and 32 degrees C were measured to assess the possible involvement of PGE1 in temperature regulation. The body temperatures, metabolic rate, respiratory evaporative heat loss and vasomotor activity in response to PGE1 were measured. Intravenous administration of PGE1 produced dose-dependent hypothermia at Ta's of both 2 and 22 degrees C. The PGE1 hypothermia was due to cutaneous vasodilation. However, at a Ta of 32 degrees C, intravenous PGE1 produced no changes in rectal temperature and ear blood flow. On the other hand, the direct injection of PGE1 into the third ventricle produced dose-dependent hyperthermia. At a Ta of 22 degrees C, PGE1 fever was due to decreased heat loss along with a small increase in heat production. In the cold, PGE1 fever was due to increased heat production while in the heat heat losses were decreased. The data suggest that elevating PGE1 levels in the periphery causes a hypothermia, while elevating PGE1 levels in the central nervous system causes a hyperthermia at Ta's of both 2 and 22 degrees C.     

Effects of prostaglandin E1 on canine nasal vascular and airway resistances

We have developed a technique which can measure directly and simultaneously changes in both nasal vascular and airway resistances in the dog. Nasal vascular resistance was measured by either direct monitoring of the arterial inflow or a change in the perfusion pressure of the nasal vascular bed with blood flow maintained constant. Nasal airway resistance was measured by a rhinomanometric method. Intra-arterial infusion of prostaglandin (PG) E1 at the rate of 1 ml/min in doses of 0.001 to 10 micrograms/min caused a dose-dependent decrease in both nasal vascular and airway resistances. When compared with the control, the average maximal effect of PGE1 on vascular resistance was -38.4%, whereas on airway resistance it was -16.4%. The present studies demonstrate that PGE1 has significant vasodilatatory activity in the canine nasal vascular bed and suggest that the vascular and airway responses to PGE1 may be due to a decrease in inflow and outflow vascular resistance and/or opening of arteriovenous anastomoses.     

Burn injury enhances brain prostaglandin E2 production through induction of cyclooxygenase-2 and microsomal prostaglandin E synthase in cerebral vascular endothelial cells in rats

OBJECTIVES: To examine whether peripheral burn injury in rats elevates prostaglandin E2 in the central nervous system and to determine where in the central nervous system enzymes responsible for prostaglandin E2 synthesis are expressed. DESIGN: Prospective controlled animal study. SETTING: University research laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: Rats received either approximately 25% full-thickness burn injury or sham treatment. At 36 hrs after the injury, the cerebrospinal fluid was sampled to measure prostaglandin E2, and the brain and the spinal cord were sampled for immunohistochemical detection of cyclooxygenase-2 and microsomal-type prostaglandin E2 synthase, enzymes that are responsible for prostaglandin E2 production. MEASUREMENTS AND MAIN RESULTS: The prostaglandin E2 concentration in the cerebrospinal fluid was significantly elevated in the injured rats, and this elevation was suppressed by a cyclooxygenase-2-specific inhibitor, NS398. Only in the injured rats, cyclooxygenase-2 and microsomal-type prostaglandin E synthase proteins were detected in vascular endothelial cells throughout the central nervous system with no regional difference. A double-immunofluorescence study revealed that cyclooxygenase-2 and microsomal-type prostaglandin E synthase were coexpressed in the perinuclear region of the endothelial cells. CONCLUSIONS: These results indicate that peripheral burn injury induces cyclooxygenase-2 and microsomal-type prostaglandin E synthase in endothelial cells of the central nervous system. These enzymes likely elevate the cerebrospinal fluid concentration of prostaglandin E2, a prostanoid that, in turn, activates prostaglandin E2 receptors on the central nervous system neurons involved in the general symptoms following burn injury.     

前列腺素E2(PGE2)在烧伤后大鼠血管内皮细胞分泌的机制研究

目的 明确外周烧伤是否可引起中枢神经系统血管内皮细胞前列腺素E2增加及其发生机制.方法 试验大鼠(SD大鼠)接受约25%的全层(Ⅲ度)烧伤,并进行相关治疗,在36小时后,对大鼠脑脊液进行采样,测量其中的前列腺素E2(PGE2)含量,同时对大鼠脑和脊椎组织进行免疫组化研究,对其中与前列腺素合成有关的2种重要酶,环氧化酶2(COX-2)和微粒体前列腺E2合成酶(mPGES)进行分析.结果 在烧伤后的大鼠脑脊液中,前列腺素E2的含量明显增加,但可以被环氧化酶2的选择性抑制剂NS398所抑制.在烧伤后,对大鼠中枢神经系统血管内皮细胞的免疫组化研究可以发现COX-2和mPGES.双重免疫荧光法发现这2种酶主要集中在内皮细胞的核周.结论 外周的烧伤主要通过诱导中枢神经内皮细胞产生COX-2和mPGES.这些酶可以提高脑脊液中的前列腺素E2浓度,从而激活中枢神经系统前列腺素E2的受体,产生烧伤后的全身症状.适当的应用COX-2抑制剂,使烧伤患者的PGE2水平处在对机体有利的合适范围内,不仅可以减少患者的临床的不适症状,以减轻烧伤早期损害和第二次打击时机体失控的炎症反应,而且可以减少患者感染的发生率.     

Renal effects of prostaglandin E1 in hypertensive patients.

The effects of prostaglandin E1 on fluid and sodium excretion, creatinine clearance and renin release were examined in 26 hypertensive patients including 9 cases of essential hypertension, 10 of renovascular hypertension and 7 of primary aldosteronism. When prostaglandin was infused intravenously in a total dose of 120 mug in 60 min, urine volume was increased in 70% of cases, and sodium excretion in 61%, but little changes were observed in creatinine clearance. The most prominent diuresis and natriuresis were obtained in primary aldosteronism (mean increase was 319% in urinary volume, and 222% in sodium output). The average increases in urinary volume were 61% in patients with essential hypertension and 97% in renovascular hypertension. And urinary output of sodium was increased by 63% in the former and 56% in the latter. The remarkable renal effects of prostaglandin E1 in primary aldosteronism were completely abolished after the administration of spironolactone. Significant elevation of plasma renin activity resulted from prostaglandin E1 infusion in essential hypertension, while no constant effect was obtained in renovascular hypertension and primary aldosteronism. The present experiments indicate that prostaglandin E1 has different effects on the kidney according to the types of hypertension and the effects correlate closely with patient's status of extracellular fluid volume or sodium balance.     

Prostaglandin E1-induced vasorelaxation in porcine coronary arteries.

The mechanism of prostaglandin E1 (PGE1)-induced vasorelaxation was studied in the porcine left anterior descending artery (diameter = 2.0-3.0 mm) and its branches (diameter = 0.6-1.0 mm). In the large coronary arteries, PGE1 increased the basal tone at concentrations from 10(-8) to 3 x 10(-7) M and decreased the tone at concentrations above 3 x 10(-7) M. However, in the small coronary arteries, PGE1 did not affect the basal tone at concentrations below 3 x 10(-6) M and evoked only relaxation at above 10(-5) M. PGE1 caused dose-dependent relaxation of vessels previously contracted by prostaglandin F2 alpha or endothelin-1 at concentrations above 10(-7) M in large coronary arteries and above 10(-8) M in small coronary arteries. Removal of the endothelium did not influence the relaxant response to PGE1 of either type of artery. In addition, 10(-4) M aspirin did not influence the PGE1-induced vasorelaxation of large and small coronary arteries. However, treatment with 5 x 10(-6) M ouabain or partial replacement of Na+ with Li+ (Na+ concentration, 25 mEq/l) significantly attenuated the relaxant response to PGE1 in large and small coronary arteries. These results indicate that the responsiveness of large and small coronary arteries to PGE1 differs in the pig and that the electrogenic Na+ pump has a primary role in the relaxant effect of PGE1 on both small and large arteries.     

Effects of prostaglandin E1 on platelet attenuation of oxidant-induced edema in isolated rabbit lungs

Numerous studies suggest that platelets may contribute to preservation of normal endothelial cell permeability in models of lung injury. We have previously shown that washed human platelets prevent xanthine oxidase-induced edema in the isolated perfused lung and that protective mechanisms depend on the platelet glutathione redox cycle. It is uncertain, however, whether platelets preserve endothelial function by reducing toxic oxygen metabolites or by aggregating and releasing endothelial cell supportive factors-an activity that may require the glutathione redox cycle. In this study, we present data demonstrating that platelet prevention of oxidant lung injury occurs independent of platelet aggregation and release. Isolated rabbit lungs perfused with a cell-free medium were instilled with purine (2 mmol/L) and xanthine oxidase (0.003 U/ml) to generate oxidant lung edema. The infusion of washed human platelets (1 x 10(10) cells) prevented lung edema formation as measured by lung weight gain, wet-to-dry lung weight ratios, and lung histology. Incubation of platelets with prostaglandin E1 (PGE1), a potent inhibitor of platelet aggregation and release, did not inhibit platelet attenuation of lung edema. Additionally, with the instillation of PGE1 into the perfusate to further inhibit platelet aggregation, no prevention of lung protection by PGE1-treated platelets was seen when these results were compared with those from studies in which lungs were infused with xanthine oxidase and PGE1. Aggregometry studies documented that the inhibitory effect of PGE1 on platelet aggregation persisted for up to 60 minutes, which was the duration of the isolated lung protocol. We conclude that platelet aggregation and release of platelet factors is not required for platelet attenuation of oxidant lung edema.     

前列腺素E1对人类脂肪源性基质细胞体外增殖的影响

背景:近年来脂肪源性基质细胞成为研究与应用的热点之一,但前列腺素 E1 对脂肪源性基质细胞增殖的作用影响尚未见报道。目的:观察前列腺素 E1 对人类脂肪源性基质细胞体外增殖的影响。方法:从人正常脂肪组织分离培养脂肪源性基质细胞,用 5 种不同浓度的前列腺素 E1 处理培养的细胞,其中 3×10-6,6×10-6,9×10-6,12×10-6 mol/L 作为实验组,0×10-6 mol/L 作为对照组,观察经不同浓度前列腺素 E1 处理后细胞的增殖情况。结果与结论:不同浓度实验组的细胞数量与对照组相比均显著升高,差异有显著性意义(P<0.05),各实验组内相比,细胞数量增殖无显著性差异(P>0.05)。提示前列腺素 E1 具有促进脂肪源性基质细胞的增殖作用,且前列腺素 E1 的影响效果无剂量依赖性。     

前列腺素E1对人类脂肪源性基质细胞体外增殖的影响

背景：近年来脂肪源性基质细胞成为研究与应用的热点之一,但前列腺素 E1 对脂肪源性基质细胞增殖的作用影响尚未见报道。目的：观察前列腺素 E1 对人类脂肪源性基质细胞体外增殖的影响。方法：从人正常脂肪组织分离培养脂肪源性基质细胞,用 5 种不同浓度的前列腺素 E1 处理培养的细胞,其中 3×10-6,6×10-6,9×10-6,12×10-6 mol/L 作为实验组,0×10-6 mol/L 作为对照组,观察经不同浓度前列腺素 E1 处理后细胞的增殖情况。结果与结论：不同浓度实验组的细胞数量与对照组相比均显著升高,差异有显著性意义（P〈0.05）,各实验组内相比,细胞数量增殖无显著性差异（P〉0.05）。提示前列腺素 E1 具有促进脂肪源性基质细胞的增殖作用,且前列腺素 E1 的影响效果无剂量依赖性。     

心力衰竭病人前列腺素E1治疗效果与其受体水平的相关性研究

目的 观察前列腺素E1(PGE1)对心力衰竭病人的治疗效果,同时通过血小板上EP 受体改变,探讨其可能机制.方法 86 例病人被随机分为两组:常规治疗组(A 组)48 例,PGE1 治疗组(B 组)38 例.常规治疗组采用目前常规抗心力衰竭治疗,而治疗组加用了PGE1 20 μg 于5%葡萄糖注射液稀释后泵静注14 d 为1 个疗程.以治疗前后心功能改善作为判断标准,同时用PCR 法测定血小板上EP 受体改变.结果 B 组总有效率为92.11%,显著高于A 组75.00%,差异有统计学意义(χ2=3.86,P<0.05);PGE1 治疗的慢性阻塞性肺病、高血压和冠心病病人疗效比较,差异无统计学意义(χ2=0.50,P＞0.05);B 组治疗后EP2 和EP4 水平显著增高,与治疗前比较,差异有统计学意义(t 分别=7.86、3.92,P 均<0.05).结论 PGE1 对慢性阻塞性肺病、高血压和冠心病所致的心力衰竭有较好的疗效,其机制可能与治疗后EP2 和EP4 受体表达增加有关.     

气管内应用脂质体前列腺素E_1对油酸致大鼠急性肺损伤的保护作用

目的：探讨气管内应用脂质体携载的前列腺素Ｅ１（ＬｉｐＰＧＥ１）对油酸致大鼠急性肺损伤的保护作用及其机制。方法：Ｗｉｓｔａｒ大鼠４０只，随机均分为５组：正常对照组、油酸致伤组、ＬｉｐＰＧＥ１组、游离前列腺素Ｅ１（ＦＰＧＥ１）组和空白脂质体（ＰＬｉｐ）组。观察肺系数、肺湿重／干重比、肺组织碱性磷酸酶（ＡＬＰ）、血管紧张素转换酶（ＡＣＥ）、髓过氧化酶（ＭＰＯ）的活性和丙二醛（ＭＤＡ）含量的变化。结果：与油酸损伤组比较，ＬｉｐＰＧＥ１组的肺系数、肺组织湿重／干重比与ＭＰＯ活性、ＭＤＡ水平明显降低，而ＡＬＰ与ＡＣＥ活性显著提高；ＬｉｐＰＧＥ１的作用显著优于ＦＰＧＥ１；ＰＬｉｐ无效。结论：经气管内给予ＬｉｐＰＧＥ１对油酸引起的大鼠急性肺损伤有良好的保护作用，其机制可能与抑制肺内中性粒细胞的聚集与抗氧自由基所造成的损伤有关。     

The effect of blood ingestion on brain serotonin synthesis in portacaval-shunted rats

In rats with a portacaval shunt (PCS), the effect on the serotonin metabolism in the brain after oral administration of blood, a mixed amino acid solution (Vamin 14; KabiVitrum, Sweden) or a 10% glucose solution was studied. One week after PCS, the animals were fed with a gastric tube for 8 h and thereafter tested for behavioral abnormalities before decapitation at 12 h. The concentration of 5-hydroxytryptophan (5-HTP), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) were analyzed chromatographically (HPLC technique with electrochemical detection) in different regions of the brain. Estimation of synthetic rates of 5-hydroxyindoles was facilitated by aromatic aminoacid decarboxylase inhibition (m-hydroxybenzyl-hydrazine; NSD 1015). The brain concentrations of 5-HTP, 5-HT, and 5-HIAA were increased in all shunted rats as compared with sham-operated animals. Whether animals received blood, glucose, or aminoacid solution made no differences in the brain concentrations of 5-HTP and 5-HT. Concentrations of 5-HIAA were lower in those animals receiving blood as compared with the other shunted groups. No reproducible differences in the behavior of the animals were observed. These results suggest that massive blood administration 1 week after PCS in rats has no influence on the rate of brain indole synthesis. While alterations in serotonin metabolism may play a role in some forms of encephalopathy, this study implies that the behavioral and neurologic disorders which follow gastrointestinal tract hemorrhage in patients with liver failure may have other etiologies.