赛庚啶对大鼠垂体-肾上腺皮质轴作用及机制的研究

目的　研究赛庚啶 (cyproheptadineCyp)对大鼠垂体 肾上腺皮质轴内分泌功能及机制的影响。方法　用放射免疫分析法 (RIA)观察Cyp对大鼠血清ACTH、可的松水平的影响。用电镜及荧光定量PCR技术 ,观察Cyp对ACTH细胞、肾上腺皮质束状带细胞超微结构及钙调素 (calmodulinCaM)mRNA在垂体、肾上腺皮质基因表达的影响。结果　Cyp 2 3、4 6mg·kg- 1 ·d- 1 ,ig,连续用药 1 4d ,可使大鼠血清ACTH和可的松含量降低 (P <0 0 5 ,P <0 0 1 )。组织形态电镜观察 ,该药亦可引起大鼠垂体ACTH细胞、肾上腺皮质束状带细胞超微结构的退行性改变。同时发现CaMmRNA在垂体、肾上腺皮质的基因表达较对照组减少 (P <0 0 5 ,P<0 0 1 )。结论　Cyp对大鼠垂体 肾上腺皮质轴分泌功能有抑制作用 ,其机制可能与抑制CaMmRNA在垂体、肾上腺皮质的基因表达有关     

雷公藤甲素对Wistar大鼠免疫毒性相关基因表达的影响

目的应用基因芯片技术研究雷公藤甲素对大鼠胸腺全基因表达谱的影响,从基因水平探讨雷公藤甲素引起免疫抑制毒性的潜在分子作用机制。方法 Wistar大鼠,连续28 d ig给予雷公藤甲素0.5和1.0 mg·kg-1以及环孢素A 20 mg·kg-1(阳性对照),进行T细胞依赖抗体反应检测、免疫器官组织病理学检查和胸腺组织基因芯片实验。结果与溶媒对照组相比,雷公藤甲素0.5和1.0 mg·kg-1组和环孢素A组大鼠血清中T细胞依赖抗体应答水平均受到了显著抑制。组织病理学检查发现,雷公藤甲素1.0 mg·kg-1使胸腺皮髓质淋巴细胞数量轻度减少,环孢素A使胸腺髓质皮质化。基因芯片检测结果显示,雷公藤甲素1.0 mg·kg-1给药第7天引起422个显著差异表达基因,其基因功能主要涉及DNA依赖的细胞转录调节、核转运、微管蛋白复合体装配、核小体装配、线粒体DNA转录、氨基酸转运和线粒体DNA复制等。KEGG通路分析发现差异表达基因主要参与移植排斥和自身免疫性疾病等多个与免疫抑制相关的基因表达调控途径。结论雷公藤甲素1.0 mg·kg-1能够引起大鼠胸腺基因表达谱的显著性改变,其免疫毒性的主要机制可能是通过下调免疫毒性相关基因的表达,抑制淋巴细胞的增殖。     

雷公藤甲素聚乳酸纳米粒对大鼠睾丸组织的影响

目的　观察采用聚乳酸纳米粒能否减轻雷公藤甲素的大鼠睾丸毒性。方法　雄性Wistar大鼠分别ig 0 .2及 0 .6mg·kg- 1雷公藤甲素 (非纳米粒组 )及其聚乳酸纳米粒混悬液 (纳米粒组 ) ,连续给药 15d ,以ig生理盐水的大鼠为对照组 ,测定睾丸的脏器系数及其组织匀浆液中酸性磷酸酶 (ACP)活性和果糖含量 ,光镜观察睾丸组织的病理学变化。结果在 0 .6mg·kg- 1剂量下 ,非纳米粒组睾丸ACP活性和果糖的含量均明显低于纳米粒组 (P <0 .0 5 )。光镜观察显示 ,雷公藤甲素 0 .6mg·kg- 1可引起大鼠睾丸的损伤 ,非纳米粒组引起的病变程度明显重于纳米粒组 ,主要表现为睾丸萎缩 ,各级生精细胞变性、坏死、数量减少或消失 ,出现了多核巨细胞。结论以聚乳酸作为药物载体的纳米体系 ,可明显减轻雷公藤甲素对睾丸的毒性     

雷公藤双层片的抗炎作用

目的　评价雷公藤双层片的抗炎作用。方法　制备大鼠佐剂性关节炎、琼脂所致大鼠足跖肿胀、大鼠巴豆油气囊肿模型,观察雷公藤双层片的作用。结果　雷公藤双层片明显抑制大鼠佐剂性关节炎继发病变,使佐剂性关节炎大鼠脾重量减轻,肾上腺重量增加,血浆皮质醇水平升高,外周血T淋巴细胞显著降低。雷公藤双层片对琼脂所致大鼠足跖肿胀也有明显抑制作用;同时能明显抑制大鼠巴豆油气囊肿的渗出和肉芽组织增生。结论　雷公藤双层片具有显著的抗炎作用,其抗炎作用与它抑制细胞免疫功能及与垂体-肾上腺皮质系统有关。     

半乳糖胺盐致肝损害与肾上腺皮质激素水平的关系

半乳糖胺盐(GaiN)一次和多次染毒后引起大鼠肝损害和肾上腺抗坏血酸含量下降,而血浆皮质酮、尿17-羟类固醇和17-羟类固酮无明显改变;肝△~4还原酶活性受抑制,而未见血浆肾上腺皮质激素水平增加和尿皮质类固醇排出减少。组织学上可见肾上腺皮质束状带细胞部分肿胀和脂质脱失。肾上腺中抗坏血酸含量下降可能是GalN直接引起的,而不是肝损害的后果。机体在皮质激素高水平的情况下可增加GalN肝毒作用。     

ACTH 联合槐杞黄对大鼠下丘脑-垂体-肾上腺轴的影响

目的 研究促肾上腺皮质激素（ACTH）联合槐杞黄对大鼠下丘脑-垂体-肾上腺（HPA）轴的影响。 方法 50 只大鼠按随机数字表法分为空白对照组（A 组）、泼尼松模型组（B 组）、槐杞黄组（C 组）、ACTH 组（D 组）和联合治疗组（E 组）, 每组 10 只。 B~E 组采用醋酸泼尼松水溶液 12.5 mg/（kg·d）连续灌胃 4 周建立 HPA 轴抑制模型, A 组以蒸馏水 10 mL/（kg· d）灌胃作为对照。 C、E 组每次在醋酸泼尼松灌胃后 30 min 加用槐杞黄颗粒 5 g/（kg· d）灌胃。 实验第 3 周时, D、E 组加用 ACTH 200 µg/（kg·d）皮下注射。 分别于实验开始前、实验 2 周、4 周时测定各组血清皮质醇水平。 实验结束后处死动物并摘取垂体和肾上腺, 称质量后计算脏器指数, HE 染色观察垂体和肾上腺的病理情况。 结果 实验 2 周后, B、C、D、E 组的血清皮质醇水平较 A 组明显降低（P < 0.05）, 提示造模成功。 实验 4 周时, C、 D、E 组的血清皮质醇水平较 B 组均明显升高（P < 0.05）, 且各治疗组之间 E 组>D 组>C 组（P < 0.05）; 同时 3 组的垂体和肾上腺的质量及脏器指数均较 B 组升高（P < 0.05）。 HE 染色显示各组垂体远侧部未见明显改变; B 组肾上腺皮质束状带结构变薄且紊乱, C、D、E 组则出现不同程度的增生, 以 E 组最为明显。 结论 ACTH 联合槐杞黄可促进肾上腺皮质束状带增生及皮质醇的分泌, 减轻糖皮质激素对大鼠 HPA 轴的抑制作用。     

雷公藤内酯酮多相脂质体的试制

雷公藤内酯酮（Triptonide）系卫茅科植物雷公藤环氧二萜类化合物，文献报道它可使大鼠血浆皮质醇含量提高，可明显降低肾上腺维生素C及胆固醇含量，提示其有兴奋垂体、肾上腺皮质系统的作用［1］。我们就其对小鼠T淋巴细胞功能的影响从细胞水平进行研究[2],证实雷公藤内酯酮对T淋巴细胞功能具有抑制作用。由于雷公藤内酯酮有一定的毒性，其属于脂溶性的和制成溶液性质不稳定的特点，我们将其试制备成雷公藤内酯酮多相脂质体。本文报道用注入法制备本品，并对其成品质量的检查。实验部分一、药品与仪器（～）药品：雷公藤内酯酮（本基地植…     

帕罗西汀对心理应激大鼠血浆皮质醇和行为的影响

目的：观察帕罗西汀对心理应激大鼠血浆皮质醇和行为的影响。方法：建立大鼠心理应激模型,观察抗焦虑药物帕罗西汀用药组大鼠下丘脑室旁核c-fos表达、血浆皮质醇和旷场行为。结果：与正常对照组比较,心理应激大鼠下丘脑室旁核c-fos表达显著增加（P〈0.05）,血浆皮质醇含量明显升高（P〈0.05）,在旷场中的穿行格数和直立次数明显增加（P〈0.05）,而帕罗西汀用药能减少大鼠下丘脑室旁核c-fos表达、血浆皮质醇含量和在旷场中的活动（P〈0.05）。结论：帕罗西汀通过抑制c-fos基因表达,下调了下丘脑-垂体-肾上腺（HPA）水平,从而减轻了心理应激所致的焦虑症状。     

帕罗西汀对心理应激大鼠下丘脑室旁核c-fos表达的影响

目的:观察帕罗西汀对心理应激大鼠下丘脑c fos表达的影响,以揭示帕罗西汀治疗心理应激引起焦虑的分子作用机制。方法:建立大鼠心理应激模型,观察抗焦虑药物帕罗西汀用药组大鼠血浆皮质醇和下丘脑c fos的表达。结果:与正常对照组比较,各应激组大鼠血浆皮质醇含量明显升高,下丘脑室旁核c fos表达显著增加,而帕罗西汀单次、连续给药能减少应激大鼠血浆皮质醇含量和下丘脑室旁核c fos表达。结论:帕罗西汀通过抑制c fos基因表达,下调下丘脑垂体肾上腺轴(HPA轴)水平,从而发挥中枢应激调节作用。     

皮质醇增多症临床回顾分析

目的探讨皮质醇增多症的临床表现、诊断和治疗方法。方法回顾性分析郑州大学第一附属医院2006年9月～2011年12月收治的81例皮质醇增多症患者的临床资料。结果术后2周血压恢复正常50例,3个月后所有患者血压、血钾、血糖均恢复正常,6～9个月后库欣综合征症状完全消失,术后病理诊断肾上腺腺瘤40例,肾上腺皮质癌2例,肾上腺皮质大结节样增生1例,肾上腺皮质束状带增生22例,肾上腺皮髓质增生16例。结论临床表现、生化检查和影像学检查三者结合可提高皮质醇增多症的确诊率,绝大多数患者可以得到确诊,针对病因治疗效果较好。     

Effects of acute administration of ethanol on the rat adrenal cortex

OBJECTIVE: The purpose of this study was to investigate the effect of a single dose of ethanol on rat adrenal cortex and to determine whether the estrous cycle can influence this effect of ethanol. METHOD: Adult female Wistar rats showing proestrus or diestrus Day 1 (n = 12) were treated intraperitoneally with ethanol (4 g/kg body weight). Untreated (n = 15) and saline-injected (n = 14) rats were used as controls. The animals were sacrificed by decapitation 0.5 hour after ethanol administration. Stereological analysis was performed on paraffin sections of adrenal glands stained with AZAN, and the following parameters were determined: absolute volume of the zona glomerulosa, the zona fasciculata and the zona reticularis, numerical density, volume and the mean diameter of adrenocortical cells and of their nuclei, and diameter and length of capillaries. RESULTS: The diameter and volume of adrenocortical cells in the zona fasciculata and the zona reticularis were significantly increased by acute ethanol treatment at proestrus. In the same group of animals, a single dose of ethanol induced significant decrease in numerical density of adrenocortical cells and of their nuclei in all three zones. Increased length of capillaries of the zona fasciculata as well as enhanced level of serum corticosterone was found in ethanol-treated rats at both phases of the estrous cycle, proestrus and diestrus Day 1. CONCLUSIONS: The obtained results indicate that a single dose of ethanol activates adrenal cortex in female rats and that the effect is more pronounced on morphometric parameters at proestrus.     

Adrenocortical toxicity of 3-methylsulphonyl-DDE; 3: Studies in fetal and suckling mice.

Irreversible binding and toxicity of the DDT metabolite 3-methylsulphonyl-DDE (MeSO2-DDE) were examined in fetuses and suckling pups following administration to pregnant or lactating C57Bl mice. Tape-section autoradiography showed a high and tissue-specific accumulation and binding of MeSO2-DDE-14C-derived radioactivity in the late gestational fetal adrenal cortex. According to microautoradiography an irreversibly bound residue was confined to the zona fasciculata. Similarly, there was a high concentration of irreversibly bound 14C-labelled material in the adrenal zona fasciculata of suckling pups. Intraperitoneal injection of MeSO2-DDE-14C to lactating mice resulted in higher concentrations of radioactivity in the liver and stomach contents (milk) of the suckling pups than in the maternal liver. This treatment also resulted in a higher level of radioactivity in the adrenals of the pups than in the maternal adrenals, both at a subtoxic and at a toxic dose. Histopathologic examination of adrenals from suckling pups revealed extensive vacuolation and necrosis of the zona fasciculata 2 days following a single dose of MeSO2-DDE (25 mg/kg) to the dam. In the fetal adrenal zona fasciculata, slight degenerative changes were observed following a maternal dose of 50 mg/kg. In conclusion, the study shows that MeSO2-DDE is a highly tissue-specific toxicant to the fetal and postnatal adrenal zona fasciculata in mice. Based on the present data and on previous results in adult mice, we propose that a tissue-specific activation to a reactive metabolite in the fetal and postnatal adrenal cortex is mediated by cytochrome P-450 (11 beta).     

EFFECTS OF ETHANE DIMETHANESULFONATE ON THE STRUCTURE OF ADULT MALE RAT ADRENAL CORTEX

The influence of ethane dimethanesulfonate (EDS), a specific toxicant for Leydig cells, on the morphometric characteristic of adult male rat adrenal cortex was examined on day 15 after administration. As expected, the dose of 75 mg kg⁻¹of EDS produced drastic reduction in serum testosterone levels followed by a decrease in testis and seminal vesicle weight. However, a considerable drop (over 50%) in adrenal weight was also found. Stereological analysis of the adrenal cortex, performed under light microscope, revealed atrophy of all adrenocortical zones. The changes were most prominent in the inner zones. Thus, in the zona fasciculata the number of parenchymal cells was markedly decreased. In the zona reticularis a layer consisting mostly of atrophic parenchymal cells was localised at the border between zona reticularis and zona fasciculata. The remaining small number of cortical cells in this zone displayed a notable hypertrophy. It is concluded that EDS at a dose that destroys Leydig cells has a strong deleterious effect on steroidogenic cells of adult male rat adrenal cortex.     

关木通对大鼠肾上腺的毒效应及其可能机制

目的观察关木通(AMK)对大鼠肾上腺的影响及其与肾损害的关系,并探讨其可能机制。方法ig给予雌性大鼠40.gkg-1.d-1AMK水煎剂1,3及5 d,观测肾上腺和肾脏的重量,肾上腺和肾脏组织学及其超微结构变化,测定血清尿素氮、肌酐和皮质醇含量,免疫组化法检测8羟-基脱氧鸟苷(8-OHdG)和诱生型一氧化氮合酶(iNOS)的表达。结果给药3 d后,大鼠血清皮质醇明显增高,肾上腺皮质明显增厚;连续给药5 d,大鼠血清尿素氮和肌酐明显增高,肾小管上皮细胞水肿,变性,坏死;给药组大鼠8-OHdG和iNOS明显表达。结论AMK可引起肾上腺皮质增生和肾损害,肾上腺损害早于肾损害,其毒效应机制可能与DNA氧化损伤和一氧化氮增多有关。     

Sex differences in adrenocortical structure and function. XXVI. Further studies on the differences in the compensatory growth of the adrenal cortex of the male and female hamster after unilateral adrenalectomy

The relative adrenal weight of the remaining right adrenal gland was significantly increased 5 days after unilateral adrenalectomy in hamsters of both sexes. This effect was associated with an enlargement of the zonae glomerulosa and fasciculata in males and of the zona fasciculata in females. Unilateral adrenalectomy raised the average volume of zona fasciculata cells in male hamsters and that of zona reticularis cells in females. The number of parenchymal cells in all adrenocortical zones remained unchanged by the removal of the contralateral gland; however, when calculating per mg of adrenal or per cell, the nucleotide uptake by adrenal quarters was notably lowered. A marked drop in plasma cortisol concentration was found in unilaterally adrenalectomized male but not in female hamsters. These findings indicate that the main component of the adrenal compensatory growth in hamsters is the hypertrophy and not the hyperplasia of parenchymal cells.     

Effect of intratracheal and oral application of corticosteroids on the adrenal function test in beagle dogs after ACTH-stimulation.

The effect of synthetic corticosteroids given intratracheally or orally on the adrenal glands of beagle dogs was investigated. The adrenal function was evaluated using a standardized ACTH stimulation test. In addition, histological and morphometrical examinations of the adrenal cortex were performed at the end of the study. Beclomethasone dipropionate given intratracheally at daily dose levels of 0.05, 0.1 and 0.5 mg/kg body weight led to a dose dependent adrenal suppression on the basis of plasma cortisol concentration and eosinophil counts after ACTH stimulation and size of zona fasciculata and reticularis. A complete adrenal suppression was observed at the highest dose level of 0.5 mg/kg body weight. Also the oral administration of 0.1 mg/kg body weight/day of beclomethasone dipropionate had a definite adrenal suppressive effect comparaable to that of 0.1 mg/kg body weight given intratracheally. However, intratracheal administration of fluocortin butylester, a local antiinflammatory drug but systemically a nearly ineffective corticosteroid (2 X 8 mg/kg body weight/day) had no suppressive effect on the adrenal gland of the beagle dog, even after a 320 times higher dose.     

Toxicity, ultrastructural effects, and metabolic studies with 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane(o,p'-DDD) and its methyl analog in the guinea pig and rat

Effects of 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane (o,p'-DDD) (Lysodren; Mitotane) (I) and 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2, 2-dichloropropane (Mitometh) (II) were investigated. Ultrastructural and toxicity studies were conducted with male Hartley outbred guinea pigs given 300 mg/kg/day ip for 14 days. Profound mitochondrial damage in the guinea pig adrenal cortex, an index of Lysodren's action as a cancer chemotherapeutic, reversible necrosis of the zona fasciculata and zona reticularis with swelling, disrupted cristae, and organelles destroyed in the mitochondria from these areas. Yet guinea pigs given Mitometh tolerated the drug better than those given an equivalent amount of Lysodren. In general the animals treated with Mitometh showed less alopecia, diarrhea, and weakness. The only deaths recorded in our study were in the Lysodren group. In addition po administration of these two drugs to male Sprague-Dawley rats and male Hartley guinea pigs for 4 days allowed for a direct comparison of urinary metabolites. Metabolites were identified from urine extracts by computerized mass spectrometry interfaced with capillary gas chromatography. Both compounds were shown to undergo dehydrohalogenation and side-chain cleavage to a limited extent; however, only Lysodren afforded side-chain oxidation metabolites. In fact, the dominant metabolite from Lysodren biotransformation was the corresponding carboxylic acid o,p'-DDA (III). On the other hand, Mitometh resisted side-chain oxidative metabolism and was less toxic than Lysodren. Therefore, when given to guinea pigs and rats, Mitometh had Lysodren-like biologic activity, did not undergo rapid inactivation, and was less toxic than Lysodren. Mitometh represents a potential alternative to Lysodren which should be investigated further for its possible use in the treatment of adrenal cortical carcinoma and Cushing's syndrome.     

Target cells for cytochrome p450-catalysed irreversible binding of 7,12-dimethylbenz[a]anthracene (DMBA) in rodent adrenal glands

7,12-Dimethylbenz[a]anthracene (DMBA) is an adrenocorticolytic agent that causes apoplexy (haemorrhage) and massive necrosis in the adrenal cortex in rat. Several explanations regarding the origin of toxicity have been proposed. Huggins and Morii (J Exp Med 114:741-60, 1961) suggested that the cells of the inner adrenal cortex are the primary target, whereas Horváth and Kovács (Pathol Eur 8:43-59, 1973) suggested the vascular endothelium as being the origin of toxicity. In the present study, cultured precision-cut tissue slices were used to localize target cells for irreversible [(3)H]DMBA binding in rat and mouse adrenal cortex. The sites of binding were confirmed by autoradiography in vivo. Irreversible [(3)H]DMBA binding was confined to zona fasciculata/reticularis cells in rat (but not in mouse) adrenal cortex. Pronounced binding was observed in clusters of cells (focal binding), localized predominantly in zona reticularis of rat. [(3)H]DMBA binding in zona fasciculata/reticularis cells was inhibited by the cytochrome p450 1A/B (CYP1A/B) inhibitors ellipticine, alpha-naphthoflavone, and 1-ethynylpyrene. The CYP11B1-inhibitor metyrapone did not reduce [(3)H]DMBA binding. In CYP1-induced (PCB 126-treated) rats and mice, intense irreversible [(3)H]DMBA binding was found also in endothelial cells of the adrenal cortex. The endothelial binding was abolished by the CYP1 inhibitors but remained unaffected by metyrapone. We conclude that the metabolic activation in adrenal parenchymal cells is presumably catalysed by CYP1B1, whereas CYP1A1 presumably catalyses the activation in endothelial cells. We suggest that the adrenocorticolytic effect of DMBA is the result of a dual mode of action, targeting both endothelial and parenchymal cells in the rat adrenal cortex.     

乳增消对乳腺增生大鼠影响的研究

目的:研究乳增消防治大鼠乳腺增生的作用。方法:将切除卵巢的大鼠肌肉注射苯甲酸雌二醇(E2)0.8mg.kg-1,隔天1次,连续90d,在造模20至30d期间,隔天注射1次黄体酮4mg.kg-1,连续5次。在造模30d后,将乳腺增生模型动物随机分组灌胃给药,(0.5%CMC-Na、乳增滴或他莫昔芬)1次.d-1,连续60d;末次给药后24h取样检测各项指标。结果:切除卵巢动物在注射E23mo后,其胸腺指数减小,子宫指数和肾上腺指数均显著增加;其乳腺组织雌激素受体(ER)水平及血清E2水平显著升高,而血清孕酮(P)水平显著降低,E2/睾酮(T)比值显著增加;其乳腺小叶数目增多、间质增生、腺泡内分泌物多,腺泡呈高度扩张状态;其血清催乳素(PRL)水平有所升高,而黄体生成素(LH)及卵泡刺激素(FSH)水平有所降低,但与去势组(卵巢切除动物未注射E2及P等)比较无统计学差异;他莫昔芬和乳增消20g.kg-1在治疗2mo时均有显著对抗E2增加子宫指数和肾上腺指数的作用;乳增消各剂量及他莫昔芬可显著升高乳腺增生大鼠血清睾酮水平,降低E2/T比值,与模型组比较有统计学差异。各药物对乳腺增生大鼠血清LH、FSH、PRL、P及E2等指标均无明显影响。结论:上述研究结果显示,乳增消对模型动物乳腺增生有较好的预防与治疗作用。其作用可能与降低动物血清E2、P及PRL水平,降低E2/T比值有关。