促肾上腺皮质激素对高脂血症兔模型血脂及肾功能的影响
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摘要
目的:观察促肾上腺皮质激素(ACTH1-24和ACTH4-10)对高脂血症模型新西兰白兔血脂、肾功能及肾上腺的影响,以期能够探讨ACTH1-24的降脂机制,了解ACTH1-24能否改善肾功能,并了解ACTH4-10是否具有类似的降脂效应及ACTH4-10是否能引起肾上腺增生。
方法:健康雄性新西兰兔45只,饲以高脂饲料(配方为95.5%普通饲料、2.5%猪油、1.25%胆固醇、0.75%蛋黄粉)8周,待高脂血症模型建立后将其随机分为3组,即ACTH1-24组(n=15)、ACTH4-10组(n=15)和对照组(n=15)。ACTH1-24组予以ACTH1-24皮下注射一周(100μg/kg/d,溶解于1ml生理盐水中),ACTH4-10组予以ACTH4-10皮下注射一周(300ug/kg/d,约是ACTH1-24组药物的5倍摩尔浓度,溶解于1ml生理盐水中),对照组每天予等量生理盐水皮下注射。分别在实验前、实验第3天及第7天抽血检测并比较注射ACTH前后兔血脂及肾功能的变化,实验第7天抽血后在麻醉下统一取左侧肾上腺称重并测体积,比较各组肾上腺质量与体积的变化,同时取右侧肾上腺置于10%福尔马林溶液中固定,常规石蜡包埋后取纵轴面切片作HE染色。
结果:ACTH1-24组:与用药前相比,用药7天后,血清TC、HDL及LDL水平下降,分别降低约9.0%、43.7%及6.3%,而血清TG水平则上升约7.6倍,其中HDL和TG有统计学意义(P值分别小于0.01和0.001);血肌酐显著下降约16.6%(P<0.01),而血尿素氮则升高约13.5%,但无统计学差异;肾上腺质量和体积显著增加。ACTH4-10组:用药7天后,兔血脂及肾功能变化无统计学差异,肾上腺质量和体积亦未见有明显变化。
结论:ACTH1-24具有一定的降脂效应,能够改善高脂血症引起的肾功能损害;ACTH4-10未见有明显降脂及改善肾功能效应;ACTH1-24能引起肾上腺明显增生,而ACTH4-10无类似作用。
Objectives: To investigate the effects of synthetic adrenocorticotropic hormone (ACTH1-24 and ACTH4-10) on serum lipid levels, renal function and the adrenal gland in hyperlipidemic rabbit model, in order to discuss the lipid-lowering mechanism and effect of renal function of ACTH1-24. And to investigate whether ACTH4-10 has the same effect on lipid levels and adrenal.
Methods: 45 healthy male NZW rabbits were fed with a high-fat diet (containing 95.5% ordinary feeder, 2.5% lard, 1.25% cholesterol and 0.75% yolk powder) for 8 weeks, and were divided into 3 groups randomly, i.e. ACTH1-24 group (n=15), ACTH4-10 group (n=15) and control group (n=15). ACTH1-24 group received a subcutaneous injection of ACTHl-24 at a dose of 100μg/(kg·d) (dissolved in 1ml saline solution) for one week. ACTH4-10 group received a subcutaneous injection of ACTH4-10 at a dose of 300μg/(kg·d) (about 5 times molar concentration compared with ACTH1-24 group, dissolved in 1ml saline solution) for one week. Control group received the same volume of saline solution daily for one week. Then we drew blood to detect and compare the change of rabbits’serum lipid levels and renal function at pre-experiment, the third day and the seventh day of the experiment, respectively. The left adrenal gland was resected for measurement of weight, volume and the right adrenal gland was resected for pathology at the seventh day after hemospasia.
Results: ACTH1-24 group: compared with pre-experiment, one week after ACTH1-24 injection, serum TC, HDL and LDL levels were reduced about 9.0%, 43.7% and 6.3% respectively, while TG level increased about 7.6 times and the differences of HDL and TG are significant (P<0.01 and P<0.001, respectively). Serum Cr level decreased 16.6% ( P<0.01). Blood urea nitrogen level increase about 13.5%, but no significant difference was found. The weight and volume of adrenal gland increased significantly. ACTH4-10 group: a week after ACTH4-10 injection, there were no difference about serum lipid and renal function in hyperlipidemic rabbits, as well as the weight and volume of adrenal gland.
Conclusions: ACTH1-24 has the effect of lipid-lowering and improving renal function in hyperlipemia model, while ACTH4-10 has no same effect; Adrenal hyperplasia was seen in ACTH1-24 group but missed in ACTH4-10 group.
方法:健康雄性新西兰兔45只,饲以高脂饲料(配方为95.5%普通饲料、2.5%猪油、1.25%胆固醇、0.75%蛋黄粉)8周,待高脂血症模型建立后将其随机分为3组,即ACTH1-24组(n=15)、ACTH4-10组(n=15)和对照组(n=15)。ACTH1-24组予以ACTH1-24皮下注射一周(100μg/kg/d,溶解于1ml生理盐水中),ACTH4-10组予以ACTH4-10皮下注射一周(300ug/kg/d,约是ACTH1-24组药物的5倍摩尔浓度,溶解于1ml生理盐水中),对照组每天予等量生理盐水皮下注射。分别在实验前、实验第3天及第7天抽血检测并比较注射ACTH前后兔血脂及肾功能的变化,实验第7天抽血后在麻醉下统一取左侧肾上腺称重并测体积,比较各组肾上腺质量与体积的变化,同时取右侧肾上腺置于10%福尔马林溶液中固定,常规石蜡包埋后取纵轴面切片作HE染色。
结果:ACTH1-24组:与用药前相比,用药7天后,血清TC、HDL及LDL水平下降,分别降低约9.0%、43.7%及6.3%,而血清TG水平则上升约7.6倍,其中HDL和TG有统计学意义(P值分别小于0.01和0.001);血肌酐显著下降约16.6%(P<0.01),而血尿素氮则升高约13.5%,但无统计学差异;肾上腺质量和体积显著增加。ACTH4-10组:用药7天后,兔血脂及肾功能变化无统计学差异,肾上腺质量和体积亦未见有明显变化。
结论:ACTH1-24具有一定的降脂效应,能够改善高脂血症引起的肾功能损害;ACTH4-10未见有明显降脂及改善肾功能效应;ACTH1-24能引起肾上腺明显增生,而ACTH4-10无类似作用。
Objectives: To investigate the effects of synthetic adrenocorticotropic hormone (ACTH1-24 and ACTH4-10) on serum lipid levels, renal function and the adrenal gland in hyperlipidemic rabbit model, in order to discuss the lipid-lowering mechanism and effect of renal function of ACTH1-24. And to investigate whether ACTH4-10 has the same effect on lipid levels and adrenal.
Methods: 45 healthy male NZW rabbits were fed with a high-fat diet (containing 95.5% ordinary feeder, 2.5% lard, 1.25% cholesterol and 0.75% yolk powder) for 8 weeks, and were divided into 3 groups randomly, i.e. ACTH1-24 group (n=15), ACTH4-10 group (n=15) and control group (n=15). ACTH1-24 group received a subcutaneous injection of ACTHl-24 at a dose of 100μg/(kg·d) (dissolved in 1ml saline solution) for one week. ACTH4-10 group received a subcutaneous injection of ACTH4-10 at a dose of 300μg/(kg·d) (about 5 times molar concentration compared with ACTH1-24 group, dissolved in 1ml saline solution) for one week. Control group received the same volume of saline solution daily for one week. Then we drew blood to detect and compare the change of rabbits’serum lipid levels and renal function at pre-experiment, the third day and the seventh day of the experiment, respectively. The left adrenal gland was resected for measurement of weight, volume and the right adrenal gland was resected for pathology at the seventh day after hemospasia.
Results: ACTH1-24 group: compared with pre-experiment, one week after ACTH1-24 injection, serum TC, HDL and LDL levels were reduced about 9.0%, 43.7% and 6.3% respectively, while TG level increased about 7.6 times and the differences of HDL and TG are significant (P<0.01 and P<0.001, respectively). Serum Cr level decreased 16.6% ( P<0.01). Blood urea nitrogen level increase about 13.5%, but no significant difference was found. The weight and volume of adrenal gland increased significantly. ACTH4-10 group: a week after ACTH4-10 injection, there were no difference about serum lipid and renal function in hyperlipidemic rabbits, as well as the weight and volume of adrenal gland.
Conclusions: ACTH1-24 has the effect of lipid-lowering and improving renal function in hyperlipemia model, while ACTH4-10 has no same effect; Adrenal hyperplasia was seen in ACTH1-24 group but missed in ACTH4-10 group.
引文
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46. Genedani S, Filaferro M, Carone C, Ostan R, Bucci L, Cevenini E, Franceschi C, Monti D: Influence of f-MLP, ACTH(1-24) and CRH on in vitro chemotaxis of monocytes from centenarians. Neuroimmunomodulation 2008, 15(4-6):285-289.
47. Bayne CJ, Levy S: Modulation of the oxidative burst in trout myeloid cells by adrenocorticotropic hormone and catecholamines: mechanisms of action. J Leukoc Biol 1991, 50(6):554-560.
48. Paltrinieri S, Panelli S, Comazzi S, Sartorelli P: Effect of 1-24ACTH administration on sheep blood granulocyte functions. Vet Res 2002, 33(1):71-82.
49. Sassi D, Kletsas D, Ottaviani E: Interactions of signaling pathways in ACTH (1-24)-induced cell shape changes in invertebrate immunocytes. Peptides 1998, 19(6):1105-1110.
50. Akmaev IG, Volkova OV, Grinevich VV, Resnenko AB: [Evolutionary aspects of a stress reaction]. Vestn Ross Akad Med Nauk 2002(6):25-27.
51. Genedani S, Bernardi M, Ottaviani E, Franceschi C, Leung MK, Stefano GB: Differential modulation of invertebrate hemocyte motility by CRF, ACTH, and its fragments. Peptides 1994, 15(2):203-206.
52. Ottaviani E, Franceschi C: The neuroimmunology of stress from invertebrates to man. Prog Neurobiol 1996, 48(4-5):421-440.
53. Franchini A, Ottaviani E: Modification induced by ACTH in hemocyte cytoskeleton of the freshwater snail Viviparus ater (Gastropoda, Prosobranchia). Eur J Histochem 1994, 38(2):145-150.
54. Ottaviani E, Cossarizza A, Ortolani C, Monti D, Franceschi C: ACTH-like molecules in gastropod molluscs: a possible role in ancestral immune response and stress. Proc Biol Sci 1991, 245(1314):215-218.
55. Brzoska T, Luger TA, Maaser C, Abels C, Bohm M: Alpha -melanocyte -stimulating hormone and related tripeptides: biochemistry, antiinflammatoryand protective effects in vitro and in vivo, and future perspectives for the treatment of immune-mediated inflammatory diseases. Endocr Rev 2008, 29(5):581-602.
56. Pepels PP, Balm PH: Ontogeny of corticotropin-releasing factor and of hypothalamic-pituitary-interrenal axis responsiveness to stress in tilapia (Oreochromis mossambicus; Teleostei). Gen Comp Endocrinol 2004, 139(3):251-265.
57. Dautzenberg FM, Py-Lang G, Higelin J, Fischer C, Wright MB, Huber G: Different binding modes of amphibian and human corticotropin-releasing factor type 1 and type 2 receptors: evidence for evolutionary differences. J Pharmacol Exp Ther 2001, 296(1):113-120.
58. Sonetti D, Peruzzi E, Stefano GB: Endogenous morphine and ACTH association in neural tissues. Med Sci Monit 2005, 11(5):MS22-30.