Structure and dynamics of adrenal mitochondria following stimulation with corticotropin releasing hormone.

The mitochondria of rat adrenals were investigated qualitatively and quantitatively in different functional states of the adrenal cortex. Following stimulation of the animals with corticotropin releasing hormone (CRH), the corticosterone serum levels reached a maximum 1 hour after stimulation with CRH. The amount of inner mitochondrial membrane within the zona fasciculata increased showing a biphasic time course, with a first maximum 2 hours and a second maximum 8 hours after stimulation. In contrast, a significant rise of mitochondrial volume occurred only 24 hours after CRH stimulation. Therefore, the dense vesicularization of mitochondrial cristae may constitute an early process to enhance the steroidogenic capacity of these cells. Within cells of the transition zone between zona glomerulosa and zona fasciculata, we could depict a special type of mitochondria with characteristic crescent-like cristae only seen after stimulation with CRH. This type of mitochondria may represent an intermediate form between mitochondria of zona glomerulosa and zona fasciculata underlining the impressive transformational capacity of adrenocortical mitochondria. After hypophysectomy, zona fasciculata cells contained mitochondria with tubular inner membranes, representing a hypofunctional state. In contrast, the hypofunctional state after hypophysectomy and the hyperfunctional state after stimulation of the adrenal cortex via CRH injection did not appear to correlate with the morphology of mitochondria from the zona reticularis and adrenal medulla.     

Urocortin-促肾上腺皮质激素释放激素肽类家族的最新成员

促肾上腺皮质激素释放激素 (ｃｏｒｔｉｃｏｔｒｏｐｉｎｒｅｌｅａｓ 员[6 ] 。1　Ｕｒｏｃｏｒｔｉｎ的发现与命名存在有ＣＲＨ结合蛋白 (ＣＲＨｂｉｎｄｉｎｇｐｒｏｔｅｉｎ ,ＣＲＨ -ＢＰ) ,并且在男性和非妊娠妇女体内有较高浓度的体[6 ,11,12 ] 。 (ａｔｒｉａｌｎａｔｒｉｕｒｅｔｉｃｐｅｐｔｉｄｅ ,ＡＮＰ)和脑利钠素 (ｂｒａｉｎｎａ ｔｒｉｕｒｅｔｉｃｐｅｐｔｉｅｄ ,ＢＮＰ)的分泌 ,这一作用远远大于　　自发现ｕｒｏｃｏｒｔｉｎ以来 ,提出了许多ｕｒｏｃｏｒｔｉｎ可能的生理作用。既然ｕｒｏｃｏｒｔｉｎ在垂体合成[18,1…     

人红细胞免疫小鼠促肾上腺皮质释放激素受体的表达特征

目的　主要探讨人红细胞（ＨＲＢＣ） 免疫过程中脾细胞促肾上腺皮质释放激素（ＣＲＨ）受体的表达特征。方法　以ＨＲＢＣ 免疫小鼠,在动态观察抗体产生及血浆中ＣＲＨ 水平的同时,采用放射配体法检测脾细胞ＣＲＨ 受体的表达情况,并分析抗体产生及受体表达与神经内分泌肽之间的相互关系。结果　测定表明脾细胞上不仅存在ＣＲＨ 受体,并且在免疫过程中第５ 天达高峰（ Ｐ＜ ０－０５） ,相关性分析得知,其与抗体产生密切相关（ ｒ ＝ ０－９３） 。结论　ＣＲＨ 样神经肽类激素可能通过免疫细胞上的ＣＲＨ 受体进行信息传递,为进一步了解神经内分泌免疫调节机制提供依据。     

GABA regulates corticotropin releasing hormone levels in the paraventricular nucleus of the hypothalamus in newborn mice

The paraventricular nucleus of the hypothalamus (PVN) is a major regulator of stress responses via release of corticotropin releasing hormone (CRH) to the pituitary gland. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is characteristic of individuals with major depressive disorder (MDD). Postmortem data from individuals diagnosed with MDD show increased levels of CRH mRNA and CRH immunoreactive neurons in the PVN. In the current study, an immunohistochemical (IHC) analysis revealed increased levels of CRH in the PVN of newborn mice lacking functional GABA_B receptors. There was no difference in the total number of CRH immunoreactive cells. By contrast, there was a significant increase in the amount of CRH immunoreactivity per cell. Interestingly, this increase in CRH levels in the GABA_B receptor R1 subunit knockout was limited to the rostral PVN. While GABAergic regulation of the HPA axis has been previously reported in adult animals, this study provides evidence of region-specific GABA modulation of immunoreactive CRH in newborns.     

Histone deacetylase 1 (HDAC1) participates in the down-regulation of corticotropin releasing hormone gene (crh) expression

The paraventricular nucleus of the hypothalamus (PVH) plays a central role in regulating the hypothalamic-pituitary-adrenal (HPA) axis. Medial parvocellular neurons of the PVH (mpPVH) integrate sensory and humoral inputs to maintain homeostasis. Humoral inputs include glucocorticoids secreted by the adrenals, which down-regulate HPA activation. A primary glucocorticoid target is the population of mpPVH neurons that synthesize and secrete corticotropin-releasing factors, the most potent of which is corticotropin-releasing hormone (CRH). Although CRH gene (crh) expression is known to be down-regulated by glucocorticoids, the mechanisms by which this process occurs are still poorly understood. To begin this study we postulated that glucocorticoid repression of crh involves HDAC recruitment to the region of the crh proximal promoter. To evaluate this hypothesis, we treated hypothalamic cells that express CRH with the HDAC inhibitor trichostatin A (TSA). As predicted, treatment with TSA led to increased CRH mRNA levels and crh promoter activity. Although co-treatment with Dex (10⁻⁷ M) reduced the TSA effect on mRNA levels, it failed to reduce promoter activity; however co-transfection of HDAC1 but not 3 restored Dex inhibition. A distinction between HDAC1 and 3 was also apparent with respect to crh promoter occupancy. Dex led to increased HDAC1 but not HDAC3 occupancy. In vivo studies revealed that CRH-immunoreactive (-ir) neurons contained HDAC1- and HDAC3-ir. Collectively, these data point to a role for HDAC1 in the physiologic regulation of crh.     

Linkage of congenital isolated adrenocorticotropic hormone deficiency to the corticotropin releasing hormone locus using simple sequence repeat polymorphisms

Genetic screening techniques using simple sequence repeat polymorphisms were applied to investigate the molecular nature of congenital isolated adrenocorticotropic hormone (ACTH) deficiency. We hypothesize that this rare cause of hypocortisolism shared by a brother and sister with two unaffected sibs and unaffected parents is inherited as an autosomal recessive single gene mutation. Genes involved in the hypothalamic-pituitary axis controlling cortisol sufficiency were investigated for a causal role in this disorder. Southern blotting showed no detectable mutations of the gene encoding pro-opiomelanocortin (POMC), the ACTH precursor. Other candidate genes subsequently considered were those encoding neuroendocrine convertase-1, and neuroendocrine convertase-2 (NEC-1, NEC-2), and corticotropin releasing hormone (CRH). Tests for linkage were performed using polymorphic di- and tetranucleotide simple sequence repeat markers flanking the reported map locations for POMC, NEC-1, NEC-2, and CRH. The chromosomal haplotypes determined by the markers flanking the loci for POMC, NEC-1, and NEC-2 were not compatible with linkage. However, 22 individual markers defining the chromosomal haplotypes flanking CRH were compatible with linkage of the disorder to the immediate area of this gene on chromosome 8. Based on these data, we hypothesize that the ACTH deficiency in this family is due to an abnormality of CRH gene structure or expression. These results illustrate the useful application of high density genetic maps constructed with simple sequence repeat markers for inclusion/exclusion studies of candidate genes in even very small nuclear families segregating for unusual phenotypes. © 1996 Wiley-Liss, Inc.     

Corticotropin releasing factor (CRF)-stimulation test in normal controls and patients with disturbances of the hypothalamo-pituitary-adrenal axis

Summary Intravenous application of 100 µg synthetic ovine corticotropin releasing factor (CRF) led to stimulation of ACTH-secretion in nine normal controls, with a maximum 30 min after CRF. Cortisol, corticosterone, cortisone and 11-deoxycortisol increased with a maximum at 60 min after CRF, whereas no rise was seen in aldosterone, 11-deoxycorticosterone, 17--hydroxyprogesterone, progesterone, DHEA-S and testosterone. The specificity of CRF-stimulation was also shown by unchanged TSH, LH, FSH, hGH, prolactin and thyroid hormone levels, als well as unchanged insulin and gastrin levels. No serious side-effects were observed during the test period and afterwards.CRF-tests were performed in ten patients with disturbances of the hypothalamo pituitary adrenal axis (HPAA). Preliminary findings show hyperresponsiveness of ACTH in all situations of ACTH-hypersecretion (two patients with Cushing's disease, one patient with Nelson's syndrome, and one with Addison's disease). In contrast, one patient with successful microadenomectomy showed no response of ACTH to CRF, whereas in another patient with a macroadenoma ACTH and cortisol-levels still increased postoperatively. Divergent patterns in ACTH-responsiveness to CRF were seen in four patients with secondary adrenal insufficiency, allowing the localization of the defect. These data point to the possible importance of the CRF-test as a differential diagnostic tool and prognostic factor in diseases of the HPAA.Mit Unterstützung der Deutschen Forschungsgemeinschaft (Sonderforschungsbereich 51)     

大鼠消化道促性腺激素释放激素受体和胰高血糖素的免疫组织化学

目的：观察大鼠胃肠道胰高血糖素免疫反应阳性细胞(EG细胞)分布情况及大鼠回肠促性腺激素释放激素(GnRH)受体和高血糖素的共存关系。方法：免疫组化SABC法。结果：EG细胞散在分布于大鼠回肠和结肠的腺上皮细胞间,阳性物质分布于细胞质。大鼠胃、十二指肠、空肠未见EG细胞分布。回肠邻片免疫染色结果显示EG细胞呈GnRH受体免疫反应阳性。结论：大鼠胃肠道内只有回肠和结肠存在胰高血糖素细胞。回肠内的胰高血糖素细胞可能存在GnRH受体,GnRH可能以自分泌或旁分泌的方式对肠道内EG细胞所分泌的胰高血糖素进行调节。     

生长素释放肽与心脏

生长素释放肽（Growth hormone releasing peptide,GHRP）是一种人工合成的促分泌肽类物质。它能促使垂体生长素的释放。近年研究表明GHRP对心脏有与生长素类似的作用。GHRP对心脏的作用主要是通过存在于心脏的一种特殊受体介导的，而且与其促生长素释放的作用无关。大量实验研究表明，GHRP对心脏具有较全面的保护效应。GHRP可以改善心肌细胞Ca^2 的转运与利用和兴奋－收缩耦联过程，并参与体液因素对心肌细胞的凋节作用。GHRP还能促进心肌细胞损伤后的修复并具有抗细胞凋亡作用。所有这些效应都有利于改善衰竭心脏心室的射血功能。本文综述了GHRP对心脏作用的研究进展，并基于心力衰竭的病理生理学基础，对GHRP作为一种心脏保护药物在心衰治疗中的前景进行了讨论。     

Effects of corticotropin releasing factor (CRF) on sleep and body temperature following controllable footshock stress in mice

Rapid eye movement sleep (REM) is increased after controllable stress (modeled by escapable footshock, ES) and decreased after uncontrollable stress (modeled by inescapable footshock, IS). Decreases in REM after IS are exacerbated by corticotropin releasing factor (CRF) and attenuated by a CRF antagonist. In this study, we trained mice with ES following injections of CRF, astressin (AST), or saline (SAL) to determine whether CRF would alter REM after ES. Male BALB/cJ mice (n = 7) were implanted for recording sleep, activity and body temperature via telemetry and with a guide cannula aimed into a lateral ventricle. After recovery from surgery, sleep following exposure to a novel chamber was recorded as a handling control (HC). The mice received one day of training with ES without injection followed by weekly training sessions in which they received counterbalanced intracerebroventricular (ICV) microinjections of either SAL or CRF (days 7 & 14) or SAL or AST (days 21 & 28) prior to ES. On each experimental day, sleep was recorded for 20 h. Compared to HC, the mice showed significantly increased REM when receiving either SAL or AST prior to ES whereas CRF prior to ES significantly reduced REM. Stress-induced hyperthermia had longer duration after ES compared to HC, and was not significantly altered by CRF or AST compared to SAL. The current results demonstrate that activity in the central CRF system is an important regulator of stress-induced alterations in REM.     

生长素释放肽的发现、发展及展望

生长素释放肽（Growth hormone-releasing peptides,GHRP)于70年代末、80年代初依据蛋氨酸－亮氨酸脑啡肽（met-enkephalin）的结构首次合成。以后又合成了数种类型的GHRP，其结构已远不同于met-enkephalin的结构。但均可强烈刺激生长素（growth hormone,GH）分泌。由于1982年下丘脑生长素释放激素的发现，GHRP研究在80年代进展不大。在90年代，由于制药界的努力和驱动，GHRP研究进展较快，非肽类生长素释放刺激剂（non-peptide GH secretagogues）于1994年首次合成，第一个GHRP受体也于1996年首次克隆成功。1999年从胃内分泌细胞首次发现可能的内源性GHRP,命名为ghrelin。Glrelin可激动GHRP受体并刺激GH分泌。最近几年，GHRP对生长素轴以外的外周组织的作用有诸多报道。GHRP的这些外周作用包括对心血管功能、摄食、脂肪细胞分化、胃酸分泌和胃肠运动的调节等。     

Secretion of growth hormone and thyroid-stimulating hormone in patients with dementia

We studied the growth hormone (GH) response to GH-releasing hormone (GHRH) and the thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) in four groups of patients with dementia and examined whether GH and TSH secretion is altered in patients with Alzheimer's disease. The four groups included those with Alzheimer's disease (n=28), parkinsonism with dementia (n=10), progressive supranuclear palsy with dementia (n=10), and dementia of vascular origin (n=28). The results showed no differences among the four groups in GH response to GHRH (12.2 ± 2, 10.7 ± 2, 8.9 ±1.1, and 9.9 ± 1.9 g/ml, respectively); there was no correlation between GH response to GHRH and sex, stage of the disease, or cerebral atrophy. The proportion of patients with exaggerated, normal, or lower GH response was similar in the four groups. There were also no differences among the groups in terms of TSH response to TRH (9.2 ±0.9, 11.1 ± 1, 11.1 ± 1, and 10.3 ± 1 mU/ml, respectively), nor was there a correlation between TSH response to TRH and sex, stage of the disease, cerebral atrophy, or GH response to GHRH. The proportion of those with exaggerated, normal, or lower TSH response was similar in the four groups. Cerebrospinal somatostatin levels were similar in Alzheimer's disease and vascular dementia patients. These findings indicate that neither GH response to GHRH nor TSH response to TRH provides a useful diagnostic adjunt in Alzheimer's disease patients.Abbreviations AD Alzheimer's disease - PD parkinsonism with dementia - PSP progressive supranuclear palsy - VD dementia of vascular origin - GH growth hormone - GHRH growth hormone releasing hormone - TRH thyrotropin releasing hormone - TSH thyroid stimulating hormone Correspondence to: J.M. Gomez     

被动吸烟下调大鼠卵泡刺激素、黄体生成素、促性腺激素释放激素及其受体的表达

目的 研究被动吸烟对Wistar大鼠卵巢结构、激素受体及血清中激素的影响. 方法 Wistar大鼠32只,分为实验组和对照组(各16只).实验组大鼠吸烟3个月,对照组不予吸烟,3个月后处死大鼠.光镜及电镜下观察各组大鼠卵巢结构的改变,免疫组织化学染色检测激素受体的改变,酶联免疫吸附试验检测血清中激素的改变情况. 结果 实验组大鼠卵巢髓质血管收缩、减少,间质疏松.卵巢颗粒细胞内线粒体水样变、空泡样变,线粒体嵴断裂、模糊;粗面内质网脱颗粒样变.血清卵泡刺激素(FSH)、黄体生成素(LH)、促性腺激素释放激素(GnRH)水平比对照组显著降低,其浓度值比较差异有显著性(P＜0.01,P＜0.05,P＜0.05).实验组大鼠卵巢组织中卵泡刺激素受体(FSHR)、黄体生成素受体(LHR)的表达显著低于对照组(P＜0.01,P＜0.05). 结论 被动吸烟可使大鼠血清中FSH、LH及GnRH水平明显降低,大鼠卵巢中FSHR及LHR的表达减少,提示被动吸烟可破坏卵巢的结构及功能,引起生殖内分泌失调.     

Restoration of disturbed respiration in cats by thyrotrophin releasing hormone

Department of Physiology of Man and Animals, Biological Faculty, M. V. Lomonosov Moscow University. (Presented by Academician of the Academy of Medical Sciences of the USSR I. P. Ashmarin.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 106, No. 7, pp. 17–19, July, 1988.     

中枢CRH在大鼠应激性体温升高和LPS性发热机制中的作用

目的:进一步观察中枢促肾上腺皮质激素释放激素(CRH)在大鼠应激性体温升高和脂多糖(LPS)性发热中枢机制中的作用。方法:第三脑室微量注射CRH受体拮抗剂α-helicalCRH(9-41)和LPS,测定大鼠结肠温度及脑腹中隔区精氨酸加压素(AVP)含量。结果:生理盐水对照组大鼠体温明显升高,最大升幅为(0.88±0.31)℃。第三脑室注射CRH受体拮抗剂α-helicalCRH(9-41)10min后再注射生理盐水组,90min内大鼠结肠温度未见明显波动,90min后体温开始上升,1.5h体温反应指数(TRI_1.5)明显低于生理盐水对照组,而脑腹中隔区AVP含量和TRI_3.5与对照组比较均没有明显差别。第三脑室注射300ng的LPS引起大鼠结肠温度双相性升高,其TRI_3.5明显高于生理盐水对照组。事先向第三脑室注射α-helicalCRH(9-41)(5μg)再注射LPS组,TRI_3.5明显高于LPS组,而脑腹中隔区AVP含量明显低于LPS组。结论:CRH介导应激诱导的早期体温升高。CRH可能通过诱导脑腹中隔区AVP的生成限制大鼠LPS性发热。在大鼠LPS性发热中,CRH可能是一种双相作用分子,一方面本身介导发热体温升高,另一方面又诱生发热体温负调节介质而限制发热体温的升高。