Cadmium effects on hypothalamic activity and pituitary hormone secretion in the male

Cadmium specifically modify amine metabolism at the central nervous system and pituitary hormone secretions. Thus, the physiological functions controlled by these hormones can be modulated by cadmium. This xenobiotic is associated with deleterious effects on the gonadal function and with changes in the secretory pattern of other pituitary hormones like prolactin, ACTH, GH or TSH. The observed changes in pituitary hormone secretion do not correlate with the modifications of central nervous system metabolism of the neurotransmitters involved in their regulation. The accumulative data indicates the existence of a disruption in the regulatory mechanisms of the hypothalamic–pituitary axis. The physiological significance of these effects remains to be elucidated.     

CO from enhanced HO activity or from CORM-2 inhibits both O2- and NO production and downregulates HO-1 expression in LPS-stimulated macrophages

Carbon monoxide (CO) arising from heme degradation, catalyzed particularly by the stress-inducible heme oxygenase-1 (HO-1), has recently been demonstrated to provide cytoprotection against cell death in macrophages stimulated with bacterial lipopolysaccharide (LPS). In the present study, we determined the effects of CO on the production of reactive oxygen species (ROS) and nitric oxide (NO) by the LPS-stimulated RAW 264.7 macrophages. In addition, effect of CO-exposure on the production of superoxide (O(2)(-)) in the phorbol myristate acetate (PMA)-stimulated PLB-985 neutrophils was determined. Production of ROS by the LPS-stimulated macrophages pretreated with 50microM [Ru(CO)(3)Cl(2)](2), a CO-releasing molecule (CORM-2), was abolished and the production of O(2)(-) by the PMA-stimulated neutrophils pretreated with the CORM-2 was decreased markedly. The CORM-2 (50microM) was not cytotoxic to both the unstimulated and LPS-stimulated macrophages when determined by employing mitochondrial reductase function test (MTT assay). In macrophages pretreated with increasing doses of CORM-2, both the LPS-derived upregulations of iNOS (NO production) and HO-1 expression (CO production) were suppressed in a dose-dependent manner. Alternatively, when the macrophages were treated with LPS and CO-donor together, the LPS-derived increase in NO production was decreased. Conversely, when the control and LPS-stimulated macrophages were treated with zinc protoporphyrin IX (ZnPP) to inhibit the HO activity blocking endogenous production of CO (basal and enhanced), macrophages died extensively. Interestingly, production of NO in the LPS-stimulated macrophages increased significantly following the ZnPP treatment. Addition of CORM-2 to the LPS-treated cells that were being treated additionally with ZnPP did not prevent the cell death. However, endogenous overproduction of CO by super-induction of HO-1 (obtained by pretreatment of macrophages with either buthionine sulfoximine or hemin) decreased the LPS-derived iNOS expression without affecting cell survival. Combined, these results indicated that enhanced HO activity is essential for the survival of LPS-stimulated macrophages. Thus, upregulation of HO-1 and overproduction of CO may allow the survival of LPS-stimulated macrophages; first, by eliminating the free heme to prevent Fenton reaction, second, by limiting the availability of free heme required for induction of NO-producing heme enzyme (i.e., iNOS), third, by limiting additional production of O(2)(-) and NO via CO-derived inhibition on the activities of heme enzymes like NADPH oxidase and iNOS, respectively. CO may allow the LPS-activated macrophages to return back to the normal quiet state insensitive to additional stimuli causing oxidative stress.     

The association between inflammatory markers (iNOS,HO-1, IL-33, MIP-1β) and depression with and without posttraumatic stress disorder

Background

Both major depression and posttraumatic stress disorder (PTSD) are characterized by inflammation, increased concentration levels of proinflammatory cytokines, decreased neurogenesis followed by neuroprogression, as well as mitochondrial and the hypothalamic-pituitary-adrenal axis dysfunction. Elevated levels of oxidative stress caused by an increased activity of prooxidants over antioxidants are also observed. Based on several reports, depressive episodes can lead to the sensitization of immune-inflammatory pathways. Thus, depression, PTSD, and depression comorbid with PTSD are associated with immune-inflammatory markers. The study aimed at evaluating concentration levels of iNOS, HO-1, IL-33, and MIP-1β in depression with and without PTSD.

Manganese acts centrally to activate reproductive hormone secretion and pubertal development in male rats

Manganese (Mn) is an important element for normal growth and reproduction. Because Mn accumulates in the hypothalamus and is capable of stimulating puberty-related hormones in female rats, we assessed whether this metal could cause similar effects in male rats. We have demonstrated that MnCl₂, when administered acutely into the third ventricle of the brain, acts dose dependently to stimulate luteinizing hormone (LH) release. Furthermore, there was a dose dependent stimulation in the secretion of LH-releasing hormone (LHRH) from the medial basal hypothalamus in vitro, and administration of an LHRH receptor antagonist in vivo blocks Mn-induced LH release. To assess potential chronic effects of the metal, male pups were supplemented with 10 or 25 mg MnCl₂ per kg by gastric gavage from day 15 until days 48 or 55, at which times developmental signs of spermatogenesis were assessed. Results demonstrate that while significant effects were not observed with the 10 mg/kg dose, the animals receiving the 25 mg/kg dose showed increased LH (p < 0.05), FSH (p < 0.01) and testosterone (p < 0.01) levels at 55 days of age. Furthermore, there was a concomitant increase in both daily sperm production (p < 0.05) and efficiency of spermatogenesis (p < 0.05), demonstrating a Mn-induced acceleration in spermatogenesis. Our results suggest Mn is a stimulator of prepubertal LHRH/LH secretion and may facilitate the normal onset of male puberty. These data also suggest that the metal may contribute to male precocious pubertal development should an individual be exposed to low but elevated levels of Mn too early in life.     

The effects of chlormequat chloride on the development of pubertal male rats

Chlormequat Chloride (CCC) is a plant growth regulator that is widely applied in agriculture. Previous studies have shown that long-term exposure of CCC could decrease body weight in animals. However, the underlying mechanisms have not been studied. In this study, CCC was administered to rats daily by gavage on postnatal days 23–60 at doses of 0, 75, 150 and 300 mg/kg bw/d. The results showed that body weight and the length of the right femur were significantly decreased in the 300 mg/kg bw/d group. Histological analysis of proximal growth plates of the right femurs showed narrowed proliferative zones and hypertrophic zones in CCC-treated groups. The mRNA expression of growth hormone, growth hormone receptor and insulin like growth factor 1 were decreased in the CCC-treated group. The results indicated that CCC may affect the expression of growth hormone and insulin-like growth factor 1 and subsequently cause a decrease in body weight and bone length.     

藿香提取液对大鼠小肠一氧化氮合酶分布的影响

目的 探讨藿香煎液促进小肠运动的可能机制。方法 32只Wistar大鼠随机分为藿香组及对照组，分别给大鼠灌服藿香水提取液或蒸馏水1小时、6小时后，用免疫组织化学的方法观察空、回肠组织一氧化氮合酶（NOSI）的分布变化。结果 灌服藿香水提液1小时后，空、回肠中NOSI阳性神经仍明显减少（P＜0.01或P＜0.05)，6小时后空肠肌间神经丛NOSI阳性神经仍明显减少（P＜0.05)，回肠中NOSI阳性神经无明显变化。结论 藿香对小肠动力的促进作用可能与空、回肠NOSI的分布减少有关。     

Vigilance and EEG power in rats: effects of potent inhibitors of the neuronal nitric oxide synthase

We examined the effects of potent neuronal nitric oxide synthase inhibitors, 3-bromo-7-nitro indazole (3-Br-7-NI) and S-methyl-L-thiocitrulline (S-Me-TC) on general behaviour, vigilance stages and electro-encephalographic (EEG) power spectra in rats. In addition, we studied the effect of 7-nitro indazole (7-NI) on EEG power spectra in rats during dark and light periods. 3-Br-7-NI induced ptosis and decrease of slow wave sleep and rapid eye movement sleep in the rat. 7-NI and 3-Br-7-NI reduced the EEG power density in all frequency bands in the rat, suggesting a depression of central neuronal activity. This effect of 7-NI was more prominent during the day than during the night, indicating a circadian variation in the nitric oxide synthase (NOS) response to NOS inhibitor. EEG power was the most reduced in the 7-9Hz range of the rhythmic slow activity (theta rhythm), which is in accordance with decreased locomotion observed following administration of NOS inhibitors. Although S-Me-TC is the most potent NOS inhibitor in vitro experiments, it had less effect on vigilance and EEG power in the rat than other NOS inhibitors used in this study, probably due to its short lasting and blood pressure raising effect. The present results indicate that nitric oxide exerts an excitatory and circadian dependent effect in the central neuronal structures involved in the regulation of vigilance. Received: 16 September 1996 / Accepted: 4 April 1997     

赖诺普利与氯沙坦预防压力负荷性心肌肥厚的实验研究

目的 探讨大鼠心肌肥厚时心血管重构的结构、生化改变及赖诺普利与氯沙坦对心血管重构的预防作用。方法 膈下腹主动脉缩窄法建立大鼠心肌肥厚模型。假手术组、模型组、降压和非降压剂量赖诺普利与氯沙坦在术后第2天用药至30天后，检测平均动脉压(MAP)、心肌肥厚程度及局部心肌组织一氧化氮(N0)、一氧化氮合酶(NOS)和胶原蛋白含量。结果 (1)与假手术组相比，模型组MAP、左室重量(LVW)、左室重量指数(LVMI)、心肌细胞横径(TDM)、胶原蛋白分别提高28．6％、20．5％、26．9％、17．9％、54．4％(P＜0．01)；NO、NOS分别降低53．4％、51．2％(P＜0．01)。(2)降压剂量赖诺普利与氯沙坦和非降压剂量氯沙坦干预后，LVW、LVMI、TDM、NO、NOS、胶原蛋白含量与假手术组无明显差异。非降压剂量赖诺普利可使LVW、LVMI和TDM下降，但仍高于假手术组(P＜0．01)，NO、NOS改善不明显；(3)LVMI与MAP、胶原蛋白含量均呈正相关(分别为γ=0．7841，γ=0．8177，P＜0．01)，与NO显负相关(γ=-0．7730，P＜0．01)。结论 心血管重构与血压、心脏间质成分及NO有密切关系；赖诺普利预防心肌肥厚可能是血流动力学和非血流动力学因素共同作用的结果；氯沙坦可能主要依靠非血流动力学因素抗心肌肥厚。     

Investigation of a possible interaction between the heme oxygenase/biliverdin reductase and nitric oxide synthase pathway in murine gastric fundus and jejunum

This study investigated the possible interaction between the heme oxygenase (HO)/biliverdin reductase (BVR) and nitric oxide synthase (NOS) pathway in murine gastric fundus and jejunum, since previous studies have shown that both HO-2 and BVR are expressed in interstitial cells of Cajal (ICCs) and co-localized with neuronal NOS in a large proportion of myenteric neurons along the gastrointestinal tract. Neither HO inhibition by chromium mesoporphyrin (CrMP) nor co-incubation with CO or biliverdin/bilirubin affected nitrergic neurotransmission - i.e. relaxations induced by non-adrenergic non-cholinergic (NANC) nerve stimulation or exogenous NO - under normal physiological conditions. However, biliverdin/bilirubin reversed the inhibitory effect of the superoxide generator LY83583 on exogenous NO-induced relaxations in both tissues. When gastric fundus muscle strips were depleted of the endogenous antioxidant Cu/Zn superoxide dismutase (SOD) by the Cu-chelator DETCA, electrically induced NANC relaxations were also affected by LY82583; however, biliverdin/bilirubin could not substitute for the loss of Cu/Zn SOD when this specific antioxidant enzyme was depleted. In jejunal muscle strips, the combination DETCA plus LY83583 nearly abolished contractile phasic activity and, hence, did not allow studying nitrergic relaxation in these experimental conditions. In conclusion, this study does not establish a role for HO/CO in inhibitory NANC neurotransmission in murine gastric fundus and jejunum under normal physiological conditions. However, the antioxidants biliverdin/bilirubin might play an important role in the protection of the nitrergic neurotransmitter against oxidative stress.     

Effects of opioid (tramadol) treatment on testicular functions in adult male rats: The role of nitric oxide and oxidative stress

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Facilitation of copulatory performance in male rats by naloxone: Effects of hypophysectomy, 17 α-estradiol,and luteinizing hormone releasing hormone

Three experiments were performed to explore the mechanism whereby systemic administration of the opiate receptor antagonist, naloxone hydrochloride (20 mg/kg) causes reductions in the frequency of intromissions preceding ejaculation and latency to ejaculation in sexually experienced male rats. Administration of naloxone to male rats which were hypophysectomized in addition to being castrated and implanted SC with 30 mm silastic capsules containing testosterone caused such behavioral changes, suggesting that these behavioral effects of naloxone do not result from interference with the binding of endorphin of pituitary origin. Surprisingly, a significant facilitatory effect of naloxone on sexual performance was absent in castrated controls bearing 30 mm testosterone implants. Recent evidence suggests that 17α-hydroxylated estrogens, which may be produced in gonadally intact males, possess appreciable affinity for opioid receptors. However, daily administration of 17α-estradiol (50 μg) to castrated, testosterone-implanted males failed to make them as behaviorally responsive to naloxone as gonadally intact animals. Administration of LHRH (1 μg given SC 1.5 hr prior to testing) caused a significant reduction in ejaculation latency in gonadally intact males but not in castrated males bearing 30 mm testosterone implants. It is suggested that the facilitatory effect of naloxone on masculine sexual performance results, in part, from a drug-induced release of LHRH.     

垂体腺瘤患者血浆神经肽Y与生长激素水平相关性研究

目的 探讨垂体腺瘤患者血浆神经肽Y与生长激素之间的相关关系。方法 收集82例垂体腺瘤患者空腹静脉血3ml,进行血浆神经肽Y放射免疫测定分析,并与生长激素水平进行相关分析。初步探讨神经肽Y与生长激素之间的相关性。结果 促性腺激素细胞腺瘤患者中血浆神经肽Y与生长激素呈负相关。而在其他组别中神经肽Y与生长激素均无相关。结论 神经肽Y参与了垂体腺瘤病理生理状态中下丘脑-垂体轴生长激素的调节,可能与垂体腺瘤的发生有关。     

左旋多巴和吡啶斯的明对脑垂体生长激素分泌的影响

目的:观察左旋多巴和吡啶斯的明对脑垂体生长激素(hGH)分泌的影响。方法:正常对照组20例、垂体性侏儒组30例,分别用左旋多巴和吡啶斯的明刺激。观察刺激后30、60、90、120min血清hGH水平,hGH峰值<10ng/mL为阳性。结果:左旋多巴和吡啶斯的明刺激后正常儿童hGH峰值为32.4±22.6和27.7±13.6ng/ml,假阳性率为10%和15%,两组无显著差异(P>0.05);垂体性侏儒组无分泌峰或峰值<10ng/ml。结论:左旋多巴和吡啶斯的明对脑垂体生长激素的分泌有良好的刺激作用,可以作为hGH激发试验的刺激药物。     

Molecular basis for arsenic-induced alteration in nitric oxide production and oxidative stress: implication of endothelial dysfunction

Accumulated epidemiological studies have suggested that prolonged exposure of humans to arsenic in drinking water is associated with vascular diseases. The exact mechanism of how this occurs currently unknown. Nitric oxide (NO), formed by endothelial NO synthase (eNOS), plays a crucial role in the vascular system. Decreased availability of biologically active NO in the endothelium is implicated in the pathophysiology of several vascular diseases and inhibition of eNOS by arsenic is one of the proposed mechanism s for arsenic-induced vascular diseases. In addition, during exposure to arsenic, overproduction of reactive oxygen species (ROS) can occur, resulting in oxidative stress, which is another major risk factor for vascular dysfunction. The molecular basis for decreased NO levels and increased oxidative stress during arsenic exposure is poorly understood. In this article, evidence for arsenic-mediated alteration in NO production and oxidative stress is reviewed. The results of a cross-sectional study in an endemic area of chronic arsenic poisoning and experimental animal studies to elucidate a potential mechanism for the impairment of NO formation and oxidative stress caused by prolonged exposure to arsenate in the drinking water are also reviewed.     

Endocrine disrupting effects of dichlorodiphenyltrichloroethane analogues on gonadotropin hormones in pituitary gonadotrope cells

It has been shown that exposure to dichlorodiphenyltrichloroethane (DDT) analogues leads to disharmony of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). However, the effects and mechanisms of DDT analogues on the expression of gonadotropin genes (FSHβ, LHβ and Cgα), which is the rate-limiting step of FSH and LH biosynthesis, remain unknown. In this study, we assessed the effects of p,p′-DDT, o,p′-DDT, p,p′-dichlorodiphenyldichloroethylene (p,p′-DDE) and methoxychlor (MXC) on gonadotropin genes expression and hormones synthesis in gonadotrope cells. p,p′-DDT and MXC at test concentrations ranging from 10⁻⁹ to 10⁻⁷ mol/L, stimulated gonadotropin genes expression and hormones synthesis in a dose-dependent manner. The activation of extracellular signal-regulated kinase (ERK) was required for the induction of gonadotropin genes expression and hormones synthesis by p,p′-DDT or MXC exposure. This study showed for the first time that p,p′-DDT and MXC regulated gonadotropin genes expression and hormones synthesis through ERK pathway in gonadotrope cells.     

一氧化氮及一氧化氮合酶在成年与老年大鼠前列腺中的变化

目的:研究一氧化氮(NO)及一氧化氮合酶(NOS)在成年与老年大鼠前列腺中的变化,探讨在大鼠前列腺老年化过程中的临床意义。方法:取4月龄及20月龄SD雄性大鼠各6只,分别取前列腺组织匀浆,检测其NO与NOS活性。结果:老年组大鼠的NO与NOS活性明显低于成年组(P<0.05)。结论:老年大鼠前列腺组织中NO水平及NOS活性的降低可能与前列腺良性增生及功能减退有关。     

慢性神经痛大鼠鞘内联合应用吗啡和氯胺酮在脊髓上水平的抗伤害性作用及对吗啡耐受的影响

目的研究鞘内联合应用吗啡和氯胺酮对慢性神经痛大鼠的抗伤害作用机制及对吗啡耐受的影响。方法 40只Wistar大鼠,体质量220～260 g,制备坐骨神经结扎模型并进行鞘内置管,随机分为5组(n=8):B组为空白对照组;C组鞘内注射0.9%盐水10μL;K组鞘内注射氯胺酮50μg;M组鞘内注射吗啡20μg;KM组鞘内注射吗啡10μg和氯胺酮25μg。坐骨神经结扎术后第4天开始鞘内给药,每日1次,连续7 d。用药7d后处死大鼠,取大脑皮质、海马、脑干组织,硝酸还原酶法测定NO浓度和NOS活性。结果与B组比较,C和K组脑干NO浓度升高,M组皮质、海马、脑干中NO浓度均升高;与C组比较,M组皮质、海马NO浓度升高,KM组海马、脑干中NO浓度降低;与M组比较,KM组皮质、海马、脑干NO浓度均降低(P<0.05或0.01)。与B组比较,C、K和M组皮质、海马、脑干中NOS活性均升高;与C和M组比较,KM组皮质、海马、脑干中NOS活性均降低(P<0.05或0.01)。结论神经病理性痛大鼠鞘内联合应用吗啡和氯胺酮可在脊髓上水平产生抗伤害性作用,并可抑制吗啡耐受的形成,这可能与大脑皮质、海马、脑干的NO水平和NOS活性有关。     

Effects of nitric oxide synthase inhibitors on the discriminative stimulus effects of cocaine in rats

RATIONALE: Nitric oxide synthase (NOS) inhibitors may modulate the discriminative stimulus effects of cocaine because they alter dopamine (DA) release. OBJECTIVES: The effects of the NOS inhibitors NG-nitro-L-arginine methyl ester (L-NAME) and 7-nitro-indazole (7-NI) were examined in experiments designed to better understand the mechanisms that may underlie the interactions between NOS inhibitors and cocaine. METHODS: Rats were trained to discriminate 10 mg/kg cocaine from saline, and then substitution and pretreatment tests with L-NAME and 7-NI were conducted. To determine if the combined effects of NOS inhibitors and cocaine might be related to DA mechanisms and/or to N-methyl-D-aspartate (NMDA) receptor mechanisms, substitution tests with other indirect DA agonists and NMDA antagonists were carried out in the presence and absence of L-NAME. In addition, the roles of the D1 and D2 families of DA receptors in mediating the cocaine-altering effects of L-NAME and 7-NI were examined in antagonism tests using SCH 23390 and haloperidol, respectively. RESULTS: The results demonstrated that neither NOS inhibitor alone substituted for the 10 mg/kg cocaine training dose, but when given as a pretreatment, 100 mg/kg L-NAME as well as 10 mg/kg 7-NI enhanced the discriminative stimulus and rate-decreasing effects of cocaine. L-NAME pretreatment also enhanced the potency of (+)-amphetamine and GBR 12909, but not MK-801, phencyclidine, or NPC 17742, for producing discriminative stimulus and rate-decreasing effects in substitution tests. Further testing showed that the cocaine-enhancing effects of L-NAME and 7-NI were attenuated by doses of haloperidol and SCH 23390 that minimally altered the effects of cocaine alone. CONCLUSIONS: These findings suggest that L-NAME and 7-NI may increase the potency of cocaine and other indirect DA agonists through a central mechanism whereby DA neurotransmission is directly enhanced by NOS inhibition.     

Chromium VI administration induces oxidative stress in hypothalamus and anterior pituitary gland from male rats

Hexavalent chromium (Cr VI)-containing compounds are known carcinogens which are present in industrial settings and in the environment. The major route of chromium exposure for the general population is oral intake. Previously we have observed that Cr VI affects anterior pituitary secretion and causes oxidative stress in vitro. The aim of the present work was to investigate if in vivo Cr VI treatment (100 ppm of Cr VI in drinking water for up 30 days) causes oxidative stress in hypothalamus and anterior pituitary gland from male rats. This treatment produced a 4-fold increase of chromium content in hypothalamus and 10-fold increase in anterior pituitary gland. Lipid peroxidation showed a significant increase in hypothalamus and anterior pituitary. Cr VI augmented superoxide dismutase activity in anterior pituitary gland and glutathione reductase activity in hypothalamus, but glutathione peroxidase and catalase activities remained unchanged in both tissues. Heme oxygenase-1 mRNA expression significantly rose in both tissues. Metallothionein 1 mRNA content increased in anterior pituitary and metallothionein 3 mRNA increased in hypothalamus. These results show, for the first time, that oral chronic administration of Cr VI produces oxidative stress on the hypothalamus and anterior pituitary gland which may affect normal endocrine function.     

低渗造影剂对老年糖尿病大鼠肾毒性的研究

目的观察低渗造影剂欧乃派克350对老年糖尿病大鼠肾功能的影响。方法建立老年糖尿病大鼠模型,观察尾静脉注射欧乃派克350(10ml/kg)后,大鼠血肌酐、尿素氮以及肾组织匀浆一氧化氮(NO)、谷胱甘肽(GSH)的含量。结果老年糖尿病大鼠血肌酐、尿素氮与正常对照组比较均升高(P<0.05),肾组织匀浆一氧化氮、谷胱甘肽与正常对照组比较均下降(P<0.01,P<0.05)。注射造影剂后,血肌酐与正常对照组比较明显升高(P<0.01),肾组织匀浆一氧化氮与糖尿病对照组比较下降(P<0.05)。结论低渗造影剂可以引起老年糖尿病大鼠肾损伤,可能与糖尿病大鼠NO合成或消耗失调,进一步激活NO信号通路有关。