Pituitary-adrenal activity and opioid release in ponies during thiopentone/halothane anaesthesia

The effect of thiopentone/halothane anaesthesia on the release of endogenous opioid, adrenocorticotrophin, arginine vasopressin, cortisol and catecholamine was investigated in ponies. The contribution made by halothane itself was studied by maintaining six ponies with a constant 12 per cent end tidal halothane concentration and five with a concentration ranging between 0.8 and 12 per cent. Cardiorespiratory depression was more prolonged in the ponies receiving a constant 1-2 per cent end tidal halothane concentration than in those which received less halothane. Plasma lactate concentration increased and haematocrit decreased during halothane anaesthesia. The concentrations of met-enkephalin, dynorphin and catecholamines did not change and those of β-endorphin, adrenocorticotrophin, arginine vasopressin and cortisol increased during halothane anaesthesia. Halothane appeared to be a major stimulus to pituitary adrenocortical activation because the adrenocortical secretion was proportional to the amount of halothane inhaled. β-endorphin increased proportionally more than adrenocorticotrophin and their plasma concentrations were not correlated, suggesting that they have independent secretion mechanisms.

Estudo comportamental, hormonal e histopatológico de animais com perda de peso progressina (SEP) e da variável peso associada a uma nova classificação ontogenética em Callithrix jacchus

The use of non-human primates in scientific research has contributed significantly to the biomedical area and, in the case of Callithrix jacchus, has provided important evidence on physiological mechanisms that help explain its biology, making the species a valuable experimental model in different pathologies. However, raising non-human primates in captivity for long periods of time is accompanied by behavioral disorders and chronic diseases, as well as progressive weight loss in most of the animals. The Primatology Center of the Universidade Federal do Rio Grande do Norte (UFRN) has housed a colony of C. jacchus for nearly 30 years and during this period these animals have been weighed systematically to detect possible alterations in their clinical conditions. This procedure has generated a volume of data on the weight of animals at different age ranges. These data are of great importance in the study of this variable from different perspectives. Accordingly, this paper presents three studies using weight data collected over 15 years (1985-2000) as a way of verifying the health status and development of the animals. The first study produced the first article, which describes the histopathological findings of animals with probable diagnosis of permanent wasting marmoset syndrome (WMS). All the animals were carriers of trematode parasites (Platynosomum spp) and had obstruction in the hepatobiliary system; it is suggested that this agent is one of the etiological factors of the syndrome. In the second article, the analysis focused on comparing environmental profile and cortisol levels between the animals with normal weight curve evolution and those with WMS. We observed a marked decrease in locomotion, increased use of lower cage extracts and hypocortisolemia. The latter is likely associated to an adaptation of the mechanisms that make up the hypothalamus-hypophysis-adrenal axis, as observed in other mammals under conditions of chronic malnutrition. Finally, in the third study, the animals with weight alterations were excluded from the sample and, using computational tools (K-means and SOM) in a non-supervised way, we suggest found new ontogenetic development classes for C. jacchus. These were redimensioned from five to eight classes: infant I, infant II, infant III, juvenile I, juvenile II, sub-adult, young adult and elderly adult, in order to provide a more suitable classification for more detailed studies that require better control over the animal development

Morfometria do cerebelo de ratos machos UChA e UChB submetidos a separação materna neonatal (consumidores voluntários de etano)

Pós-graduação em Biologia Geral e Aplicada - IBB

Long-term citalopram administration reduces responsiveness of HPA axis in patients with major depression: relationship with S-citalopram concentrations in plasma and cerebrospinal fluid (CSF) and clinical response.

RATIONALE: A dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a well-documented neurobiological finding in major depression. Moreover, clinically effective therapy with antidepressant drugs may normalize the HPA axis activity. OBJECTIVE: The aim of this study was to test whether citalopram (R/S-CIT) affects the function of the HPA axis in patients with major depression (DSM IV). METHODS: Twenty depressed patients (11 women and 9 men) were challenged with a combined dexamethasone (DEX) suppression and corticotropin-releasing hormone (CRH) stimulation test (DEX/CRH test) following a placebo week and after 2, 4, and 16 weeks of 40 mg/day R/S-CIT treatment. RESULTS: The results show a time-dependent reduction of adrenocorticotrophic hormone (ACTH) and cortisol response during the DEX/CRH test both in treatment responders and nonresponders within 16 weeks. There was a significant relationship between post-DEX baseline cortisol levels (measured before administration of CRH) and severity of depression at pretreatment baseline. Multiple linear regression analyses were performed to identify the impact of psychopathology and hormonal stress responsiveness and R/S-CIT concentrations in plasma and cerebrospinal fluid (CSF). The magnitude of decrease in cortisol responsivity from pretreatment baseline to week 4 on drug [delta-area under the curve (AUC) cortisol] was a significant predictor (p<0.0001) of the degree of symptom improvement following 16 weeks on drug (i.e., decrease in HAM-D21 total score). The model demonstrated that the interaction of CSF S-CIT concentrations and clinical improvement was the most powerful predictor of AUC cortisol responsiveness. CONCLUSION: The present study shows that decreased AUC cortisol was highly associated with S-CIT concentrations in plasma and CSF. Therefore, our data suggest that the CSF or plasma S-CIT concentrations rather than the R/S-CIT dose should be considered as an indicator of the selective serotonergic reuptake inhibitors (SSRIs) effect on HPA axis responsiveness as measured by AUC cortisol response.

Reação do tecido conjuntivo subcutâneo de ratos ao implante de Artglass®: estudo histológico

Indirect composite resin systems have been routinely recommended for making restorations in distressed patients. The purpose of this study was to evaluate histologically in rats the effect of chronic stress on the reaction of subcutaneous connective tissue after implant of Artglass™. For this purpose, 60 rats were divided into four groups (GI (control), GII (stressed), GIII (Artglass™) and GIV (Artglass™. / stressed) received dorsal subcutaneous implants of polyethylene tubes containing saline solution (GI and GII) or Artglass™ (GIII and GIV). In groups of four animals were sacrificed at 7,14 and 28 days postoperatively. The results allowed to observe more intense inflammatory reaction and tissue organization later in the animals subjected to stress.

Efeito do estresse crônico e benzodiazepínicos no reparo ósseo: estudo histológico em ratos

Stress is an environmental factor that may predispose individuals to depression. Benzodiazepines have been prescribed as effective drugs in these situations. The purpose of this study was histological evaluate of the effect of chronic stress and benzodiazepine drugs on bone healing. Bone cavities were created in both tibias of 40 male rats were divided into two groups: Control and Treaty. In this, the stressor stimulus was applied 40 days pre-operative and all post-operative days until sacrifice in the morning for 2 hours, by immobilizing restraint. These animals also received diazepam benzodiazepine group, daily, at a concentration of 5mg/Kg/peso body within 15 days of preoperative. In groups of five animals were sacrificed at 7, 14, 30 and 60 days post-surgery. At 7 days postoperatively, while the control group exhibited tissue rich in fibroblasts, the treated group showed newly formed tissue with few fibroblasts and capillaries along with lymphocytes and macrophages. At 14 days postsurgery, the control group showed newly formed trabecular bone while the treated group progressed to thin trabecular bone with numerous osteoblasts on their borders. At 30 days post-operative bone healing is complete in both groups. At 60 days post-operative characteristics observed in the treated and control groups are similar to the previous period, but with more advanced osteogenesis.

Efeito do envelhecimento e do estresse crônico sobre a reação do tecido conjuntivo subcutâneo: estudo histológico em ratos

Physiological functions undergo a gradual retardation that begins around 25-30 years and extends to the death. Moreover, this change affects most severely the activities more complex and more intricate responses to tensions or stress. The purpose of this study was to evaluate histologically in aged rats the effect of chronic stress on the reaction of subcutaneous connective tissue. The purpose of this study was to evaluate histologically in aged rats the effect of chronic stress on the reaction of subcutaneous connective tissue. For this purpose, 60 rats were divided into four groups (GI (control), GII (stressed), GIII (elderly) and GIV (aged / stressed) received dorsal subcutaneous implants of polyethylene tubes containing saline solution. In groups of four animals were sacrificed at 7,14 and 28 days postoperatively. The results allowed to observe more intense inflammatory reaction and tissue organization later in the aged animals subjected to stress.

Long-term exposure to high corticosterone levels attenuates serotonin responses in rat hippocampal CA1 neurons

Recent studies indicated that hyperactivity of the hypothalamo-pituitary-adrenal system is a considerable risk factor for the precipitation of affective disorders, most notably of major depression. The mechanism by which this hyperactivity eventually leads to clinical symptoms of depression is unknown. In the present animal study, we tested one possible mechanism, i.e., that long-term exposure to high corticosterone levels alters functional responses to serotonin in the hippocampus, an important area in the etiology of depression. Rats were injected daily for 3 weeks with a high dose of corticosterone; electrophysiological responses to serotonin were recorded intracellularly from CA1 pyramidal neurons in vitro. We observed that daily injections with corticosterone gradually attenuate the membrane hyperpolarization and resistance decrease mediated by serotonin-1A receptors. We next used single-cell antisense RNA amplification from identified CA1 pyramidal neurons to resolve whether the functional deficits in serotonin responsiveness are accompanied by decreased expression levels of the serotonin-1A receptor. It appeared that expression of serotonin-1A receptors in CA1 pyramidal cells is not altered; this result was supported by in situ hybridization. Expression of corticosteroid receptors in the same cells, particularly of the high-affinity mineralocorticoid receptor, was significantly reduced after long-term corticosterone treatment. The present findings indicate that prolonged elevation of the corticosteroid concentration, a possible causal factor for major depression in humans, gradually attenuates responsiveness to serotonin without necessarily decreasing serotonin-1A receptor mRNA levels in pyramidal neurons. These functional changes may occur by a posttranscriptional mechanism or by transcriptional regulation of genes other than the serotonin-1A receptor gene itself.

The sympathetic adrenomedullary system, but not the hypothalamic-pituitary-adrenal axis, participates in aorta adaptive response to stress: nitric oxide involvement

Stress induced a decrease in the reactivity of the aorta to noradrenaline (NA), as a consequence of an endothelial nitric oxide (NO) system hyperactivity. The main characteristic of the stress response is activation of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic adrenomedullary (SA) system. The participation of the HPA axis and SA system in the decreased reactivity to NA in the aorta of rats exposed to 4-h immobilization was investigated. Concentration-response relationships for NA were obtained in the aorta, with and without endothelium, isolated from normal and stressed rats, following these procedures: (1) in the absence and presence of L-NAME; (2) after adrenalectomy (ADX) or not, in the absence or presence of L-NAME; (3) ADX rats treated or not with corticosterone; (4) ADX associated with stress; and (5) treated or not with reserpine. The reactivity of aorta without endothelium was unaffected by the procedures. The reactivity of aorta with endothelium was decreased by either stress or ADX. This effect was reversed by both L-NAME and corticosterone. ADX did not potentiate the decrease in the aorta reactivity induced by stress. Reserpine did not change the reactivity of aorta with endothelium from normal rats, but prevented the decrease in reactivity induced by stress. It is concluded that the HPA axis participates in endothelium-dependent modulation of aorta reactivity in normal conditions and that thr SA system participates in hyperactivity of the endothelial NO-system induced by stress, which is responsible for the decreased aorta reactivity to NA. (C) 2000 Elsevier B.V. B.V. All rights reserved.

Glucocorticoid receptor haploinsufficiency causes hypertension and attenuates hypothalamic-pituitary-adrenal axis and blood pressure adaptions to high-fat diet

Glucocorticoid hormones are critical to respond and adapt to stress. Genetic variations in the glucocorticoid receptor (GR) gene alter hypothalamic-pituitary-adrenal (HPA) axis activity and associate with hypertension and susceptibility to metabolic disease. Here we test the hypothesis that reduced GR density alters blood pressure and glucose and lipid homeostasis and limits adaption to obesogenic diet. Heterozygous GR βgeo/+ mice were generated from embryonic stem (ES) cells with a gene trap integration of a β-galactosidase-neomycin phosphotransferase (βgeo) cassette into the GR gene creating a transcriptionally inactive GR fusion protein. Although GRβgeo/+ mice have 50% less functional GR, they have normal lipid and glucose homeostasis due to compensatory HPA axis activation but are hypertensive due to activation of the renin-angiotensin- aldosterone system (RAAS). When challenged with a high-fat diet, weight gain, adiposity, and glucose intolerance were similarly increased in control and GRβgeo/+ mice, suggesting preserved control of intermediary metabolism and energy balance. However, whereas a high-fat diet caused HPA activation and increased blood pressure in control mice, these adaptions were attenuated or abolished in GRβgeo/+ mice. Thus, reduced GR density balanced by HPA activation leaves glucocorticoid functions unaffected but mineralocorticoid functions increased, causing hypertension. Importantly, reduced GR limits HPA and blood pressure adaptions to obesogenic diet.

A preliminary investigation into adrenal responsiveness and outcomes in patients with cardiogenic shock after acute myocardial infarction

PURPOSE: This study investigated the significance of baseline cortisol levels and adrenal response to corticotropin in shocked patients after acute myocardial infarction (AMI). METHODS: A short corticotropin stimulation test was performed in 35 patients with cardiogenic shock after AMI by intravenously injecting of 250 μg of tetracosactrin (Synacthen). Blood samples were obtained at baseline (T0) before and at 30 (T30) and 60 (T60) minutes after the test to determine plasma total cortisol (TC) and free cortisol concentrations. The main outcome measure was in-hospital mortality and its association with T0 TC and maximum response to corticotropin (maximum difference [Δ max] in cortisol levels between T0 and the highest value between T30 and T60). RESULTS: The in-hospital mortality was 37%, and the median time to death was 4 days (interquartile range, 3-9 days). There was some evidence of an increased mortality in patients with T0 TC concentrations greater than 34 μg/dL (P=.07). Maximum difference by itself was not an independent predictor of death. Patients with a T0 TC 34 μg/dL or less and Δ max greater than 9 μg/dL appeared to have the most favorable survival (91%) when compared with the other 2 groups: T0 34 μg/dL or less and Δ max 9 μg/dL or less or T0 34 μg/dL or higher and Δ max greater than 9 μg/dL (75%; P=.8) and T0 greater than 34 μg/dL and Δ max 9 μg/dL or less (60%; P=.02). Corticosteroid therapy was associated with an increased mortality (P=.03). There was a strong correlation between plasma TC and free cortisol (r=0.85). CONCLUSIONS: A high baseline plasma TC was associated with a trend toward increased mortality in patients with cardiogenic shock post-AMI. Patients with lower baseline TC, but with an inducible adrenal response, appeared to have a survival benefit. A prognostic system based on basal TC and Δ max similar to that described in septic shock appears feasible in this cohort. Corticosteroid therapy was associated with adverse outcomes. These findings require further validation in larger studies.

Alterações do Funcionamento da Glândula da Tiróide

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

Renal responses to three types of renin-angiotensin system blockers in patients with diabetes mellitus on a high-salt diet: a need for higher doses in diabetic patients?

Objective Activation of the renal renin-angiotensin system in patients with diabetes mellitus appears to contribute to the risk of nephropathy. Recently, it has been recognized than an elevation of prorenin in plasma also provides a strong indication of risk of nephropathy. This study was designed to examine renin-angiotensin system control mechanisms in the patient with diabetes mellitus.Methods We enrolled 43 individuals with type 2 diabetes mellitus. All individuals were on a high-salt diet to minimize the contribution of the systemic renin-angiotensin system. After an acute exposure to captopril (25 mg), they were randomized to treatment with either irbesartan (300 mg) or aliskiren (300 mg) for 2 weeks.Results All agents acutely lowered blood pressure and plasma aldosterone, and increased renal plasma flow and glomerular filtration rate. Yet, only captopril and aliskiren acutely increased plasma renin and decreased plasma angiotensin II, whereas irbesartan acutely affected neither renin nor angiotensin II. Plasma renin and angiotensin II subsequently did increase upon chronic irbesartan treatment. When given on day 14, irbesartan and aliskiren again induced the above hemodynamic, renal and adrenal effects, yet without significantly changing plasma renin. Irbesartan at that time did not affect plasma angiotensin II, whereas aliskiren lowered it to almost zero.Conclusion The relative resistance of the renal renin response to acute (irbesartan) and chronic (irbesartan and aliskiren) renin-angiotensin system blockade supports the concept of an activated renal renin-angiotensin system in diabetes, particularly at the level of the juxtaglomerular cell, and implies that diabetic patients might require higher doses of renin-angiotensin system blockers to fully suppress the renal renin-angiotensin system. J Hypertens 29: 2454-2461 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

The role of the melanocortin 3 receptor in mediating the effects of gamma-MSH peptides on the adrenal

The pro-opiomelanocortin (POMC)-derived peptides, pro-gamma-MSH (16K fragment), and Lys-gamma(3)-MSH, have been shown to potentiate the steroidogenic action of corticotrophin (ACTH) on the adrenal cortex. Using a continuously perfused adrenal cell column system, we have tested the hypothesis that gamma-MSH peptides exert their effect through the Melanocortin 3 Receptor (MC3-R), since this is the only known receptor to have high affinity for gamma-MSH peptides and has been suggested to be expressed in the rat adrenal. To investigate this hypothesis we tested whether the MC3-R agonist MTII and antagonist SHU9119 could mimic or block the actions of pro-gamma-MSH. We found that MTII could not mimic, and SHU9119 could not block pro-gamma-MSH mediated potentiation of ACTH-induced steroidogenesis. These results suggest that the MC3-R is not involved in mediating the potentiation effect, adding further evidence to the argument that another melanocortin receptor exists.