Fludrocortisone: Role in Central Regulation of Fluid Balance

We have performed 7 experiments in rats on the effects of systemic treatment with fludrocortisone (9a-FF) given in a variety of doses over a variety of times, in the AM and in the PM. These experiments were designed to determine the best treatment protocol to use in the head-down rat model studies which were performed at NASA-Ames Research Center during the final year. The results of the experiments in non-stressed rats have been, on the whole, disappointing in that we have so far been unable to obtain direct evidence that the 9a-FF acts as a mineralocorticoid. In the ultimate experiments using control and suspended rats, we showed mineralocorticoid and glucocorticoid effects of 9aFF. However, suspension served in our rats as a chronic stressor when they were examined 5 d after the onset of treatment

Origin of ultradian pulsatility in the hypothalamic–pituitary–adrenal axis

The hypothalamic–pituitary–adrenal (HPA) axis is a neuroendocrine system that regulates the circulating levels of vital glucocorticoid hormones. The activity of the HPA axis is characterized not only by a classic circadian rhythm, but also by an ultradian pattern of discrete pulsatile release of glucocorticoids. A number of psychiatric and metabolic diseases are associated with changes in glucocorticoid pulsatility, and it is now clear that glucocorticoid responsive genes respond to these rapid fluctuations in a biologically meaningful way. Theoretical modelling has enabled us to identify and explore potential mechanisms underlying the ultradian activity in this axis, which to date have not been identified successfully. We demonstrate that the combination of delay with feed-forward and feedback loops in the pituitary–adrenal system is sufficient to give rise to ultradian pulsatility in the absence of an ultradian source from a supra-pituitary site. Moreover, our model enables us to predict the different patterns of glucocorticoid release mediated by changes in hypophysial-portal corticotrophin-releasing hormone levels, with results that parallel our experimental in vivo data

Gender differences in endocrine responses to posture and 7 days of 6 deg head down bed rest

Endocrine regulation of fluids and electrolytes during seven days of 6 deg head down bed rest (HDBR) was compared in male (n = 8) and, for the first time, female (n = 8) volunteers. The subjects' responses to quiet standing for 2 hr before and after HDBR were also tested. In both sexes, diuresis and natriuresis were evident during the first 2-3 days of HDBR, resulting in a marked increase in the urinary Na/K ratio and significant Na retention on reambulation. After the first day of HDBR, plasma renin activity (PRA) was increased relative to aldosterone, plasma volume was decreased, and the renal response to aldosterone appeared to be appropriate. Circulating levels of arginine vasopressin (AVP), cortisol, and ACTH were unchanged during HDBR. Plasma testosterone decreased slightly on day 2 of HDBR in males. The ratio of AM ACTH to cortisol was lower in females than in males because ACTH was lower in females. Urinary cortisol increased and remained elevated throughout the HDBR in males only. There were no gender differences in the responses to 7 day HDBR, except those in the pituitary-adrenal system; those differences appeared unrelated to the postural change. The provocative cardiovascular test of quiet standing before and after bed rest revealed both sex differences and effects of HDBR. There were significant sex differences in cardiovascular responses to standing, before and after HDBR. Females had greater PRA and aldosterone responses to standing before bedrest and larger aldosterone responses to standing after HDBR than males. Cardiovascular responses to standing before and after bedrest differed markedly: arterial pressure and heart rates increased with standing before HDBR, by contrast, arterial pressure decreased, with greater increases in heart rates after HDBR. In both sexes, all hormonal responses to standing were greater after HDBR. The results show clearly that similar responses to standing as well as to HDBR occur in both sexes, but that females exhibit greater PRA and aldosterone responses than males

Dietary cholesterol directly induces acute inflammasome-dependent intestinal inflammation

Prolonged ingestion of a cholesterol- or saturated fatty acid-enriched diet induces chronic, often systemic, auto-inflammatory responses resulting in significant health problems worldwide. In vivo information regarding the local and direct inflammatory effect of these dietary components in the intestine and, in particular, on the intestinal epithelium is lacking. Here we report that both mice and zebrafish exposed to high-fat (HFDs) or high-cholesterol (HCDs) diets develop acute innate inflammatory responses within hours, reflected in the localized interleukin-1β-dependent accumulation of myeloid cells in the intestine. Acute HCD-induced intestinal inflammation is dependent on cholesterol uptake via Niemann-Pick C1-like 1 and inflammasome activation involving apoptosis-associated Speck-like protein containing a caspase recruitment domain, which leads to Caspase-1 activity in intestinal epithelial cells. Extended exposure to HCD results in localized, inflammation-dependent, functional dysregulation as well as systemic pathologies. Our model suggests that dietary cholesterol initiates intestinal inflammation in epithelial cells

Immunomagnetic t-lymphocyte depletion (ITLD) of rat bone marrow using OX-19 monoclonal antibody

Graft versus host disease (GVHD) may be abrogated and host survival prolonged by in vitro depletion of T lymphocytes from bone marrow (BM) prior to allotransplantation. Using a mouse anti-rat pan T-lymphocyte monoclonal antibody (0×19) bound to monosized, magnetic, polymer beads, T lymphocytes were removed in vitro from normal bone marrow. The removal of the T lymphocytes was confirmed by flow cytometry. Injection of the T-lymphocyte-depleted bone marrow into fully allogeneic rats prevents the induction of GVHD and prolongs host survival. A highly efficient technique of T-lymphocyte depletion using rat bone marrow is described. It involves the binding of OX-19, a MoAb directed against all rat thy-mocytes and mature peripheral T lymphocytes, to monosized, magnetic polymer spheres. Magnetic separation of T lymphocytes after mixing the allogeneic bone marrow with the bead/OX-19 complex provides for a simple, rapid depletion of T lymphocytes from the bone marrow. In vitro studies using flow cytometry and the prevention of GVHD in a fully allogeneic rat bone marrow model have been used to demonstrate the effectiveness of the depletion procedure. © 1989 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted

Development neurobiology of the stress response: multilevel regulation of corticotropin-releasing hormone function.

The ability to respond to adverse environmental cues is present in the neonatal and infant rat, although in an immature form: A number of laboratories have demonstrated stress-induced elevations of plasma glucocorticoids during the first two postnatal weeks. The limbic and hypothalamic mechanisms controlling the hormonal stress-response during this period are not fully understood and are, therefore, the focus of this report. Both hypothalamic corticotropin-releasing hormone (CRH) and vasopressin contribute to the release of ACTH from the pituitary in the adult. The relative roles of these two peptides during the neonatal (first week) and infant (second week) developmental period, are controversial. Evidence is presented that argues strongly for a major role for CRH. Up-regulation of hypothalamic CRH synthesis is a major component in the mature stress response. CRH-mRNA levels in the hypothalamic PVN are increased with cold stress by ninth postnatal day, but not during the first postnatal week. Further, down-regulation of CRH gene expression by glucocorticoids (GC) constitutes a critical "shut-down" mechanism for the hormonal stress response. In vivo and in vitro experiments supporting the "immaturity" of GC feedback on CRH synthesis during the first postnatal week are described. CRH-mediated neurotransmission, in both the endocrine and neuronal effector arms of the response to stress may be modulated via alteration of receptor number. The first member of the CRH receptor family, CRF1, probably mediates the neuroendocrine effects of CRH. The developmental profile of CRF1-mRNA reveals several distinctive spatial and temporal patterns. In the hippocampal CA1, CA2, and CA3a peak (300-600% adult values) CRF1-mRNA is found on postnatal day 6. In the amygdala, CRH receptor mRNA levels are maximal on the ninth postnatal day (at 180% of adult values). In cortex, a steady decline from high postnatal day 2 levels results in adult levels by 12. These findings demonstrate distinct, regional, age-specific control of the synthesis of CRF1. Receptor expression profile may provide important information regarding modulation of the age-specific roles of CRH in different regions. For example, a high ratio of hippocampus/amygdala receptors may preferentially activate negative hippocampal input to the hypothalamus during the neonatal period. Additionally, increased CRH receptor mRNA in the infant compared with the adult provides a mechanism for enhanced excitatory effect of the peptide at this age. In conclusion, increasing evidence exists for multiple control points of the early postnatal response and adaptation to stress. CRH synthesis in hypothalamus and amygdala, its sensitivity to GC feedback, and the abundance and distribution of at least two distinct CRH receptors in the limbic central nervous system and the pituitary are developmentally regulated. All serve as control points permitting an effective endocrine, autonomic, and behavioral response to stressful environmental cues

Olive phenology as a sensitive indicator of future climatic warming in the Mediterranean

Experimental and modelling work suggests a strong dependence of olive flowering date on spring temperatures. Since airborne pollen concentrations reflect the flowering phenology of olive populations within a radius of 50 km, they may be a sensitive regional indicator of climatic warming. We assessed this potential sensitivity with phenology models fitted to flowering dates inferred from maximum airborne pollen data. Of four models tested, a thermal time model gave the best fit for Montpellier, France, and was the most effective at the regional scale, providing reasonable predictions for 10 sites in the western Mediterranean. This model was forced with replicated future temperature simulations for the western Mediterranean from a coupled ocean-atmosphere general circulation model (GCM). The GCM temperatures rose by 4·5 °C between 1990 and 2099 with a 1% per year increase in greenhouse gases, and modelled flowering date advanced at a rate of 6·2 d per °C. The results indicated that this long-term regional trend in phenology might be statistically significant as early as 2030, but with marked spatial variation in magnitude, with the calculated flowering date between the 1990s and 2030s advancing by 3–23 d. Future monitoring of airborne olive pollen may therefore provide an early biological indicator of climatic warming in the Mediterranean

Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone

The adrenal hormone corticosterone transcriptionally regulates responsive genes in the rodent hippocampus through nuclear mineralocorticoid and glucocorticoid receptors. Via this genomic pathway the hormone alters properties of hippocampal cells slowly and for a prolonged period. Here we report that corticosterone also rapidly and reversibly changes hippocampal signaling. Stress levels of the hormone enhance the frequency of miniature excitatory postsynaptic potentials in CA1 pyramidal neurons and reduce paired-pulse facilitation, pointing to a hormone-dependent enhancement of glutamate-release probability. The rapid effect by corticosterone is accomplished through a nongenomic pathway involving membrane-located receptors. Unexpectedly, the rapid effect critically depends on the classical mineralocorticoid receptor, as evidenced by the effectiveness of agonists, antagonists, and brain-specific inactivation of the mineralocorticoid but not the glucocorticoid receptor gene. Rapid actions by corticosterone would allow the brain to change its function within minutes after stress-induced elevations of corticosteroid levels, in addition to responding later through gene-mediated signaling pathways

Periprandial changes of the sympathetic–parasympathetic balance related to perceived satiety in humans

Food intake regulation involves various central and peripheral mechanisms. In this study the relevance of physiological responses reflecting the autonomic nervous system were evaluated in relation to perceived satiety. Subjects were exposed to a lunch-induced hunger-satiety shift, while profiling diverse sensory, physiological, and biochemical characteristics at 15 min intervals. Sensory ratings comprised questionnaires with visual analogues scales about their feeling of satiety, desire to eat, fullness, and hunger. Physiological characteristics included heart rate, heart rate variability, and blood pressure, while biochemical markers such as cortisol levels and α-amylase activity were monitored in saliva. The four sensory ratings correlated with heart rate and salivary α-amylase suggesting a higher sympathetic tone during satiety. Furthermore, heart rate variability was associated with age and waist-to-hip ratio and cortisol levels negatively correlated with body mass index. Finally, neither chewing nor swallowing contributed to a heart rate increase at food consumption, but orosensory stimulation, as tested with modified sham feeding, caused a partial increase of heart rate. In conclusion, after meal ingestion critical physiological alterations reveal a elevated sympathetic tone, which is a potential measure of satiety