Effect of adrenocorticotrophic hormone on sodium appetite in mice.
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A main vector of the effects of stress is secretion of corticotrophin releasing factor (CRF), adrenocorticotrophin (ACTH), and adrenal steroids. Systemic administration of ACTH (2.8 microgram/day sc) for 7 days in BALB/c mice caused a very large increase of voluntary intake of 0.3 M NaCl equivalent to turnover of total body sodium content each day. Intracerebroventricular infusion of ACTH (20 ng/day) had no effect. Intracerebroventricular infusion of ovine CRF (10 ng/h for 7 days) caused an increase of sodium intake. The large sodium appetite-stimulating effect of systemic ACTH was not influenced by concurrent systemic infusion of captopril (2 mg/day). Induction of stress by immobilization of mice on a running wheel caused an increase in Na appetite associated with a 50% decrease of thymus weight, indicative of corticosteroid effects. The present data suggest that stress and the hormone cascade initiated by stress evoke a large sodium appetite in mice, which may be an important survival mechanism in environmental conditions causing stress. (+info)
Essential role of CREB family proteins during Xenopus embryogenesis.
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The leucine zipper transcription factors cAMP response element binding protein (CREB), cAMP response element modulatory protein (CREM) and activating transcription factor 1 (ATF1) bind to the cAMP response element (CRE) with the palindromic consensus sequence TGACGTCA. Their transcriptional activities are dependent on serine phosphorylation induced by various extracellular signals such as hormones, growth factors and neurotransmitters. Here we show that CREB is the predominant CRE-binding protein in Xenopus embryos and that it plays an essential role during early development. The importance of CREB for morphogenetic processes was assessed by injection of RNA encoding a dominant-negative form of CREB that is fused to a truncated progesterone receptor ligand binding domain. In this fusion protein, a dominant-negative function can be induced by application of the synthetic steroid RU486 at given developmental stages. The inhibition of CREB at blastula and early gastrula stages leads to severe posterior defects of the embryos reflected by strong spina bifida, whereas the inhibition of CREB at the beginning of neurulation resulted in stunted embryos with microcephaly. In these embryos, initial induction of neural and mesodermal tissues is not dependent on CREB function, as genes such as Otx2, Krox20, Shh and MyoD are still expressed in injected embryos. But the expression domains of Otx2 and MyoD were found to be distorted reflecting the abnormal development in both neural and somitic derivatives. In summary, our data show that CREB is essential during several developmental stages of Xenopus embryogenesis. (+info)
Up-regulation of multidrug resistance-associated protein 2 (MRP2) expression in rat hepatocytes by dexamethasone.
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Regulation of multidrug resistance-associated protein (MRP2) expression in response to dexamethasone (DEX) was analyzed using mainly primary rat hepatocytes. Enhanced levels of MRP2 mRNAs associated with increased amounts of a 190 kDa MRP2 were found in cultured DEX-treated hepatocytes; similarly, administration of DEX to rats (100 mg/kg, i.p.) led to a marked increase of hepatic amounts of MRP2 mRNAs. Maximal induction of MRP2 expression in DEX-treated primary hepatocytes was reached with 10(-5) M DEX, a concentration higher than that (10(-7) M) required for maximal up-regulation of tyrosine aminotransferase (TAT), a typical glucocorticoid receptor-regulated enzyme. In addition, the anti-glucocorticoid compound RU486 failed to inhibit MRP2 induction caused by DEX whereas it fully blocked that of TAT. These findings therefore demonstrate that DEX is a potent inducer of MRP2 expression in rat hepatocytes through a mechanism that seems not to involve the classical glucocorticoid receptor pathway. (+info)
Medical abortion still not available in most countries.(36/1154)
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Postischemic steroid modulation: effects on hippocampal neuronal integrity and synaptic plasticity.
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Elimination of corticosteroids after ischemia, by removal of the adrenals, has been reported to preserve neuronal integrity later. To establish the therapeutic potential of this observation, the authors address two questions: first, whether clinically more relevant steroid manipulations after ischemia exert similar protective effects, and second, whether changes in synaptic functioning occur along with structural alterations. To test this, the authors treated animals immediately after hypoxia-ischemia with (1) the steroid synthesis inhibitor metyrapone, (2) the synthetic glucocorticoid receptor agonist dexamethasone, (3) the selective glucocorticoid antagonist RU 38486, or (4) corticosterone. Metyrapone, but none of the other compounds, attenuated the occurrence of seizures immediately after ischemia. Twenty-four hours after hypoxia-ischemia, CAI hippocampal field potentials in response to stimulation of Schaffer/commissural fibers were found to be reduced. The attenuation of synaptic transmission was partly prevented by metyrapone. None of the other experimental treatments influenced the impaired synaptic function. Gross morphologic analysis revealed no differences in the loss of neuronal structure between the experimental groups at this time point. Taken together, these data suggest that metyrapone preserves neuronal functioning despite loss of neuronal structure. The authors tentatively conclude that preventing the ongoing production of steroids shortly after ischemia can delay and attenuate the appearance of ischemia-related pathology. (+info)
Contraceptive efficacy of daily administration of 0.5 mg mifepristone.
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The antiprogestin mifepristone has shown potential to be used as a contraceptive. If 200 mg mifepristone is administered immediately after ovulation, the endometrium shows sufficient impairment of secretory development to prevent implantation. Low daily doses of mifepristone have been shown to reduce several of the local factors regarded as crucial for implantation in human endometrium. To find out if this regimen is sufficient to prevent pregnancy, 32 women were recruited for a study where 0.5 mg mifepristone was administered daily. A total of 141 cycles were studied. Five pregnancies occurred, which was significantly less than if no contraceptive method had been used. However, the dose chosen did not seem sufficient to act as a contraceptive although it is probably not possible to increase the dose without disturbing ovulation and bleeding pattern. (+info)
Differential regulation of renal sodium-phosphate transporter by glucocorticoids during rat ontogeny.
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The effects of chronic administration of methylprednisolone (MP) were studied on the ontogeny of the renal type II Na-P(i) transporter (NaPi-2). Immunoblot analysis showed that MP did not alter the expression of NaPi-2 protein levels in suckling and weanling rats; however, there was an approximately 50% decrease in adolescent and adult rats. There was no change in Na-dependent P(i) uptake in brush-border membrane vesicles in suckling rats, but there was an almost twofold decrease in adolescent rats induced by MP treatment. MP administration did not alter mRNA levels in suckling or adolescent rats. Dual injections with the glucocorticoid receptor blocker RU-486 (mifepristone) and MP did not reverse the downregulation of NaPi-2 immunoreactive protein levels in adolescent rats. To control for RU-486 antagonism efficiency, Na/H exchanger isoform 3 (NHE3) protein levels were also assayed after injection with RU-486 and MP. As expected, NHE3 protein levels increased after MP injection; however, the increase was blocked in adolescent rats by RU-486. We conclude that there is an age-dependent responsiveness to glucocorticoids and that the marked decrease in NaPi-2 immunoreactive protein levels and activity in adolescent rats is due to posttranscriptional mechanisms. (+info)
Neural and endocrine mechanisms mediating noxious stimulus-induced inhibition of bradykinin plasma extravasation in the rat.
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We studied the mechanisms by which activation of primary afferent nociceptors inhibits bradykinin-induced plasma extravasation in the rat. First, capsaicin, administered into the plantar surface of the hindpaw, dose-dependently inhibited bradykinin-induced plasma extravasation in the knee joint, a site distant from the noxious stimulus. The inhibitory effect of capsaicin was markedly attenuated after T(12)/L(1) spinal transection combined with lumbar preganglionic sympathectomy, which interrupts ascending spinal tracts to rostral sites and to spinal sympathetic and sympathoadrenal outflow. Second, interruption of the sympathetics (cutting the L(1-3) white rami) or surgical adrenal denervation significantly attenuated capsaicin-induced inhibition of bradykinin-induced plasma extravasation. Interruption of the sympathoadrenal pathway produced the largest attenuation. Lesioning of the hypothalamic-pituitary-adrenal axis did not affect the inhibitory action of capsaicin. Third, intra-articular perfusion with phentolamine (10(-5) M, an alpha-adrenoceptor antagonist), propranolol (10(-5) M, a beta-adrenoceptor antagonist), and naloxone (10(-5) M, an opioidergic receptor antagonist) each attenuated the inhibitory action of capsaicin. Propranolol and naloxone produced the largest attenuation. Blocking glucocorticoid receptors (RU-38, 486, 30 mg/kg s.c.) did not affect the inhibitory action of intraplantar capsaicin. Fourth, the magnitude of the attenuation of capsaicin-induced inhibition of bradykinin-induced plasma extravasation after a combined treatment of surgical lumbar sympathetic decentralization with intra-articular phentolamine or surgical adrenal denervation with intra-articular propranolol or naloxone was similar to each of the surgical or pharmacological treatments of the same axis alone. These results support the suggestion that two neural/endocrine circuits, sympathoadrenal and sympathetic, account for most, if not all, of nociceptor activity-induced inhibition of bradykinin-induced plasma extravasation produced by capsaicin. (+info)