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In airway and renal epithelia, the glucocorticoid-mediated stimulation of amiloride-sensitive Na+ transport is associated with increased expression of the epithelial Na+ channel alpha subunit (alphaENaC). In H441 lung cells, 100 nM dexamethasone increases amiloride-sensitive short-circuit current (3.3 microA/cm2 to 7.5 microA/cm2), correlating with a 5-fold increase in alphaENaC mRNA expression that could be blocked by actinomycin D. To explore transcriptional regulation of alphaENaC, the human alphaENaC 5'-flanking region was cloned and tested in H441 cells. By deletion analysis, a approximately 150-base pair region 5' to the upstream promoter was identified that, when stimulated with 100 nM dexamethasone, increased luciferase expression 15-fold. This region, which contains two imperfect GREs, also functioned when coupled to a heterologous promoter. When individually tested, only the downstream GRE functioned in cis and bound GR in a gel mobility shift assay. In the M-1 collecting duct line Na+ transport, malphaENaC expression and luciferase expression from alphaENaC genomic fragments were also increased by 100 nM dexamethasone. In a colonic cell line, HT29, trans-activation via a heterologously expressed glucocorticoid receptor restored glucocorticoid-stimulated alphaENaC gene transcription. We conclude that glucocorticoids stimulate alphaENaC expression in kidney and lung via activation of a hormone response element in the 5'-flanking region of halphaENaC and this response, in part, is the likely basis for the up-regulation of Na+ transport in these sites.

We have developed and validated a new force field for cations in zeolites, which explicitly distinguishes Si and Al atoms, as well as different types of oxygens in the framework. Our new force field gives excellent agreement with experimental data on cation positions, site occupancies and vibrational frequencies. Energy minimizations show that Na cations in site I are not at the centers of hexagonal prisms, but rather are in one of two symmetric SI sites displaced by about 0.6 Å along the [111] direction. Molecular dynamics (MD) simulations show that most cations are immobile in Na−X and Na−Y on the MD time scale, even at 1000 K. Only Na−X cations in site III‘ exhibit diffusive motion at 1000 K, with a self-diffusivity from MD of 3.6 × 10^-10 m² s^-1. The MD simulations also show that cation movement is highly correlated, composed of jumps involving at least 4 cations or more.

Total financial planning is the financial growth industry of the eighties. Research shows that the number of households with incomes of over $40,000 per year is expected to be over twelve million by 1987. Large brokerage houses are extremely interested in this new market. Most houses are opting for computerized financial planning to cut their costs. Unfortunately, the major houses do not seem to be ready to offer their product efficiently yet.

Because monoamine reuptake inhibitors and releasing agents both increase extracellular neurotransmitter levels, establishing in vivo experimental criteria for their classification has been difficult. Using microdialysis in the hypothalamus of unanesthetized rats, we provide evidence that serotonin- (5-HT) selective and nonselective reuptake inhibitors can be distinguished from the 5-HT-releasing agent fenfluramine by four criteria: 1) Systemic fenfluramine produces a much greater increase in 5-HT than the reuptake inhibitors. 2) The 5-HT somatodendritic autoreceptor agonist, (+/-)-8-hydroxy-(dipropylamino)tetralin (8-OH-DPAT), attenuates the increase in 5-HT produced by reuptake inhibitors, but not by fenfluramine. 3) The large increase in 5-HT produced by infusion of reuptake inhibitors into the hypothalamus is attenuated by their systemic administration. However, systemic injection of fenfluramine during its local infusion does not attenuate this increase. 4) Reuptake inhibitor pretreatment attenuates fenfluramine-induced increases in 5-HT. According to these criteria, the in vivo effects of the novel antiobesity drug sibutramine are consistent with its characterization as a 5-HT reuptake inhibitor and not a 5-HT releaser. Thus, sibutramine produced increases in hypothalamic 5-HT similar in magnitude to the effects of the known reuptake inhibitors, and the increase was attenuated by 8-OH-DPAT. Also, sibutramine attenuated fenfluramine-induced 5-HT release. Systemic administration of sibutramine failed to attenuate the increase in 5-HT produced by its local infusion, suggesting that this criterion is not applicable to compounds with low affinity for the 5-HT transporter.

Without Abstract:

Regulation of serotonin (5-HT) release may be altered during the development of opioid tolerance and dependency. To test this hypothesis, changes in extracellular 5-HT during prolonged administration of morphine were determined by microdialysis in the dorsal raphe nucleus (DRN) of freely behaving rats. Morphine or placebo pellets were implanted s.c. As compared to placebo, morphine pellets induced a sustained, approximately 50% increase in DRN 5-HT and a significant elevation in hot plate latency during the 12-hr period after implantation. One week later DRN 5-HT had returned to control levels, and implanting additional morphine pellets had no effect on 5-HT or hot plate latency. One day after removing the pellets from rats exposed to morphine for 2 wk, acute challenge with morphine (20 mg/kg, s.c.) had a significantly smaller effect on 5-HT in the DRN as compared to the placebo treatment group. Administration of naltrexone to rats implanted with morphine pellets for 2 wk induced signs of withdrawal and a significant decrease in DRN 5-HT. These results suggest that the regulation of 5-HT release is altered during the development of tolerance to morphine. Thus, DRN 5-HT may be one of the factors involved in the changes in physiology and behavioral state during opioid withdrawal.

The effect of acute uptake inhibition on serotonin (5-HT) in the rat central nervous system was monitored by using in vivo dialysis. Peripheral administration of the selective 5-HT uptake blocker, fluoxetine, caused a dose-dependent increase in extracellular 5-HT in both the diencephalon and the striatum. Administration of fluoxetine or sertraline, another selective 5-HT uptake inhibitor, caused a prolonged (24 hr) increase in 5-HT and decrease in 5-hydroxyindoleacetic acid. In addition, fluoxetine and sertraline attenuated the 5-HT releasing effect of fenfluramine administered 24 hr later. Local infusion of fluoxetine into the diencephalon caused an increase in 5-HT that was twice as large as the effect of peripheral injection. Peripheral fluoxetine, by enhancing extracellular 5-HT in the raphe, probably resulted in activation of somatodendritic autoreceptors and inhibition of 5-HT neuronal discharge. Thus, the increase in 5-HT in the diencephalon after peripheral fluoxetine presumably reflected a balance between decreased release and inhibition of reuptake. In support of this, after first infusing fluoxetine into the diencephalon to maximally block reuptake, peripheral injection of the uptake inhibitor caused a decrease in 5-HT.

Molecular dynamics simulations of the diffusion of trans-2-butene in zeolite type MEL at 623 K have revealed an initial increase of the self-diffusivity with increasing loading, in contrast to simulation data collected for the other butene isomers. This is usually the signature of repulsive guest−guest interactions. At higher loadings, however, the concentration dependence was shown to decrease in a way consistent with attractive guest−guest interactions (Jousse, F.; et al. J. Phys. Chem. B 1997, 101, 4717). The initial rise reaches a maximum of about 25% for a loading of 1.5−2 molecules per unit cell. A jump diffusion model with parameters deduced from the molecular dynamics simulations accurately reproduces the diffusivity simulated at infinite dilution. For higher loadings guest−guest interaction parameters must be included in the jump diffusion model. Two simple models are presented, in order to rationalize the simulation results with a small number of parameters. The simpler model considers spherically symmetric adsorption sites and uses only two parameters; it is shown, however, that this model is unable to account for the simulated concentration dependence of the trans-2-butene self-diffusivity. The second model, with three parameters, includes the channel-like structure of the adsorption site and fits very effectively the concentration dependence of the diffusivity. Repulsive interactions between two molecules in the same site are responsible for the initial increase of the diffusivity. Attractive interactions arise when more than two molecules are in the same site, leading to a steeper decrease of the diffusivities with increasing loading.