The results argue against the heterozygote manifestation and suggest that the residual POR activity reflected by the R457H dosage constitutes the underlying factor for clinical variability in some features but not other features, probably due to the simplicity and complexity of POR-dependent metabolic pathways relevant to each phenotype.
The serial changes in systemic and renal hemodynamics, water and electrolyte balances and various vasoactive hormones were examined in 12 conscious dogs before, during (10 days) the administration of dexamethasone (DEX: 0.5 mg/kg/day) and after the cessation of DEX. In addition, during the administration of DEX, pressor responses to angiotensin II, norepinephrine, an angiotensin II analogue, saralasin, and an alpha-1-blocker, prazosin, were studied. Abrupt elevation of blood pressure to 106 +/- 5 mmHg on Day 1 (vs. 91 +/- 6 mmHg control: P less than 0.05) associated with marked increases in total peripheral resistance (P less than 0.01) was shown in DEX treated animals. Accompanied with these changes, renal blood flow increased to 146 +/- 12 ml/min (vs. 103 +/- 8 ml/min control: P less than 0.05) on Day 1 and maintained. In contrast, the results of serial alterations in hormones could not show any significant changes except significant elevations in atrial natriuretic peptide and reductions of cortisol and arginine vasopressin. Also, marked natriuresis and diuresis were observed in DEX administration dogs. Pressor response to norepinephrine was significantly increased and administration of either saralasin and prazosin significantly reduced the blood pressure of DEX treated animals. These results in DEX-treated conscious dogs confirmed our previous findings in human and rats. Glucocorticoid-induced hypertension mainly depends on the increases in total peripheral resistance but not volume factors.
Although estrogen is known to protect against -amyloid (A )-induced neurotoxicity, the mechanisms responsible for this effect are only beginning to be elucidated. In addition, the effect of raloxifene on A -induced neurotoxicity remains unknown. Here we investigated whether raloxifene exhibits similar neuro-protective effects to estrogen against A -induced neurotoxicity and the mechanism of the effects of these agents in PC12 cells transfected with the full-length human estrogen receptor (ER) gene (PCER). Raloxifene, like 17 -estradiol (E 2 ), significantly inhibited A -induced apoptosis in PCER cells, but not in a control line of cells transfected with vector DNA alone (PCCON). Since telomerase activity, the level of which is modulated by regulation of telomerase catalytic subunit (TERT) at both the transcriptional and posttranscriptional levels, is known to be involved in suppressing apoptosis in neurons, we examined the effect of E 2 and raloxifene on telomerase activity. Although both E 2 and raloxifene induced telomerase activity in PCER cells, but not in PCCON cells, treated with A , they had no effect on the level of TERT expression. These results suggest that neither E 2 nor raloxifene affects the telomerase activity at the transcriptional level. We therefore studied the mechanism by which E 2 and raloxifene induce the telomerase activity at the post-transcriptional level. Both E 2 and raloxifene induced the phosphorylation of Akt, and pretreatment with a phosphatidylinositol 3-kinase inhibitor, LY294002, attenuated both E 2 -and raloxifene-induced activation of the telomerase activity. Moreover, both E 2 and raloxifene induced both the phosphorylation of TERT at a putative Akt phosphorylation site and the association of nuclear factor B with TERT. Our findings suggest that E 2 and raloxifene exert neuroprotective effects by telomerase activation via a post-transcriptional cascade in an experimental model relevant to Alzheimer's disease.
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